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Sample records for autoimmune gene rs7574865

  1. Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn's disease and early disease onset.

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    Jürgen Glas

    Full Text Available BACKGROUND: Recent studies demonstrated an association of STAT4 variants with systemic lupus erythematosus (SLE and rheumatoid arthritis (RA, indicating that multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 variants on the susceptibility and phenotype of inflammatory bowel diseases (IBD in a large patient and control cohort. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2704 individuals of Caucasian origin including 857 patients with Crohn's disease (CD, 464 patients with ulcerative colitis (UC, and 1383 healthy, unrelated controls was analyzed for seven SNPs in the STAT4 gene (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694, rs10174238. In addition, a detailed genotype-phenotype analysis was performed. Our analysis revealed an association of the STAT4 SNP rs7574865 with overall decreased susceptibility to CD (p = 0.047, OR 0.86 [95% CI 0.74-0.99]. However, compared to CD patients carrying the wild type genotype, the STAT4 SNP rs7574865 was significantly associated with early CD onset (p = 0.021 and colonic CD (p = 0.008; OR = 4.60, 95% CI 1.63-12.96. For two other STAT4 variants, there was a trend towards protection against CD susceptibility (rs7568275, p = 0.058, OR 0.86 [95% CI 0.74-1.00]; rs10174238, p = 0.057, OR 0.86 [95% CI 0.75-1.00]. In contrast, we did not observe any association with UC susceptibility. Evidence for weak gene-gene interaction of STAT4 with the IL23R SNP rs11209026 was lost after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our results identified the STAT4 SNP rs7574865 as a disease-modifying gene variant in colonic CD. However, in contrast to SLE and RA, the effect of rs7574865 on CD susceptibility is only weak.

  2. Association between STAT4 Gene Polymorphisms and Autoimmune Thyroid Diseases in a Chinese Population

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    Ni Yan

    2014-07-01

    Full Text Available The STAT4 gene encodes a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. The aim of this study was to explore the association of STAT4 polymorphism with Graves’ disease (GD and Hashimoto’s thyroiditis (HT. A total of 1048 autoimmune thyroid diseases (AITDs patients (693 with GD and 355 with HT and 909 age- and gender-matched controls were examined. STAT4 polymorphisms (rs7574865/rs10181656/ rs7572482 were genotyped by multiplex polymerase chain reaction (PCR and ligase detection reaction (LDR. The results indicated that the frequencies of rs7574865 genotypes in patients with GD differed significantly from the controls (p = 0.028, the T allele frequency of GD patients was also significantly higher than the controls (p = 0.020. The genotypes of rs10181656 differed significantly in GD patients from controls (p = 0.012; G allele frequencies were significantly higher in AITD patients than the controls (p = 0.014 and 0.031, respectively. The frequencies of haplotype GC with GD and HT patients were significantly lower than their controls (p = 0.015 and 0.030, respectively. In contrast, the frequencies of haplotype TG with GD and HT patients were significantly higher than their controls (p = 0.016 and 0.048, respectively. These findings strongly suggest that STAT4 rs7574865/rs10181656 polymorphisms increase the risk of AITD in a Chinese population.

  3. Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population.

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    Kiyoshi Migita

    Full Text Available BACKGROUND/AIMS: Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO AIH multicenter cohort study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694. The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23-2.11; P = 0.001, and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13-1.99; P = 0.005. Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44 or without liver cirrhosis (n = 186 demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies. CONCLUSIONS/SIGNIFICANCE: This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.

  4. Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant.

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    Wun, Cheng Mun; Piao, Zhe; Hong, Kyung Taek; Choi, Jung Yoon; Hong, Che Ry; Park, June Dong; Park, Kyung Duk; Shin, Hee Young; Kang, Hyoung Jin

    2017-02-01

    STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. The TT genotype of the STAT4 rs7574865 polymorphism is associated with high disease activity and disability in patients with early arthritis.

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    Amalia Lamana

    Full Text Available BACKGROUND: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS: We studied 640 patients with early arthritis (76% women; median age, 52 years, recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28 as compared with the GG genotype (β coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044. Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162. After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.

  6. No Evidence of Association between Common Autoimmunity STAT4 and IL23R Risk Polymorphisms and Non-Anterior Uveitis

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    Cordero-Coma, Miguel; Gorroño-Echebarría, Marina Begoña; Fonollosa, Alejandro; Adán, Alfredo; Martínez-Berriotxoa, Agustín; Díaz Valle, David; Pato, Esperanza; Blanco, Ricardo; Cañal, Joaquín; Díaz-Llopis, Manuel; García Serrano, José Luis; de Ramón, Enrique; del Rio, María José; Martín-Villa, José Manuel; Molins, Blanca; Ortego-Centeno, Norberto; Martín, Javier

    2013-01-01

    Objective STAT4 and IL23R loci represent common susceptibility genetic factors in autoimmunity. We decided to investigate for the first time the possible role of different STAT4/IL23R autoimmune disease-associated polymorphisms on the susceptibility to develop non-anterior uveitis and its main clinical phenotypes. Methods Four functional polymorphisms (rs3821236, rs7574865, rs7574070, and rs897200) located within STAT4 gene as well as three independent polymorphisms (rs7517847, rs11209026, and rs1495965) located within IL23R were genotyped using TaqMan® allelic discrimination in a total of 206 patients with non-anterior uveitis and 1553 healthy controls from Spain. Results No statistically significant differences were found when allele and genotype distributions were compared between non-anterior uveitis patients and controls for any STAT4 (rs3821236: P=0.39, OR=1.12, CI 95%=0.87-1.43; rs7574865: P=0.59 OR=1.07, CI 95%=0.84-1.37; rs7574070: P=0.26, OR=0.89, CI 95%=0.72-1.10; rs897200: P=0.22, OR=0.88, CI 95%=0.71-1.08;) or IL23R polymorphisms (rs7517847: P=0.49, OR=1.08, CI 95%=0.87-1.33; rs11209026: P=0.26, OR=0.78, CI 95%=0.51-1.21; rs1495965: P=0.51, OR=0.93, CI 95%=0.76-1.15). Conclusion Our results do not support a relevant role, similar to that described for other autoimmune diseases, of IL23R and STAT4 polymorphisms in the non-anterior uveitis genetic predisposition. Further studies are needed to discard a possible weak effect of the studied variant. PMID:24312163

  7. Gene expression profiling in autoimmune diseases

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    Bovin, Lone Frier; Brynskov, Jørn; Hegedüs, Laszlo

    2007-01-01

    ) patients and healthy individuals were specific for the arthritic process or likewise altered in other chronic inflammatory diseases such as chronic autoimmune thyroiditis (Hashimoto's thyroiditis, HT) and inflammatory bowel disease (IBD). Using qPCR for 18 RA-discriminative genes, there were no significant......A central issue in autoimmune disease is whether the underlying inflammation is a repeated stereotypical process or whether disease specific gene expression is involved. To shed light on this, we analysed whether genes previously found to be differentially regulated in rheumatoid arthritis (RA...... immunoinflammatory diseases, but only if accompanied by pronounced systemic manifestations. This suggests that at least some of the genes activated in RA are predominantly or solely related to general and disease-nonspecific autoimmune processes...

  8. Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies.

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    Palma, Alessia; Gianchecchi, Elena; Palombi, Melania; Luciano, Rosa; Di Carlo, Pierluigi; Crinò, Antonino; Cappa, Marco; Fierabracci, Alessandra

    2013-09-01

    The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Disruption of immunological tolerance: role of AIRE gene in autoimmunity.

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    Rizzi, M; Ferrera, F; Filaci, G; Indiveri, F

    2006-02-01

    The mechanism underlying the generation of T and B autoreactive clones in autoimmune diseases is still unknown. Among genetic factors implicated in autoimmunity, Autoimmune Regulator gene (AIRE) is one of the candidates to better understand the complex scenario of autoimmune manifestations. AIRE mutations are responsible for the development of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with monogenic autosomal recessive inheritance; it has been shown that AIRE regulates the negative selection of autoreactive T cells clones, driving the transcription of tissue-specific antigens in thymic epithelial cells. In various autoimmune manifestations correlated or not to APECED, AIRE variants act in a semidominant manner, leading to a reduction in AIRE protein amount per cell, and consequently to a marked decrease in ectopic proteins expression in the thymus. The co-occurrence of autoimmune diseases in the same individual has prompted several studies aimed to recognize shared patho-physiological mechanisms; in this scenario small reductions in function could explain the predisposition to autoimmunity in AIRE-heterozygous carriers of missense mutations; further studies to investigate whether the AIRE gene is involved in determining these autoimmune manifestations should be carried out.

  10. Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity.

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    Fierabracci, Alessandra

    2011-01-01

    Since many years immunologists have being tried to answer the tantalizing enigma of immunological tolerance. Complex mechanisms in both thymus (central tolerance) and peripheral lymphoid organs (peripheral tolerance) underly lymphocyte tolerance and its maintenance. The genesis of autoimmunity involves environmental and genetic mechanisms, both contributing to the disruption and deregulation of central and peripheral tolerance, allowing autoreactive pathogenetic T and B-cell clones arising. Among genetic factors the autoimmune regulator (AIRE) gene is one of the best candidates to understand the complex scenario of autoimmunity. Autoimmune polyendocrinopathy syndrome type 1 is a rare autosomal recessive disease caused by mutations in the AIRE gene. Therefore, the disorder has certainly been a powerful model to address the question concerning how a tolerant state is achieved or maintained and to explore how it has gone lost in the context of autoimmunity. AIRE has been proposed to function as a 'non classical' transcription factor, strongly implicated in the regulation of organ-specific antigen expression in thymic epithelial cells and in the imposition of T cell tolerance, thus regulating the negative selection of autoreactive T cell clones. A plethora of proposal have been suggested for AIRE's potential mechanism of action, thus regulating the negative selection of autoreactive T cells. In this review recent discoveries are presented into the role and molecular mechanisms of the AIRE protein in APECED and other autoimmune diseases. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Gene therapy in nonhuman primate models of human autoimmune disease

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    t'Hart, B. A.; Vervoordeldonk, M.; Heeney, J. L.; Tak, P. P.

    2003-01-01

    Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey

  12. Spontaneous autoimmunity in 129 and C57BL/6 mice-implications for autoimmunity described in gene-targeted mice.

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    Anne E Bygrave

    2004-08-01

    Full Text Available Systemic lupus erythematosus (SLE is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 x C57BL/6 model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.

  13. Evolutionary dynamics of human autoimmune disease genes and malfunctioned immunological genes

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    Podder Soumita

    2012-01-01

    Full Text Available Abstract Background One of the main issues of molecular evolution is to divulge the principles in dictating the evolutionary rate differences among various gene classes. Immunological genes have received considerable attention in evolutionary biology as candidates for local adaptation and for studying functionally important polymorphisms. The normal structure and function of immunological genes will be distorted when they experience mutations leading to immunological dysfunctions. Results Here, we examined the fundamental differences between the genes which on mutation give rise to autoimmune or other immune system related diseases and the immunological genes that do not cause any disease phenotypes. Although the disease genes examined are analogous to non-disease genes in product, expression, function, and pathway affiliation, a statistically significant decrease in evolutionary rate has been found in autoimmune disease genes relative to all other immune related diseases and non-disease genes. Possible ways of accumulation of mutation in the three steps of the central dogma (DNA-mRNA-Protein have been studied to trace the mutational effects predisposed to disease consequence and acquiring higher selection pressure. Principal Component Analysis and Multivariate Regression Analysis have established the predominant role of single nucleotide polymorphisms in guiding the evolutionary rate of immunological disease and non-disease genes followed by m-RNA abundance, paralogs number, fraction of phosphorylation residue, alternatively spliced exon, protein residue burial and protein disorder. Conclusions Our study provides an empirical insight into the etiology of autoimmune disease genes and other immunological diseases. The immediate utility of our study is to help in disease gene identification and may also help in medicinal improvement of immune related disease.

  14. Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis.

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    Kinugawa, Yasuhiro; Uehara, Takeshi; Sano, Kenji; Matsuda, Kazuyuki; Maruyama, Yasuhiro; Kobayashi, Yukihiro; Nakajima, Tomoyuki; Hamano, Hideaki; Kawa, Shigeyuki; Higuchi, Kayoko; Hosaka, Noriko; Shiozawa, Satoshi; Ishigame, Hiroki; Ota, Hiroyoshi

    Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP. Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing. Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP. These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

  15. Gene expression profiling in autoimmune diseases: chronic inflammation or disease specific patterns?

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    Bovin, Lone Frier; Brynskov, Jørn; Hegedüs, Laszlo

    2007-01-01

    A central issue in autoimmune disease is whether the underlying inflammation is a repeated stereotypical process or whether disease specific gene expression is involved. To shed light on this, we analysed whether genes previously found to be differentially regulated in rheumatoid arthritis (RA......) patients and healthy individuals were specific for the arthritic process or likewise altered in other chronic inflammatory diseases such as chronic autoimmune thyroiditis (Hashimoto's thyroiditis, HT) and inflammatory bowel disease (IBD). Using qPCR for 18 RA-discriminative genes, there were no significant...... immunoinflammatory diseases, but only if accompanied by pronounced systemic manifestations. This suggests that at least some of the genes activated in RA are predominantly or solely related to general and disease-nonspecific autoimmune processes....

  16. Common variable immune deficiency with mutated TNFSRF13B gene presenting with autoimmune hematologic manifestations

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    Elpis Mantadakis

    2016-10-01

    Full Text Available Patients with common variable immunodeficiency (CVID develop autoimmune hematologic manifestations. We report a 14-year-old boy with Evans syndrome, who presented at the age of 11.5 years with autoimmune hemolysis and was successfully managed with corticosteroids. Initially, the serum immunoglobulins were within the low-normal range for age, but two years after presentation he definitely fulfilled the diagnostic criteria for CVID, despite a negative history for serious infections. DNA sequencing by PCR of the TNFSRF13B gene that encodes the TACI receptor disclosed the heterozygous mutation C104R that is found in approximately 10–15% of patients with CVID. Common variable immunodeficiency should be considered in the differential diagnosis of autoimmune hematologic manifestations, since its timely diagnosis may considerably affect clinical management and patient outcome.

  17. DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes.

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    Guha, Mithu; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Liiv, Ingrid; Haljasorg, Uku; Tasa, Tõnis; Metspalu, Andres; Milani, Lili; Peterson, Pärt

    2017-04-21

    The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients.

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    Umemura, Takeji; Joshita, Satoru; Hamano, Hideaki; Yoshizawa, Kaname; Kawa, Shigeyuki; Tanaka, Eiji; Ota, Masao

    2017-11-01

    Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single-nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio (OR)=0.68; corrected P=0.025). Haplotype 2 (rs2238154 A, rs11065904 T and rs739496 G) was associated with resistance to AIH (OR 0.67, P=0.021) as well as to autoimmune pancreatitis (OR=0.70, P=0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.

  19. Insulin gene polymorphisms in type 1 diabetes, Addison's disease and the polyglandular autoimmune syndrome type II

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    Hahner Stefanie

    2008-07-01

    Full Text Available Abstract Background Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods We investigated the role of the -2221Msp(C/T and -23HphI(A/T polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317, Addison's disease (AD, n = 107 or Hashimoto's thyroiditis (HT, n = 61], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62 as well as in healthy controls (HC, n = 275. Results T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T and "AA" -23HphI(A/T polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively. The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion We demonstrate that the allele "C" of the -2221Msp(C/T and "A" -23HphI(A/T insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.

  20. Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b.

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    Matsuo, Tomohito; Noguchi, Yukiko; Shindo, Mieko; Morita, Yoshifumi; Oda, Yoshie; Yoshida, Eiko; Hamada, Hiroko; Harada, Mine; Shiokawa, Yuichi; Nishida, Takahiro; Tominaga, Ryuji; Kikushige, Yoshikane; Akashi, Koichi; Kudoh, Jun; Shimizu, Nobuyoshi; Tanaka, Yuka; Umemura, Tsukuru; Taniguchi, Taketoshi; Yoshimura, Akihiko; Kobayashi, Takashi; Mitsuyama, Masao; Kurisaki, Hironori; Katsuta, Hitoshi; Nagafuchi, Seiho

    2013-11-01

    Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive. We found that IL-2-stimulated CD4(+) T (IL-2T) cells showed a high expression of AIRE gene, but very low AIRE protein production, while Epstein-Barr virus-transformed B (EBV-B) cells express both AIRE gene and AIRE protein. By using microarray analysis, we could identify miR-220b as a possible regulatory mechanism for AIRE gene translation in IL-2T cells. Here we report that miR-220b significantly reduced the expression of AIRE protein in AIRE gene with 3'UTR region transfected 293T cells, whereas no alteration of AIRE protein production was observed in the open reading frame of AIRE gene alone transfected cells. In addition, anti-miR-220b reversed the inhibitory function of miR-220b for the expression of AIRE protein in AIRE gene with 3'UTR region transfected cells. Moreover, when AIRE gene transfected cells with mutated 3'UTR were transfected with miR-220b, no reduction of AIRE protein production was observed. Taken together, it was concluded that miR-220b inhibited the AIRE gene translation through the 3'UTR region of AIRE gene, indicating that miR-220b could serve as a regulator for human AIRE gene translation. © 2013.

  1. Genes, autoimmunity and pathogenesis of rheumatic heart disease

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    Guilherme, L; Köhler, K F; Postol, E; Kalil, J

    2011-01-01

    Pathogenesis of rheumatic heart disease (RHD) remains incompletely understood. Several genes associated with RHD have been described; most of these are involved with immune responses. Single nucleotide polymorphisms in a number of genes affect patients with RHD compared to controls. Molecular mimicry between streptococcal antigens and human proteins, including cardiac myosin epitopes, vimentin and other intracellular proteins is central to the pathogenesis of RHD. Autoreactive T cells migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specific cytokines. The types of cells involved in the inflammation as well as different cytokine profiles in these patients are being investigated. High TNF alpha, interferon gamma, and low IL4 are found in the rheumatic valve suggesting an imbalance between Th1 and Th2 cytokines and probably contributing to the progressive and permanent valve damage. Animal model of ARF in the Lewis rat may further contribute towards understanding the ARF

  2. Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

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    Perniola, Roberto

    2012-01-01

    The autoimmune polyendocrine syndrome type 1 (APS-1) is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE) gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs) in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIR...

  3. Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives.

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    Cervato, Sara; Mariniello, Barbara; Lazzarotto, Francesca; Morlin, Luca; Zanchetta, Renato; Radetti, Giorgio; De Luca, Filippo; Valenzise, Mariella; Giordano, Roberta; Rizzo, Daniela; Giordano, Carla; Betterle, Corrado

    2009-03-01

    Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is a rare syndrome characterized by chronic candidiasis, chronic hypoparathyroidism and Addison's disease. APECED has been associated with mutations in autoimmune regulator (AIRE) gene. Our aim is to perform a genetic analysis of the AIRE gene in Italian APECED patients and in their relatives. Design AIRE mutations were determined by DNA sequencing in all subjects. Patients were tested for clinical autoimmune or non-autoimmune diseases, or for organ and non-organ specific autoantibodies. A total of 24 Italian patients with APECED (15 from the Venetian region, 2 from Southern-Tyrol, 4 from Apulia, 3 from Sicily), 25 relatives and 116 controls were studied. Ten out of the 15 Venetian patients (66%) were homozygous for R257X or compound heterozygous with 1094-1106del13. One patient was homozygous for 1094-1106del13 and another for R139X. A novel mutation (1032-1033delGT) in combination with 1094-1106del13 was identified in one patient. No mutations were found in two cases. Two patients from Southern Tyrol were homozygous for R257X and for 1094-1106del13bp. All patients from Apulia were homozygous or heterozygous for W78R combined with Q358X. The patients from Sicily were homozygous for R203X or compound heterozygous with R257X. The analysis of the genotype-phenotype revealed that patients carrying 1094-1106del13 at the onset of Addison's disease were significantly older than those carrying other mutations. The genetic study of 25 relatives identified 20 heterozygous subjects. They suffered from various autoimmune and non-autoimmune diseases but no major disease of APECED was found. These data demonstrate the great genetic heterogeneity for the AIRE mutations in Italian APECED patients, and that the heterozygosity for AIRE mutations do not produce APECED.

  4. Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue.

    Science.gov (United States)

    Eldershaw, S A; Sansom, D M; Narendran, P

    2011-03-01

    Educational immune tolerance to self-antigens is induced primarily in the thymus where tissue-restricted antigens (TRAs) are presented to T lymphocytes by cells of the thymic stroma - a process known as central tolerance. The expression of these TRAs is controlled in part by a transcription factor encoded by the autoimmune regulatory (Aire) gene. Patients with a mutation of this gene develop a condition known as autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), characterized by autoimmune destruction of endocrine organs, fungal infection and dental abnormalities. There is now evidence for TRA expression and for mechanisms of functional tolerance outside the thymus. This has led to a number of studies examining Aire expression and function at these extra-thymic sites. These investigations have been conducted across different animal models using different techniques and have often shown discrepant results. Here we review the studies of extra thymic Aire and discuss the evidence for its expression and function in both human and murine systems. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  5. FCRL3 gene polymorphisms confer autoimmunity risk for allergic rhinitis in a Chinese Han population.

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    Zheng Gu

    Full Text Available Heredity and environmental exposures may contribute to a predisposition to allergic rhinitis (AR. Autoimmunity may also involve into this pathologic process. FCRL3 (Fc receptor-like 3 gene, a novel immunoregulatory gene, has recently been reported to play a role in autoimmune diseases.This study was performed to evaluate the potential association of FCRL3 polymorphisms with AR in a Chinese Han population.Five single-nucleotide polymorphisms of FCRL3, rs945635, rs3761959, rs7522061, rs10489678 and rs7528684 were genotyped in 540 AR patients and 600 healthy controls using a PCR-restriction fragment length polymorphism assay. Allele, genotype and haplotype frequencies were compared between patients and controls using the χ2 test. The online software platform SHEsis was used to analyze their haplotypes.This study identified three strong risk SNPs rs7528684, rs10489678, rs7522061 and one weak risk SNP rs945635 of FCRL3 in Chinese Han AR patients. For rs7528684, a significantly increased prevalence of the AA genotype and A allele in AR patients was recorded. The frequency of the GG genotype and G allele of rs10489678 was markedly higher in AR patients than those in controls. For rs7522061, a higher frequency of the TT genotype, and a lower frequency of the CT genotype were found in AR patients. Concerning rs945635, a lower frequency of the CC genotype, and a higher frequency of G allele were observed in AR patients. According to the analysis of the three strong positive SNPs, the haplotype of AGT increased significantly in AR cases (AR = 38.8%, Controls = 24.3%, P = 8.29 × 10(-14, OR [95% CI] 1.978 [1.652~2.368].This study found a significant association between the SNPs in FCRL3 gene and AR in Chinese Han patients. The results suggest these gene polymorphisms might be the autoimmunity risk for AR.

  6. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster...

  7. Epigenetic regulation of HLA class II genes and their role in autoimmune diseases.

    OpenAIRE

    Čepek, Pavel

    2012-01-01

    Abstract Background: Type 1 diabetes (T1D) is a multifactorial autoimmune disease. Its incidence in Europe is continuously rising. The highest T1D risk is associated with HLA (human leukocyte antigen) class II genes. HLA class II molecules play a key role in regulation of immune response. They contribute to the selection of T cell repertoire by presenting antigenic peptides to the CD4+ T lymphocytes. HLA class II expression is controlled by regulatory module that is situated 150 - 300 base pa...

  8. Schizophrenia: a pathogenetic autoimmune disease caused by viruses and pathogens and dependent on genes.

    Science.gov (United States)

    Carter, C J

    2011-01-01

    Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a "pathogenetic" autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

  9. Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes

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    C. J. Carter

    2011-01-01

    Full Text Available Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

  10. A functional alternative splicing mutation in AIRE gene causes autoimmune polyendocrine syndrome type 1.

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    Junyu Zhang

    Full Text Available Autoimmune polyendocrine syndrome type 1 (APS-1 is a rare autosomal recessive disease defined by the presence of two of the three conditions: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. Loss-of-function mutations of the autoimmune regulator (AIRE gene have been linked to APS-1. Here we report mutational analysis and functional characterization of an AIRE mutation in a consanguineous Chinese family with APS-1. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. We identified a homozygous missense AIRE mutation c.463G>A (p.Gly155Ser in two siblings with different clinical features of APS-1. In silico splice-site prediction and minigene analysis were carried out to study the potential pathological consequence. Minigene splicing analysis and subsequent cDNA sequencing revealed that the AIRE mutation potentially compromised the recognition of the splice donor of intron 3, causing alternative pre-mRNA splicing by intron 3 retention. Furthermore, the aberrant AIRE transcript was identified in a heterozygous carrier of the c.463G>A mutation. The aberrant intron 3-retaining transcript generated a truncated protein (p.G155fsX203 containing the first 154 AIRE amino acids and followed by 48 aberrant amino acids. Therefore, our study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1.

  11. Identification of gene expression patterns crucially involved in experimental autoimmune encephalomyelitis and multiple sclerosis

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    Martin M. Herrmann

    2016-10-01

    Full Text Available After encounter with a central nervous system (CNS-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1 rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.

  12. Association between vitamin D metabolism gene polymorphisms and risk of islet autoimmunity and progression to type 1 diabetes: the diabetes autoimmunity study in the young (DAISY).

    Science.gov (United States)

    Frederiksen, Brittni N; Kroehl, Miranda; Fingerlin, Tasha E; Wong, Randall; Steck, Andrea K; Rewers, Marian; Norris, Jill M

    2013-11-01

    Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases. The objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D. The Diabetes Autoimmunity Study in the Young is a longitudinal, observational study. Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado. A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D. IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures. The risk of IA was associated with DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 [hazard ratio 1.36, 95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/G compared with the A/A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels. DHCR7/NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.

  13. Expression of the Autoimmune Regulator Gene and Its Relevance to the Mechanisms of Central and Peripheral Tolerance

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    Roberto Perniola

    2012-01-01

    Full Text Available The autoimmune polyendocrine syndrome type 1 (APS-1 is a monogenic disease due to pathogenic variants occurring in the autoimmune regulator (AIRE gene. Its related protein, AIRE, activates the transcription of genes encoding for tissue-specific antigens (TsAgs in a subset of medullary thymic epithelial cells: the presentation of TsAgs to the maturating thymocytes induces the apoptosis of the autoreactive clones and constitutes the main form of central tolerance. Dysregulation of thymic AIRE expression in genetically transmitted and acquired diseases other than APS-1 may contribute to further forms of autoimmunity. As AIRE and its murine homolog are also expressed in the secondary lymphoid organs, the extent and relevance of AIRE participation in the mechanisms of peripheral tolerance need to be thoroughly defined.

  14. Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

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    Atkinson Mark A

    2011-02-01

    Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

  15. NKT cell development in the absence of the autoimmune regulator gene (Aire).

    Science.gov (United States)

    Pitt, Lauren A; Hubert, Francois-Xavier; Scott, Hamish S; Godfrey, Dale I; Berzins, Stuart P

    2008-10-01

    Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP3+ Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence self-tolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.

  16. Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease.

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    Cecília Durães

    Full Text Available Autoimmune thyroid disease (AITD comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.Polymorphisms in the IL6-174 G/C (rs1800795, TNFA-308 G/A (rs1800629, IL1B-511 C/T (rs16944, and IFNGR1-56 T/C (rs2234711 genes were assessed in a case-control study comprising 420 Hashimoto's thyroiditis patients, 111 Graves' disease patients and 735 unrelated controls from Portugal. Genetic variants were discriminated by real-time PCR using TaqMan SNP genotyping assays.A significant association was found between the allele A in TNFA-308 G/A and Hashimoto's thyroiditis, both in the dominant (OR = 1.82, CI = 1.37-2.43, p-value = 4.4×10(-5 and log-additive (OR = 1.64, CI = 1.28-2.10, p-value = 8.2×10(-5 models. The allele C in IL6-174 G/C is also associated with Hashimoto's thyroiditis, however, only retained significance after multiple testing correction in the log-additive model (OR = 1.28, CI = 1.06-1.54, p-value = 8.9×10(-3. The group with Graves' disease also registered a higher frequency of the allele A in TNFA-308 G/A compared with controls both in the dominant (OR = 1.85, CI = 1.19-2.87, p-value = 7.0×10(-3 and log-additive (OR = 1.69, CI = 1.17-2.44, p-value = 6.6×10(-3 models. The risk for Hashimoto's thyroiditis and Graves' disease increases with the number of risk alleles (OR for two risk alleles is, respectively, 2.27 and 2.59.This study reports significant associations of genetic variants in TNFA and IL6 with the risk for AITD, highlighting the

  17. Autoimmune Hepatitis

    Science.gov (United States)

    ... with type 1 autoimmune hepatitis commonly have other autoimmune disorders, such as celiac disease, an autoimmune disease in ... 2 can also have any of the above autoimmune disorders. What are the symptoms of autoimmune hepatitis? The ...

  18. Altered expression of circadian clock genes in polyglandular autoimmune syndrome type III.

    Science.gov (United States)

    Angelousi, Anna; Nasiri-Ansari, Narjes; Spilioti, Eliana; Mantzou, Emilia; Kalotyxou, Vasiliki; Chrousos, George; Kaltsas, Gregory; Kassi, Eva

    2018-01-01

    Circadian timing system is a highly conserved, ubiquitous molecular "clock" which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PAS type III). Nineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence. There were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (R pm/am ) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (F pm/am ) was positively correlated with GILZ mRNA circadian pattern (R pm/am ) in the patient group and with the GR-a mRNA (R pm/am ) in the control group. Our findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease.

  19. Expression level of risk genes of MHC class II is a susceptibility factor for autoimmunity: New insights.

    Science.gov (United States)

    Gianfrani, Carmen; Pisapia, Laura; Picascia, Stefania; Strazzullo, Maria; Del Pozzo, Giovanna

    2018-01-10

    To date, the study of the impact of major hystocompatibility complex on autoimmunity has been prevalently focused on structural diversity of MHC molecules in binding and presentation of (auto)antigens to cognate T cells. Recently, a number of experimental evidences suggested new points of view to investigate the complex relationships between MHC gene expression and the individual predisposition to autoimmune diseases. Irrespective of the nature of the antigen, a threshold of MHC-peptide complexes needs to be reached, as well as a threshold of T cell receptors engaged is required, for the activation and proliferation of autoantigen-reactive T cells. Moreover, it is well known that increased expression of MHC class II molecules may alter the T cell receptor repertoire during thymic development, and affect the survival and expansion of mature T cells. Many evidences confirmed that the level of both transcriptional and post-transcriptional regulation are involved in the modulation of the expression of MHC class II genes and that both contribute to the predisposition to autoimmune diseases. Here, we aim to focus some of these regulative aspects to better clarify the role of MHC class II genes in predisposition and development of autoimmunity. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Analysis of Associations of Human BAFF Gene Polymorphisms with Autoimmune Thyroid Diseases.

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    Jiunn-Diann Lin

    Full Text Available The B-lymphocyte-activating factor (BAFF is associated with B-cell functions, and gene polymorphisms of the BAFF have been linked to autoimmune diseases (AIDs. In this study, we explored possible associations of two BAFF single-nucleotide polymorphisms (SNPs, rs1041569 and rs2893321, with autoimmune thyroid diseases (AITDs in an ethnic Chinese population.In total, 319 Graves' disease (GD, 83 Hashimoto's thyroiditis (HT patients, and 369 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism and direct sequencing were used to genotype rs2893321 and rs1041569.There was a significant difference in frequencies of the G allele and AG+GG genotype of rs2893321 between the GD and control groups (p = 0.013, odds ratio (OR = 0.76, and p = 0.017, OR = 0.68, respectively and between the AITD and control groups (p = 0.009, OR = 0.76, and, p = 0.014, OR = 0.69, respectively. The AA genotype of rs2893321 was associated with low titers of the thyroid-stimulating hormone receptor antibody (TSHRAb (p = 0.015 in males but not in females. The AA genotype of rs2893321 was associated with the presence of two different types of thyroid autoantibody (TAb (TSHRAb and Hashimoto's autoantibody (anti-thyroglobulin or anti-microsomal antibody in females and with that of one type in males.rs2893321 may be a susceptible genetic variant for the development of GD and AITDs. Associations of rs2893321 with susceptibility to GD and AITDs and the correlation between rs2893321 and TAb exhibit a dimorphic pattern. Additional studies with larger sample sizes are required to confirm our findings.

  1. Effects of Non-HLA Gene Polymorphisms on Development of Islet Autoimmunity and Type 1 Diabetes in a Population With High-Risk HLA-DR,DQ Genotypes

    NARCIS (Netherlands)

    Steck, Andrea K.; Wong, Randall; Wagner, Brandie; Johnson, Kelly; Liu, Edwin; Romanos, Jihane; Wijmenga, Cisca; Norris, Jill M.; Eisenbarth, George S.; Rewers, Marian J.

    We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children

  2. Bioinformatics analysis of the factors controlling type I IFN gene expression in autoimmune disease and virus-induced immunity

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    Di eFeng

    2013-09-01

    Full Text Available Patients with systemic lupus erythematosus (SLE and Sjögren's syndrome (SS display increased levels of type I IFN-induced genes. Plasmacytoid dendritic cells (PDCs are natural interferon producing cells and considered to be a primary source of IFN-α in these two diseases. Differential expression patterns of type I IFN inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes - those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI-3K pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell type-specific gene signatures as well as identify distinct transcription factors that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by transcription factors, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as IRF5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease.

  3. Insight into Gene Polymorphisms Involved in Toll-Like Receptor/Interferon Signalling Pathways for Systemic Lupus Erythematosus in South East Asia

    Directory of Open Access Journals (Sweden)

    Hwa Chia Chai

    2014-01-01

    Full Text Available Polymorphisms in genes involved in toll-like receptor/interferon signalling pathways have been reported previously to be associated with SLE in many populations. This study aimed to investigate the role of seven single nucleotide polymorphisms within TNFAIP3, STAT4, and IRF5, which are involved in upstream and downstream pathways of type I interferon production, in SLE in the South East Asian populations. Genotyping of 360 Malaysian SLE patients and 430 normal healthy individuals revealed that minor alleles of STAT4 rs7574865 and rs10168266 were associated with elevated risk of SLE in the Chinese and Malay patients, respectively (P=0.028, odds ratio (OR=1.42; P=0.035, OR=1.80, respectively. Polymorphisms in TNFAIP3 and IRF5 did not show significant associations with SLE in any of the ethnicities. Combined analysis of the Malays, Chinese, and Indians for each SNP indicated that STAT4 rs10168266 was significantly associated with the Malaysian SLE as a whole (P=0.014; OR=1.435. The meta-analysis of STAT4 rs10168266, which combined the data of other studies and this study, further confirmed its importance as the risk factor for SLE by having pooled OR of 1.559 and P value of <0.001.

  4. MicroRNA mediated network motifs in autoimmune diseases and its crosstalk between genes, functions and pathways.

    Science.gov (United States)

    Prabahar, Archana; Natarajan, Jeyakumar

    2017-01-01

    Autoimmune diseases (AIDs) are incurable but suppressible diseases whose molecular mechanisms are yet to be elucidated. In this work, we selected five systemic autoimmune diseases such as Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Inflammatory Bowel Disease (IBD), Autoimmune Thyroid Disease (ATD) and Systemic Lupus Erythematosus (SLE). Heterogeneous data such as miRNA, transcription factor (TF), target genes and protein-protein interactions involved in these AIDs were integrated to understand their roles at different functional levels of miRNA such as transcription initiation, gene regulatory network formation and post transcriptional regulation. To understand the functional characteristics of these complex biological networks, they can be simplified as network motifs (sub networks) and motif-motif interacting pairs (MMIs). The network motif patterns and motif-motif interacting pairs that occur for the selected five diseases were identified. To further understand the functional association between AIDs, functions and pathways were determined using gene set enrichment analysis and five selected immune signaling pathways (ISPs). The crosstalk within AIDs and between the immune signaling pathways (ISPs) could provide novel insights in deciphering disease mechanisms. This study represents the first investigation of miRNA-TF regulatory network for AIDs and its association with ISPs using sub-network motifs. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS): partial gene deletions contribute to APS I.

    Science.gov (United States)

    Bøe Wolff, A S; Oftedal, B; Johansson, S; Bruland, O; Løvås, K; Meager, A; Pedersen, C; Husebye, E S; Knappskog, P M

    2008-03-01

    Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.

  6. Association between allelic variants of the human glucocorticoid receptor gene and autoimmune diseases: A systematic review and meta-analysis.

    Science.gov (United States)

    Herrera, Cristian; Marcos, Miguel; Carbonell, Cristina; Mirón-Canelo, José Antonio; Espinosa, Gerard; Cervera, Ricard; Chamorro, Antonio-Javier

    2018-03-08

    The human glucocorticoid receptor gene (NR3C1) is considered to play a role in the differences and sensitivities of the glucocorticoid response in individuals with autoimmune diseases. The objective of this study was to examine by means of a systematic review previous findings regarding allelic variants of NR3C1 in relation to the risk of developing systemic autoimmune diseases. Studies that analysed the genotype distribution of NR3C1 allelic variants among patients with systemic autoimmune diseases were retrieved. A meta-analysis was conducted with a random effects model. Odds ratios (ORs) and their confidence intervals (CIs) were calculated. In addition, sub-analysis by ethnicity, sensitivity analysis and tests for heterogeneity of the results were performed. Eleven studies met the inclusion criteria for meta-analysis. We found no evidence that the analysed NR3C1 polymorphisms, rs6198, rs56149945, and rs6189/rs6190, modulate the risk of developing a systemic autoimmune disease. Nonetheless, a protective role for the minor allele of rs41423247 was found among Caucasians (OR = 0.78; 95% CI: 0.65, 0.92; P = 0.004). A subgroup analysis according to underlying diseases revealed no significant association either for Behçet's disease or rheumatoid arthritis, while correlations between NR3C1 polymorphisms and disease activity or response to glucocorticoids could not be evaluated due to insufficient data. There is no clear evidence that the analysed NR3C1 allelic variants confer a risk for developing systemic autoimmune diseases although the minor G allele of rs41423247 may be protective among Caucasians. Copyright © 2018. Published by Elsevier B.V.

  7. Gene Environment Interaction: A Trigger Point of Developing Polyglandular Autoimmunity in A Minor Girl from Rural India

    Directory of Open Access Journals (Sweden)

    Dastidar Rinini

    2017-05-01

    Full Text Available A six-year-old girl from rural Bengal was admitted in our hospital with complaints of thirst, frequent micturition, pain in abdomen and constipation. Polyglandular endocrinopathies were identified in the girl thorough clinical and biochemical examination. Hashimoto’s thyroiditis along with Type 1 diabetes mellitus made her a candidate of Polyglandular Autoimmune disease type IIIA. Patient’s history revealed that she was on cow milk since birth. Presence of high risk alleles for T1DM HLA DQA1*0101-DQB1*0302 and DQA1*0301-DQB1*0501 in the girl was disclosed by genetic study. The effect of environmental factors along with genetic susceptibility might contribute to the aggravation and early expression of these rare autoimmune diseases in this girl. This could be a classic example of gene environment interaction in case of unexplained endocrinopathies

  8. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas.

    Science.gov (United States)

    Scarpino, S; Di Napoli, A; Stoppacciaro, A; Antonelli, M; Pilozzi, E; Chiarle, R; Palestro, G; Marino, M; Facciolo, F; Rendina, E A; Webster, K E; Kinkel, S A; Scott, H S; Ruco, L

    2007-09-01

    Expression of the autoimmune regulator gene (AIRE) and the presence of CD25(+)/forkhead box p3 (FoxP3)(+) T regulatory (T(reg)) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial-like cells located in the medulla; in thymomas AIRE-positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non-neoplastic thymi obtained from 11 myasthenic (MG(+)) and 10 non-myasthenic (MG(-)) patients. It was found that AIRE is 8.5-fold more expressed in non-neoplastic thymi than in thymomas (P = 0.01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE-deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG(-) patients and 14 MG(+) patients. No significant difference was found in the two groups (thymoma MG(+), CHRNA1 = 0.013 +/- 0.03; thymoma MG-, CHRNA1 = 0.01 +/- 0.03). In normal and hyperplastic thymi CD25(+)/Foxp3(+) cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3(+) and CD25(+) cells were significantly less numerous in thymomas. A quantitative estimate of T(reg) cells revealed that the levels of Foxp3 RNA detected in non-neoplastic thymi were significantly higher (P = 0.02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of

  9. Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation.

    Science.gov (United States)

    Giordano, C; Modica, R; Allotta, M L; Guarnotta, V; Cervato, S; Masiero, S; Giordano, R; Garelli, S; Betterle, C

    2012-04-01

    Autoimmune polyendocrinopathycandidiasis-ectodermal-dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1) (OMIM 240300), is a very rare disease. Accepted criteria for diagnosis require the presence of at least 2 of 3 major clinical features: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), and Addison's disease (AD). We analyzed AIRE gene mutations and genotype-phenotype correlation in APECED patients originating from Sicily and in their relatives. In 4 patients, clinical evaluations, genetic analysis of AIRE, and APECED-related autoantibodies were performed. Two patients carried the mutation R203X in homozygosis on exon 5. One had the mutation R203X combined with R139X. The fourth had the R203X mutation in heterozygosis with R257X. Expression of the disease showed wide variability of clinical manifestations. Analysis of relatives allowed the identification of 10 heterozygotes for AIRE gene mutations. None of these subjects presented major findings of APECED. Three of the 4 patients were positive for autoantibodies to interferon-ω. In Sicily, R203X is confirmed to be the typical recessive and prevalent AIRE gene mutation on exon 5. Genotype-phenotype correlation failed to reveal a relationship between detected mutations and clinical expression. Mutations in heterozygosity in AIRE gene are not associated with major findings of APECED.

  10. Polymorphism in the KCNA3 Gene Is Associated with Susceptibility to Autoimmune Pancreatitis in the Japanese Population

    Directory of Open Access Journals (Sweden)

    Masao Ota

    2011-01-01

    Full Text Available Autoimmune pancreatitis (AIP, characterized by irregular narrowing of the main pancreatic duct, swelling of the pancreas, and histological evidence of lymphoplasmacytic inflammation by high serum immunoglobulin G4, is distinct from ordinary pancreatitis. However, genetic factors involved in the etiology and pathophysiology of AIP remain unclear. Sixty-four patients with autoimmune pancreatitis (53 men, 11 women; mean age, 62.4 years and 104 healthy Japanese controls were enrolled in this study. We performed an association analysis using 400 microsatellite markers with an average spacing of 10.8 cM in the genome. We also evaluated the association of AIP with seven single nucleotide polymorphisms (SNPs within the 20-kb region around the potassium voltage-gated channel, shaker-related subfamily, member 3 gene (KCNA3. We identified six statistically significant markers (D1S2726, D5S410, D6S460, D10S548, D15S128, and D20S186; P < 0.05 related to susceptibility. The surrounding region showing the strong association (P = 7.4 × 10−7, Pc = 0.0015 contained the KCNA3 gene. Further analysis by SNP genotyping in KCNA3 gene revealed that four SNPs (rs2840381, rs1058184, rs2640480, rs1319782 were significantly associated with the AIP susceptibility (P < 0.007. KCNA3 is known to be involved in immunomodulation of autoreactive effector and memory T cell–mediated autoimmune diseases. Our findings provide the first evidence that KCNA3 is associated with AIP and suggest that KCNA3 may influence the risk for AIP.

  11. A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED).

    Science.gov (United States)

    Fierabracci, Alessandra; Bizzarri, Carla; Palma, Alessia; Milillo, Annamaria; Bellacchio, Emanuele; Cappa, Marco

    2012-12-10

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is an autosomal recessive disease due to mutations of the autoimmune regulator (AIRE) gene. Typical manifestations include candidiasis, Addison's disease, and hypoparathyroidism. Type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia and premature ovarian failure are other rare associated diseases although other conditions have been associated with APECED. What follows is the clinical, endocrinological and molecular data of a female APECED patient coming from Lithuania. The patient was affected by chronic mucocutaneous candidiasis, hypoparathyroidism and pre-clinical Addison's disease. Using direct sequencing of all the 14 exons of the AIRE gene in the patient's DNA, we identified in exon 6 the known mutation c.769 C>T (p.Arg257X) in compound heterozygosity with the newly discovered mutation c.1214delC (p.Pro405fs) in exon 10. The novel mutation results in a frameshift that is predicted to alter the sequence of the protein starting from amino acid 405 as well as to cause its premature truncation, therefore a non-functional Aire protein. A novel mutation has been described in a patient with APECED with classical clinical components, found in compound heterozygosity with the c.769 C>T variation. Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical and immunological findings. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster...

  13. Genetic susceptibility to autoimmune thyroid diseases in a Chinese Han population: Role of vitamin D receptor gene polymorphisms.

    Science.gov (United States)

    Meng, Shuai; He, Shuang-tao; Jiang, Wen-juan; Xiao, Ling; Li, Dan-feng; Xu, Jian; Shi, Xiao-hong; Zhang, Jin-an

    2015-12-01

    Previous studies have found that some immune-related genes were associated with autoimmune thyroid diseases (AITDs). A couple of studies have explored the association between vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR) gene polymorphisms and susceptibility to AITDs in different populations and found conflicting results. This case-control study was designed to evaluate the role of polymorphisms of VDR gene in the predisposition of AITDs in a Chinese Han population. A total of 417 patients with Graves' disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy subjects were enrolled. The Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometer (MALDI-TOF-MS) Platform was applied to detect four SNPs (rs1544410, rs2228570, rs731236 and rs7975232) in the VDR gene. In the rs7975232 allele A frequency showed a significant increase in GD patients (30.34% vs. 25.42% in controls; P=0.041, OR=1.278, 95%CI=1.010-1.617). However, no relationship was found between clinical phenotypes and the four SNPs. This result suggests that the VDR gene may be one susceptibility gene which contributes to the risk of GD. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Gene expression in the spinal cord in female lewis rats with experimental autoimmune encephalomyelitis induced with myelin basic protein.

    Directory of Open Access Journals (Sweden)

    Hayley R Inglis

    Full Text Available BACKGROUND: Experimental autoimmune encephalomyelitis (EAE, the best available model of multiple sclerosis, can be induced in different animal strains using immunization with central nervous system antigens. EAE is associated with inflammation and demyelination of the nervous system. Micro-array can be used to investigate gene expression and biological pathways that are altered during disease. There are few studies of the changes in gene expression in EAE, and these have mostly been done in a chronic mouse EAE model. EAE induced in the Lewis with myelin basic protein (MBP-EAE is well characterised, making it an ideal candidate for the analysis of gene expression in this disease model. METHODOLOGY/PRINCIPAL FINDINGS: MBP-EAE was induced in female Lewis rats by inoculation with MBP and adjuvants. Total RNA was extracted from the spinal cords and used for micro-array analysis using AffimetrixGeneChip Rat Exon 1.0 ST Arrays. Gene expression in the spinal cords was compared between healthy female rats and female rats with MBP-EAE. Gene expression in the spinal cord of rats with MBP-EAE differed from that in the spinal cord of normal rats, and there was regulation of pathways involved with immune function and nervous system function. For selected genes the change in expression was confirmed with real-time PCR. CONCLUSIONS/SIGNIFICANCE: EAE leads to modulation of gene expression in the spinal cord. We have identified the genes that are most significantly regulated in MBP-EAE in the Lewis rat and produced a profile of gene expression in the spinal cord at the peak of disease.

  15. Serum Anti-TPO and TPO Gene Polymorphism as a Predictive Factor for Hidden Autoimmune Thyroiditis in Patient with Bronchial Asthma and Allergic Rhinitis.

    Science.gov (United States)

    El Shabrawy, Reham M; Atta, Amal H; Rashad, Nearmeen M

    2016-01-01

    Thyroid peroxidase (TPO) is the key enzyme in the biosynthesis of thyroid hormones T3 and T4. Autoimmune thyroiditis is a common disorder affecting 10% of population worldwide. A key feature of autoimmune thyroiditis is the presence of anti TPO antibodies, and some mutation of the TPO gene. Association between autoimmune thyroiditis and other autoimmune disorders has been reported but little is known about association with allergic diseases. In this study, we aimed to evaluate frequency of hidden autoimmune thyroiditis among allergic patient and examine possible relationship between anti-TPO levels and polymorphism at the TPO gene A2173/C exon 12 and different types of allergens. The study included 50 adult Egyptian patients with allergic rhinitis and /or bronchial asthma and 50 controls. For each subject, thyroid stimulating hormone (TSH), thyroxin 4 (T4) and Triiodothyronine (T3) hormones were measured. Anti-thyroid peroxidase (anti-TPO) level was detected by ELISA; and TPO gene polymorphism 2173A>C exon 12 was analyzed using restriction fragment length polymorphism (RFLP). Skin prick test was done to assess allergic response in patients. Serum levels of T3, T4 and TSH did not show any statistical significant difference between patients and groups. However, mean serum anti-TPO level was statistically higher in patients than controls, and correlated positively with body mass index, age, diastolic blood pressure, suggesting higher prevalence of hidden autoimmune thyroiditis in allergic patients than in control group. 2173A>C Genotyping revealed that the frequency of C allele is increased in the patient group. C allele represents a risk factor with odds ratio of 2.37 (1.035-5.44) and a significant P value TPO 2173A>C polymorphism may be considered as a risk factor for developing autoimmune thyroiditis in patients with allergic rhinitis and asthma and that these patients should regularly be checked for hidden thyroiditis. Copyright© by the Egyptian Association of

  16. Oral Administration of Lactococcus lactis Expressing Synthetic Genes of Myelin Antigens in Decreasing Experimental Autoimmune Encephalomyelitis in Rats.

    Science.gov (United States)

    Kasarello, Kaja; Kwiatkowska-Patzer, Barbara; Lipkowski, Andrzej W; Bardowski, Jacek K; Szczepankowska, Agnieszka K

    2015-05-31

    Multiple sclerosis is a human autoimmunological disease that causes neurodegeneration. One of the potential ways to stop its development is induction of oral tolerance, whose effect lies in decreasing immune response to the fed antigen. It was shown in animal models that administration of specific epitopes of the three main myelin proteins - myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and proteolipid protein (PLP) - results in induction of oral tolerance and suppression of disease symptoms. Use of bacterial cells to produce and deliver antigens to gut mucosa seems to be an attractive method for oral tolerance induction in treatment of diseases with autoimmune background. Synthetic genes of MOG35-55, MBP85-97, and PLP139-151 myelin epitopes were generated and cloned in Lactococcus lactis under a CcpA-regulated promoter. The tolerogenic effect of bacterial preparations was tested on experimental autoimmune encephalomyelitis, which is the animal model of MS. EAE was induced in rats by intradermal injection of guinea pig spinal cord homogenate into hind paws. Rats were administered preparations containing whole-cell lysates of L. lactis producing myelin antigens using different feeding schemes. Our study demonstrates that 20-fold, but not 4-fold, intragastric administration of autoantigen-expressing L. lactis cells under specific conditions reduces the clinical symptoms of EAE in rats. The present study evaluated the use of myelin antigens produced in L. lactis in inhibiting the onset of experimental autoimmune encephalomyelitis in rats. Obtained results indicate that application of such recombinant cells can be an attractive method of oral tolerance induction.

  17. Update in endocrine autoimmunity.

    Science.gov (United States)

    Anderson, Mark S

    2008-10-01

    The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases. Rapid progress has recently been made in our understanding of the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and confirmed many new genes outside of the established role of the human leukocyte antigen locus with these diseases, and indicate an essential role of immune response pathways in these diseases. Progress has also been made in identifying new autoantigens and the development of new animal models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for potentially treating and reversing the underlying autoimmune process. Although autoimmune endocrine disorders are complex in etiology, these recent advances should help contribute to improved outcomes for patients with, or at risk for, these disorders.

  18. Autoimmune disorders

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000816.htm Autoimmune disorders To use the sharing features on this page, please enable JavaScript. An autoimmune disorder occurs when the body's immune system attacks and ...

  19. A simple estimate of the general population frequency of the MHC susceptibility gene for autoimmune polygenic disease.

    Science.gov (United States)

    Alper, C A; Dubey, D P; Yunis, E J; Awdeh, Z

    2000-01-01

    We wished to determine the frequencies of the MHC and non-MHC susceptibility genes for polygenic autoimmune diseases like type 1 diabetes (IDDM). We used Mendelian inheritance and the Hardy-Weinberg equilibrium to calculate the frequencies of mating pairs and susceptible offspring under classical recessive and dominant inheritance of the MHC susceptibility gene. We then analyzed the distribution of haplotype sharing by affected sib pairs of the 4 MHC haplotypes in each of the kinds of mating pairs in terms of the frequency of the disease susceptibility gene. For IDDM, the analysis was consistent with a recessive, but not a dominant, MHC susceptibility gene of frequency 0.525 at a distribution of 55, 38 and 7% of affected sib pairs who share 2, 1 and 0 MHC haplotypes, respectively. A simple relationship was obtained: if inheritance is recessive, the MHC susceptibility gene frequency is the square root of the fraction of affected sib pairs who share no MHC haplotypes multiplied by 4. For recessive inheritance, affected sib pairs who share no haplotypes are solely in families where both parents are homozygous MHC-susceptible. Although homozygous MHC susceptibles represent over 25% of the population, only 2-3% of them are IDDM-susceptible at non-MHC susceptibility loci, also required for disease expression. Predictions from our analysis fit all published observations of the familial occurrence of disease. The analysis is general, simple and provides a single estimate (not a range) of the MHC susceptibility gene frequency. This approach should be applicable to other MHC-determined polygenic diseases. Copyright 2000 S. Karger AG, Basel

  20. Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases.

    Science.gov (United States)

    Wang, X; Zhu, Y F; Li, D M; Qin, Q; Wang, Q; Muhali, F S; Jiang, W J; Zhang, J A

    2016-02-01

    Interleukin 33 (IL33) / ST2 pathway and ST2-interlukin18 receptor1-interlukin18 receptor accessory protein (ST2-IL18R1-IL18RAP) gene cluster have been involved in many autoimmune diseases but few report in autoimmune thyroid diseases (AITD). In this study, we investigated whether polymorphisms of IL33, ST2, IL18R1, and IL18RAP are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITD, among a Chinese population. A total of 11 SNPs were explored in a case-control study including 417 patients with GD, 250 HT patients and 301 controls, including rs1929992, rs10975519, rs10208293, rs6543116, rs1041973, rs3732127, rs11465597, rs1035130, rs2293225, rs1035127, rs917997 of IL 33, ST2-IL18R1-IL18RAP gene cluster. Genotyping of these SNPs was performed using matrix-assisted laser desorption / ionization-time-of-flight mass spectrometer (MALDI-TOF-MS) platform from Sequenom. The frequencies of allele A and AA+AG genotype of rs6543116 (ST2) in HT patients were significantly increased compared with those of the controls (P = 0.029/0.021, OR = 1.31/1.62). And in another SNP rs917997, AA+AG genotype presented an increased frequency in HT subjects compared with controls (P = 0.046, OR = 1.53). Furthermore, the haplotype GAGCCCG from ST2-IL18R1-IL18RAP gene cluster (rs6543116, rs1041973, rs1035130, rs3732127, rs1035127, rs2293225, rs917997) was associated with increased susceptibility to GD with an OR of 2.03 (P = 0.022, 95% CI = 1.07-3.86). Some SNPs of ST2-IL18R1-IL18RAP gene cluster might increase the risk of susceptibility of HT and GD in Chinese Han population. © 2015 John Wiley & Sons Ltd.

  1. Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes

    OpenAIRE

    C. J. Carter

    2011-01-01

    Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matc...

  2. Generation of Gene-Engineered Chimeric DNA Molecules for Specific Therapy of Autoimmune Diseases

    Science.gov (United States)

    Gesheva, Vera; Szekeres, Zsuzsanna; Mihaylova, Nikolina; Dimitrova, Iliyana; Nikolova, Maria; Erdei, Anna; Prechl, Jozsef

    2012-01-01

    Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the development of self-reactive B and T cells and autoantibody production. In particular, double-stranded DNA-specific B cells play an important role in lupus progression, and their selective elimination is a reasonable approach for effective therapy of SLE. DNA-based vaccines aim at the induction of immune response against the vector-encoded antigen. Here, we are exploring, as a new DNA-based therapy of SLE, a chimeric DNA molecule encoding a DNA-mimotope peptide, and the Fv but not the immunogenic Fc fragment of an FcγRIIb-specific monoclonal antibody. This DNA construct was inserted in the expression vector pNut and used as a naked DNA vaccine in a mouse model of lupus. The chimeric DNA molecule can be expressed in eukaryotic cells and cross-links cell surface receptors on DNA-specific B cells, delivering an inhibitory intracellular signal. Intramuscular administration of the recombinant DNA molecule to lupus-prone MRL/lpr mice prevented increase in IgG anti-DNA antibodies and was associated with a low degree of proteinuria, modulation of cytokine profile, and suppression of lupus nephritis. PMID:23075110

  3. Parental genes do not codominantly confer susceptibility to experimental autoimmune encephalomyelitis in F1 rats.

    Science.gov (United States)

    Lenz, D C; Wolf, N A; Swanborg, R H

    2001-03-01

    Lewis (LEW) and DA rats are highly susceptible to experimental autoimmune encephalomyelitis (EAE) induced with guinea pig myelin basic protein (MBP), but respond to different epitopes. The dominant epitope for LEW rats is MBP73-86, and disease is mediated primarily by Vbeta8.2 Th1 cells. DA rats lack conventional Vbeta8.2 T cells and do not respond to MBP73-86. Rather, DA rats respond to the cryptic epitope MBP63-81, which is not encephalitogenic for LEW rats. Responses to these neuroantigens were investigated in (DAxLEW) F1 hybrids to determine if experimental findings in inbred rats remain valid in more genetically complex models. Surprisingly, MBP63-81, a cryptic epitope for DA rats, induced moderate-to-severe EAE in F1 hosts, whereas MBP73-86, the dominant LEW epitope, was only weakly encephalitogenic in F1 hosts. The poor clinical response to MBP73-86 appears to be a consequence of an inability to expand Vbeta8.2 T cells. These results suggest that parental responses to neuroantigens are poor predictors for determining encephalitogenicity in F1 progeny.

  4. [Polyglandular autoimmune syndromes : An overview].

    Science.gov (United States)

    Komminoth, P

    2016-05-01

    Polyglandular autoimmune syndromes (PGAS), also known as autoimmune polyendocrinopathy syndromes (APS), are a heterogeneous group of rare, genetically caused diseases of the immune system which lead to inflammatory damage of various endocrine glands resulting in malfunctions. In addition, autoimmune diseases of non-endocrine organs may also be found. Early diagnosis of PGAS is often overlooked because of heterogeneous symptoms and the progressive occurrence of the individual diseases. The two most important forms of PGAS are the juvenile and adult types. The juvenile type (PGAS type 1) is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21, exhibits geographic variations in incidence and is defined by the combination of mucocutaneous candidiasis, Addison's disease and hypoparathyroidism. In addition, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome and other autoimmune diseases can also occur. The adult form of PGAS (PGAS type 2) is a multigenetic disorder associated with some HLA haplotypes, is more common than the juvenile type, shows female predominance and exhibits the combination of type 1 diabetes, autoimmune thyroid disease, Addison's disease and other autoimmune disorders. The histological alterations in affected organs of PGAS patients are similar to findings in sporadically occurring autoimmune diseases of these organs but there are no pathognomic fine tissue findings. If patients exhibit autoimmune changes in two different endocrine glands or if there are indications of several autoimmune disorders from the patient history, it is important to consider PGAS and inform the clinicians of this suspicion.

  5. β-Thalassemia trait association with autoimmune diseases: β-globin locus proximity to the immunity genes or role of hemorphins?

    Science.gov (United States)

    Altinoz, Meric A; Gedikoglu, Gunduz; Deniz, Gunnur

    2012-04-01

    Thalassemia major continues to be a significant health problem for Mediterranean, Afro-Arabic countries, India and South Easth Asia. It was generally assumed that the β-thalassemia heterozygotes do not bear significant medical risks except a mild microcytic anemia. Nonetheless, increasing number of reports associate β-thalassemia trait with autoimmune conditions, nephritis, diabetes, arthritis, fibromyalgia and asthma. Available sparse data indicate reduced incidence of systemic lupus erythematosus (SLE) in β-thalassemia heterozygotes; yet, if two conditions coexist, the SLE manifestations occur much severer. These associations make sense when considering that the hemoglobin β-chain locus at 11p15.5 resides in close proximity to eight genes with profound roles in immune regulation: STIM1, CD151, TC21/RRAS2, SIGIRR/TOLL/IL1R8, pp52/LSP1 (lymphocyte specific protein), TRIM21, toll interacting protein (TOLLIP) and SLEN3. β-Thalassemia trait accompaniment to autoimmune disease may be the result of haplotypal associations between the close proximity genes. An alternative explanation to thalassemia heterozygosity: autoimmune disease association may be the changed concentrations of hemorphins. Hemorphins are endogenous opioid peptides derived via proteolytical cleavage of hemoglobin. They are shown to bind diverse opioid receptors and act anti-inflammatory. Their reduced expression in thalassemia heterozygosity may explain a proinflammatory stage and autoimmunity vulnerability.

  6. Investigation of susceptibility genes triggering lachrymal/salivary gland lesion complications in Japanese patients with type 1 autoimmune pancreatitis.

    Directory of Open Access Journals (Sweden)

    Takaya Oguchi

    Full Text Available Autoimmune pancreatitis (AIP is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group and 53 type 1 AIP patients without (B group. The mean values of IgG and IG4 were both significantly different (P<0.05 between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001 were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021] and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]. Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P = 0.00062, Pc = 0.003, OR = 2.98, 95%CI = 1.58–5.65 in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P = 0.00015, OR = 3.38, 95%CI = 1.77–6.45. In the LOC101928923 gene, the frequency of the minor T allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C

  7. Investigation of Susceptibility Genes Triggering Lachrymal/Salivary Gland Lesion Complications in Japanese Patients with Type 1 Autoimmune Pancreatitis

    Science.gov (United States)

    Oguchi, Takaya; Ota, Masao; Ito, Tetsuya; Hamano, Hideaki; Arakura, Norikazu; Katsuyama, Yoshihiko; Meguro, Akira; Kawa, Shigeyuki

    2015-01-01

    Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS) with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA) that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs) in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group) and 53 type 1 AIP patients without (B group). The mean values of IgG and IG4 were both significantly different (P<0.05) between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001) were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021]) and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]). Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P=0.00062, Pc=0.0018, OR=2.98, 95%CI=1.58-5.65) in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P=0.00015, OR=3.38, 95%CI=1.77-7.65). In the LOC101928923 gene, the frequency of the minor C allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C allele of MPPED2 rs514644

  8. Restriction fragment length polymorphism of two HLA-B-associated transcripts genes in five autoimmune diseases

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Ryder, L P

    1991-01-01

    The restriction fragment length polymorphism of the two human HLA-B-associated transcripts (BATs) genes, BAT1 and BAT2, identifying polymorphic bands of 12, 8, 2.5, and 1.1 kb, and at 3.3, 2.7, 2.3, and 0.9 kb, respectively, was investigated in patients with primary biliary cirrhosis (PBC...

  9. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

    Science.gov (United States)

    Kisand, Kai; Peterson, Pärt

    2015-07-01

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. This review focuses on the clinical and immunological features of APECED, summarizes the current knowledge on the function of AIRE and discusses the importance of autoantibodies in disease diagnosis and prognosis. Additionally, we review the outcome of recent immunomodulatory treatments in APECED patients.

  10. Transcriptional programs that control expression of the autoimmune regulator gene Aire.

    Science.gov (United States)

    Herzig, Yonatan; Nevo, Shir; Bornstein, Chamutal; Brezis, Miriam R; Ben-Hur, Sharon; Shkedy, Aya; Eisenberg-Bord, Michal; Levi, Ben; Delacher, Michael; Goldfarb, Yael; David, Eyal; Weinberger, Leehee; Viukov, Sergey; Ben-Dor, Shifra; Giraud, Matthieu; Hanna, Jacob H; Breiling, Achim; Lyko, Frank; Amit, Ido; Feuerer, Markus; Abramson, Jakub

    2017-02-01

    Aire is a transcriptional regulator that induces promiscuous expression of thousands of genes encoding tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). While the target genes of Aire are well characterized, the transcriptional programs that regulate its own expression have remained elusive. Here we comprehensively analyzed both cis-acting and trans-acting regulatory mechanisms and found that the Aire locus was insulated by the global chromatin organizer CTCF and was hypermethylated in cells and tissues that did not express Aire. In mTECs, however, Aire expression was facilitated by concurrent eviction of CTCF, specific demethylation of exon 2 and the proximal promoter, and the coordinated action of several transcription activators, including Irf4, Irf8, Tbx21, Tcf7 and Ctcfl, which acted on mTEC-specific accessible regions in the Aire locus.

  11. A network analysis of the human T-cell activation gene network identifies JAGGED1 as a therapeutic target for autoimmune diseases.

    Directory of Open Access Journals (Sweden)

    Ricardo Palacios

    2007-11-01

    Full Text Available Understanding complex diseases will benefit the recognition of the properties of the gene networks that control biological functions. Here, we set out to model the gene network that controls T-cell activation in humans, which is critical for the development of autoimmune diseases such as Multiple Sclerosis (MS. The network was established on the basis of the quantitative expression from 104 individuals of 20 genes of the immune system, as well as on biological information from the Ingenuity database and Bayesian inference. Of the 31 links (gene interactions identified in the network, 18 were identified in the Ingenuity database and 13 were new and we validated 7 of 8 interactions experimentally. In the MS patients network, we found an increase in the weight of gene interactions related to Th1 function and a decrease in those related to Treg and Th2 function. Indeed, we found that IFN-ss therapy induces changes in gene interactions related to T cell proliferation and adhesion, although these gene interactions were not restored to levels similar to controls. Finally, we identify JAG1 as a new therapeutic target whose differential behaviour in the MS network was not modified by immunomodulatory therapy. In vitro treatment with a Jagged1 agonist peptide modulated the T-cell activation network in PBMCs from patients with MS. Moreover, treatment of mice with experimental autoimmune encephalomyelitis with the Jagged1 agonist ameliorated the disease course, and modulated Th2, Th1 and Treg function. This study illustrates how network analysis can predict therapeutic targets for immune intervention and identified the immunomodulatory properties of Jagged1 making it a new therapeutic target for MS and other autoimmune diseases.

  12. A high-throughput sequence analysis of Japanese patients revealed 11 candidate genes associated with type 1 autoimmune pancreatitis susceptibility.

    Science.gov (United States)

    Fujibayashi, Shugo; Sasajima, Junpei; Goto, Takuma; Tanaka, Hiroki; Kawabata, Hidemasa; Fujii, Tsuneshi; Nakamura, Kazumasa; Chiba, Atsushi; Yanagawa, Nobuyuki; Moriichi, Kentaro; Fujiya, Mikihiro; Kohgo, Yutaka

    2016-07-01

    The pathogenesis of autoimmune pancreatitis is unknown. In the present study we used high-throughput sequencing with next generation sequencing to identify the candidate genes associated with AIP. A total of 27 type 1 AIP patients and 30 healthy blood donors were recruited, and DNA samples were isolated from their mononuclear cells. A high-throughput sequencer with an original custom panel of 1031 genes was used to detect the genetic variants in each sample. Polymorphisms of CACNA1S (c.4642C>T), rs41554316, rs2231119, rs1042131, rs2838171, P2RX3 (c.195delG), rs75639061, SMAD7 (c.624delC) and TOP1 (c.2007delG), were identified as candidate genetic variants in patients with type 1 AIP. P2RX3 and TOP1 were significantly associated with AIP, even after adjusting bay means of Bonferroni's correction. In addition, we also identified eight candidate genetic variants that were associated with the relapse of type 1 AIP, namely: rs1143146, rs1050716, HLA-C (c.759_763delCCCCCinsTCCCG), rs1050451, rs4154112, rs1049069, CACNA1C (c.5996delC) and CXCR3 (c.630_631delGC). Finally polymorphisms of rs1050716 and rs111493987 were identified as candidate genetic variants associated with extra-pancreatic lesions in patients with type 1 AIP. These candidates might be used as markers of AIP susceptibility and could contribute to the pathogenesis of type 1 AIP.

  13. Gene expression profiling of anti-CTLA4-treated metastatic melanoma in patients with treatment-induced autoimmunity.

    Science.gov (United States)

    Bresler, Scott C; Min, Le; Rodig, Scott J; Walls, Andrew C; Xu, Shuyun; Geng, Songmei; Hodi, F Stephen; Murphy, George F; Lian, Christine G

    2017-02-01

    Ipilimumab (IPI) is a monoclonal antibody that targets the inhibitory CTLA4 receptor of T cells, enhancing T-cell-driven antitumor responses. IPI therapy in metastatic melanoma results in significant improvement in disease-free and overall survival, although after initial responses disease progression generally ensues. Identification of specific responses in tissue where melanoma tumor cells are subjected to IPI-driven immune attack may reveal mechanisms of treatment efficacy or resistance, permitting refinement of targeted therapeutic approaches. We used NanoString digital barcoding chemistry to identify changes in the transcriptome of metastatic melanoma cells before and after IPI treatment using two comprehensive panels containing a total of 1330 unique genes. Only patients who developed autoimmune disorders following treatment, signifying a robust immune response, were included. Despite evidence of an enhanced immune response, most patients eventually exhibited disease progression. Overall, data from five pre-IPI tumors and four post-IPI tumor samples (from three patients) permitted identification of several candidate genes that showed increased expression based on normalized counts after therapy. These included TTK (~3.1-fold, P=1.18e-4), which encodes a dual-specificity protein tyrosine kinase, a known cell cycle regulator, and BIRC5 (~3.0-fold, P=9.36e-4), which encodes the antiapoptotic protein survivin. Both TTK (MPS1) and survivin are targetable proteins against which a number of pharmacologic agents have been developed. CDK1, which encodes a protein tyrosine kinase known to phosphorylate survivin, was also upregulated (~3.2-fold, P=2.80-3). Tumor cell expression of TTK and survivin proteins was confirmed using immunohistochemistry in an expanded patient cohort. Differences in gene expression for several commonly encountered immune antigens, such as CD3, CD4, CD8, and CTLA4, were not statistically significant, likely reflecting the long length of time

  14. Tracking Differential Gene Expression in MRL/MpJ Versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

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    Amy G. Clark

    2008-01-01

    Full Text Available Background: Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profiling recently identified transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6 milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype.Results: Global gene expression was evaluated in purified transgenic B cells using Operon version 3.0 oligonucleotide microarray assaying 31,000 oligoprobes. Genes with a 2-fold expression difference in B6 as compared to MRL anergic B cells were identified. Expression of selected genes was confirmed using quantitative RT-PCR. This approach identified 43 probes corresponding to 37 characterized genes, including Ptpn22, CD74, Birc1f/Naip, and Ctla4, as differentially expressed in anergic B cells in the two strains. Gene Ontology classification identified differentiation, cell cycle, proliferation, development, apoptosis, and cell death as prominently represented ontology groups. Ingenuity Pathway Analysis identified two major networks incorporating 27 qualifying genes. Network 1 centers on beta-estradiol and TP53, and Network 2 encompasses RB1, p38 MAPK, and NFkB cell growth, proliferation, and cell cycle signaling pathways.Conclusion: Using microarray analysis we identified 37 characterized genes and two functional pathways engaged in maintenance of B cell anergy for which expression is

  15. Polymorphisms in the selenoprotein S gene: lack of association with autoimmune inflammatory diseases

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    Díaz-Rubio Manuel

    2008-07-01

    Full Text Available Abstract Background Selenoprotein S (SelS protects the functional integrity of the endoplasmic reticulum against the deleterious effects of metabolic stress. SEPS1/SelS polymorphisms have been involved in the increased release of pro-inflammatory cytokines interleukin (IL-1β, tumor necrosis factor (TNF-α and IL-6 in macrophages. We aimed at investigating the role of the SEPS1 variants previously associated with higher plasma levels of these cytokines and of the SEPS1 haplotypes in the susceptibility to develop immune-mediated diseases characterized by an inflammatory component. Results Six polymorphisms distributed through the SEPS1 gene (rs11327127, rs28665122, rs4965814, rs12917258, rs4965373 and rs2101171 were genotyped in more than two thousand patients suffering from type 1 diabetes, rheumatoid arthritis or inflammatory bowel diseases and 550 healthy controls included in the case-control study. Conclusion Lack of association of SEPS1 polymorphisms or haplotypes precludes a major role of this gene increasing predisposition to these inflammatory diseases.

  16. Autoimmune gastritis.

    Science.gov (United States)

    Kulnigg-Dabsch, Stefanie

    2016-10-01

    Autoimmune gastritis is a chronic inflammatory disease with destruction of parietal cells of the corpus and fundus of the stomach. The known consequence is vitamin B12 deficiency and, consequently, pernicious anemia. However, loss of parietal cells reduces secretion of gastric acid which is also required for absorption of inorganic iron; thus, iron deficiency is commonly found in patients with autoimmune gastritis. This usually precedes vitamin B12 deficiency and is found mainly in young women. Patients with chronic iron deficiency, especially those refractory to oral iron therapy, should therefore be evaluated for the presence of autoimmune gastritis.

  17. A comparative study of mRNA and protein expression of the autoimmune regulator gene (Aire) in embryonic and adult murine tissues.

    Science.gov (United States)

    Adamson, K A; Pearce, S H S; Lamb, J R; Seckl, J R; Howie, S E M

    2004-02-01

    Autoimmune polyendocrine syndrome type 1 (APS1) is a rare autosomal recessive human disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by multiple autoimmune diseases. As reports of the tissue expression pattern of the murine Aire gene are discordant, a comprehensive survey of Aire expression was undertaken in adult and embryonic tissues at the mRNA and protein levels using real-time RT-PCR, in situ hybridization, and immunohistochemistry. In the adult, the highest Aire mRNA expression was in the thymus. All the other tissues investigated expressed Aire mRNA at low levels, but it was barely detectable in the adrenal gland. Aire protein expression was observed in the thymus, spleen, and lymph nodes. A common pattern was observed in other tissues, with staining in epithelial cells. An exception to this was the gut, where staining was seen in the mucin spaces. In embryonic tissue, Aire mRNA and protein expression was detected from E14.5 in the thymus. In the fetal liver, unlike the adult, staining was observed at E14.5 and decreased towards term. Thus, Aire is expressed in immunologically relevant tissues and in a restricted number of extra-immunological tissues in the adult. Furthermore, the presence of Aire protein is reported in extra-thymic tissues of the embryo. Copyright 2004 John Wiley & Sons, Ltd.

  18. Autoimmune pancreatitis

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    Davorin Dajčman

    2007-05-01

    Full Text Available Background: Autoimmune pancreatitis is a recently described type of pancreatitis of presumed autoimmune etiology. Autoimmune pancreatitis is often misdiagnosed as pancreatic cancer difficult, since their clinical presentations are often similar. The concept of autoimmune pancreatitis was first published in 1961. Since then, autoimmune pancreatitis has often been treated not as an independent clinical entity but rather as a manifestation of systemic disease. The overall prevalence and incidence of the disease have yet to be determined, but three series have reported the prevalence as between 5 and 6 % of all patients with chronic pancreatitis. Patient vary widely in age, but most are older than 50 years. Patients with autoimmune pancreatitis usually complain of the painless jaundice, mild abdominal pain and weight loss. There is no laboratory hallmark of the disease, even if cholestatic profiles of liver dysfunction with only mild elevation of amylase and lipase levels have been reported.Conclusions: Proposed diagnostic criteria contains: (1 radiologic imaging, diffuse enlargement of the pancreas and diffusely irregular narrowing of the main pancreatic duct, (2 laboratory data, elevated levels of serum ã-globulin and/or IgG, specially IgG4, or the presence of autoantibodies and (3 histopathologic examination, fibrotic change with dense lymphoplasmacytic infiltration in the pancreas. For correct diagnosis of autoimmune pancreatitis, criterion 1 must be present with criterion 2 and/or 3. Autoimmune pancreatitis is frequently associated with rheumatoid arthritis, Sjogren’s syndrome, inflammatory bowel disease, tubulointersticial nephritis, primary sclerosing cholangitis and idiopathic retroperitoneal fibrosis. Pancreatic biopsy using an endoscopic ultrasound-guided fine needle aspiration biopsy is the most important diagnostic method today. Treatment with corticosteroids leads to the and resolution of pancreatic inflamation, obstruction and

  19. Epigenetics and Autoimmune Diseases

    Science.gov (United States)

    Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis

    2012-01-01

    Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches. PMID:22536485

  20. Autoimmune polyendocrine syndrome type 1 and NALP5, parathyroid autoantigen

    NARCIS (Netherlands)

    Alimohammadi, Mohammad; Bjorklund, Peyman; Hallgren, Asa; Pontynen, Nora; Szinnai, Gabor; Shikama, Noriko; Keller, Marcel P.; Ekwall, Olov; Kinkel, Sarah A.; Husebye, Eystein S.; Gustafsson, Jan; Rorsman, Fredrik; Peltonen, Leena; Betterle, Corrado; Perheentupa, Jaakko; Akerstrom, Goran; Westin, Gunnar; Scott, Hamish S.; Hollaender, Georg A.; Kampe, Olle

    2008-01-01

    Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a multiorgan autoimmune disorder caused by mutations in AIRE, the autoimmune regulator gene. Though recent studies concerning AIRE deficiency have begun to elucidate the molecular pathogenesis of organ-specific autoimmunity in patients

  1. Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Taishin eAkiyama

    2013-08-01

    Full Text Available Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla (mTECs contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs. Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE protein, of which dysfunctional mutations are the causative factor of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED. In addition to the elimination of self-reactive T cells, recent studies indicated roles of mTECs in the development of Foxp3-positive regulatory T cells, which suppress autoimmunity and excess immune reactions in peripheral tissues. The TNF family cytokines, RANK ligand, CD40 ligand and lymphotoxin were found to promote the differentiation of AIRE- and TSA-expressing mTECs. Furthermore, activation of NF-κB is essential for mTEC differentiation. In this mini-review, we focus on molecular mechanisms that regulate induction of AIRE and TSA expression and discuss possible contributions of these mechanisms to prevent the onset of autoimmune diseases.

  2. Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.

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    Diana Chang

    Full Text Available Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS. We present tailored analytical methods and software that facilitate X-wide association studies (XWAS, which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID. We associated several X-linked genes with disease risk, among which (1 ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD. Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2 CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3 We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4 we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

  3. Common immunogenetic profile in children with multiple autoimmune diseases: the signature of HLA-DQ pleiotropic genes.

    Science.gov (United States)

    Larizza, Daniela; Calcaterra, Valeria; Klersy, Catherine; Badulli, Carla; Caramagna, Claudia; Ricci, Antonio; Brambilla, Paola; Salvaneschi, Laura; Martinetti, Miryam

    2012-09-01

    Type 1 diabetes mellitus (T1DM), celiac disease (CD) and autoimmune thyroid disease (ATD) are autoimmune conditions relatively common in paediatric age and frequently occur in association in the same subject. This event is not by chance and requires an explanation. Here, we studied the distribution of HLA-DQ αβ heterodimers in 334 Italian children with T1DM, ATD and CD alone or in association and in 224 Italian healthy controls. In particular, 164 patients had T1DM (133 alone, 20+ATD, 7+CD and 4+CD+ATD), 118 had ATD (110 alone, 8+CD) and 52 had CD (40 alone, 11+ATD and 1+T1DM). 51 patients suffered from multiple autoimmune diseases. The risk for multiple autoimmune diseases was significantly associated with the increased number of HLA-DQ markers of susceptibility for both T1DM (p = 0.003) and CD (p = 0.006). The presence of one or more diabetogenic DQ molecules significantly increased the probability of developing not only T1DM (p HLA-DQ heterodimers significantly increased the likelihood of developing not only CD (p diseases although with a different risk according to the number and type of susceptible HLA-DQ heterodimers as reported in the algorithm proposed here. It is likely that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and HLA-DQ genomic typing will improve the capability to predict associated autoimmune diseases in infancy.

  4. Understanding Autoimmune Diseases

    Science.gov (United States)

    ... What are they? Points To Remember About Autoimmune Diseases Autoimmune diseases refer to problems with the immune system, ... Infectious Diseases Website: https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases American Autoimmune Related Diseases Association Website: https:// ...

  5. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either......Autoimmune hypophysitis (AH) - often referred to as lymphocytic hypophysitis - is a rare disease that affects the pituitary gland and causes inflammation. The disease enlarges the pituitary gland and the clinical presentations are lack of pituitary function and headaches. AH is mostly seen in women...

  6. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either......Autoimmune hypophysitis (AH) - often referred to as lymphocytic hypophysitis - is a rare disease that affects the pituitary gland and causes inflammation. The disease enlarges the pituitary gland and the clinical presentations are lack of pituitary function and headaches. AH is mostly seen in women...... immunosuppressive treatment or surgery....

  7. Analysis of IL12B gene variants in inflammatory bowel disease.

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    Jürgen Glas

    Full Text Available BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD. However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD and ulcerative colitis (UC. Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695. Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066 and UC (OR 1.18 [0.97-1.43], p = 0.092. CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5; OR = 2.84, 95% CI 1.66-4.84, while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92. In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694 in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05 but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695

  8. Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

    Science.gov (United States)

    Wagner, Johanna; Olszak, Torsten; Fries, Christoph; Tillack, Cornelia; Friedrich, Matthias; Beigel, Florian; Stallhofer, Johannes; Steib, Christian; Wetzke, Martin; Göke, Burkhard; Ochsenkühn, Thomas; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

    2012-01-01

    Background IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. Methodology/Principal Findings We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01–1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99–1.31], p = 0.066) and UC (OR 1.18 [0.97–1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10−5; OR = 2.84, 95% CI 1.66–4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14–0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. Conclusions/Significance The IL12B SNP rs6887695 modulates

  9. Autoimmun hypophysitis

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    during pregnancy or postpartum, but also occurs in males and children. AH is often associated with other autoimmune diseases, most frequently with Hashimoto's thyroiditis. The symptoms are caused by enlargement of the pituitary gland and disturbances of the hormone function. Treatment is either...

  10. Autoimmune sialadenitis

    NARCIS (Netherlands)

    Guntinas-Lichius, O.; Vissink, A.; Ihrler, S.

    Using the European-American classification criteria the diagnosis of autoimmune sialadenitis in Sjogren's syndrome can generally be easily established or excluded. In addition, sonography performed by the ENT physician is helpful in diagnosing and especially in follow-up screening for MALT

  11. AIRE-mutations and autoimmune disease.

    Science.gov (United States)

    Bruserud, Øyvind; Oftedal, Bergithe E; Wolff, Anette B; Husebye, Eystein S

    2016-12-01

    The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Interaction of HLA-DRB1* alleles and CTLA4 (+49 AG) gene polymorphism in Autoimmune Thyroid Disease.

    Science.gov (United States)

    Ramgopal, Sivanadham; Rathika, Chinniah; Padma, Malini Ravi; Murali, Vijayan; Arun, Kannan; Kamaludeen, Mohamed Nainar; Balakrishnan, Karuppiah

    2018-02-05

    Autoimmune Thyroid Diseases (AITDs), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), arise by the complex interaction of genes and environmental factors. The aim of present study was to study the susceptible associations of HLA-DRB1* alleles and CTLA4 +49 AG polymorphism in AITD in south India. AITD patients (n=235; HT=180; GD=55) and age/sex matched healthy controls (n, 235) were enrolled to type HLA-DRB1* alleles and 'CTLA4 +49 AG' by PCR-SSP and PCR-RFLP methods respectively. Analysis revealed CTLA4 +49 'GG' genotype was increased significantly in patients (PL: p=8.7×10 -8 ; HT: p=9.3×10 -6 ; GD: p=0.006). Decreased frequencies of 'AA' genotype was observed in patients (PL: p=9.4×10 -6 ; HT: p=0.008; GD: p=9.0×10 -6 ). Increased frequencies were observed for HLA alleles DRB1*12 (PL: p=1.42×10 -10 ; HT: p=5.75×10 -8 ; GD: p=0.002) and DRB1*11 (PL: p=0.0025; HT: p=0.013) in patients. Decreased frequencies for alleles DRB1*10 (PL: p=0.00002; HT: p=0.018; GD: p=1.63×10 -5 ) and DRB1*03 (PL: p=0.003; HT: p=0.003) were observed, suggesting a protective association. Combinatorial/Synergistic analysis have revealed an increased frequencies for 'DRB1*11+AG' (PL: p=0.022), 'DRB1*12+AG' (PL: p=6.1×10 -5 ; HT: p=0.0001), 'DRB1*04+GG' (PL: p=0.003; HT: p=0.008), 'DRB1*07+GG' (PL: p=0.009; HT: p=0.014) and 'DRB1*12+GG' (PL: p=0.005; HT: p=0.005) in patients. However, the combinations such as 'DRB1*10+AA' (PL: p=1.8×10 -6 ; HT: p=0.003) and 'DRB1*15+AA' (PL: p=0.006; GD: p=0.011) were decreased in patients showing a protective association. The 'GG/G' of CTLA4 +49AG SNP, HLA-DRB1*11/-DRB1*12 (DR5) alleles and the combinations of DRB1*11/DRB1*12 alleles with AG/GG genotype and DRB1*04/07/12 alleles with GG genotype may act as synergistic manner to confer the strong susceptibility to AITD in south India. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. [Autoimmune channelopathies].

    Science.gov (United States)

    Michaud, M; Delrieu, J; Astudillo, L

    2011-12-01

    Autoimmune channelopathies are rare neuromuscular diseases that have been characterized clinically for several decades but for which the evidence of associated antibodies has only been recently demonstrated. Ion channels have an important role of activation, inhibition and regulation in neuromuscular transmission. Myasthenia gravis, generally associated with the presence of anti-acetylcholine receptor antibody, is the best-known channelopathy. Other anti-channel antibodies, including voltage-dependent, are associated with several neurological diseases, as illustrated by anti-voltage-gated calcium channels found in Lambert-Eaton myasthenic syndrome and paraneoplastic cerebellar ataxia, and anti-voltage-gated potassium channels found in neuromyotonia, Morvan's syndrome and limbic encephalitis. The treatment of autoimmune channelopathies is logically based on corticosteroids, immunosuppressant drugs, intravenous immunoglobulins and plasmapheresis. Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  14. Autoimmun pankreatitis

    DEFF Research Database (Denmark)

    Fjordside, Eva; Novovic, Srdan; Schmidt, Palle Nordblad

    2015-01-01

    Autoimmune pancreatitis (AIP) is a rare inflammatory disease. AIP has characteristic histology, serology and imaging findings. Two types of AIP exist, type 1, which is a part of the systemic immunoglobulin G4-related disease, and type 2, which is only localized to the pancreas. Patients with type...... are predominantly older men, have involvement of other organs and more often experience relapse than patients with type 2. Both types respond well to steroid treatment. The most important differential diagnose is pancreatic cancer....

  15. Epigenetic alterations underlying autoimmune diseases.

    Science.gov (United States)

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-01-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.

  16. AUTOIMMUNE HEPATITIS

    Directory of Open Access Journals (Sweden)

    Yusri Dianne Jurnalis

    2010-05-01

    Full Text Available AbstrakHepatitis autoimun merupakan penyakit inflamasi hati yang berat dengan penyebab pasti yang tidak diketahui yang mengakibatkan morbiditas dan mortalitas yang tinggi. Semua usia dan jenis kelamin dapat dikenai dengan insiden tertinggi pada anak perempuan usia prepubertas, meskipun dapat didiagnosis pada usia 6 bulan. Hepatitis autoimun dapat diklasifikasikan menjadi 2 bagian berdasarkan adanya antibodi spesifik: Smooth Muscle Antibody (SMA dengan anti-actin specificity dan/atau Anti Nuclear Antibody (ANA pada tipe 1 dan Liver-Kidney Microsome antibody (LKM1 dan/atau anti-liver cytosol pada tipe 2. Gambaran histologisnya berupa “interface hepatitis”, dengan infiltrasi sel mononuklear pada saluran portal, berbagai tingkat nekrosis, dan fibrosis yang progresf. Penyakit berjalan secara kronik tetapi keadaan yang berat biasanya menjadi sirosis dan gagal hati.Tipe onset yang paling sering sama dengan hepatitis virus akut dengan gagal hati akut pada beberapa pasien; sekitar sepertiga pasien dengan onset tersembunyi dengan kelemahan dan ikterik progresif ketika 10-15% asimptomatik dan mendadak ditemukan hepatomegali dan/atau peningkatan kadar aminotransferase serum. Adanya predominasi perempuan pada kedua tipe. Pasien LKM1 positif menunjukkan keadaan lebih akut, pada usia yang lebih muda, dan biasanya dengan defisiensi Immunoglobulin A (IgA, dengan durasi gejala sebelum diagnosis, tanda klinis, riwayat penyakit autoimun pada keluarga, adanya kaitan dengan gangguan autoimun, respon pengobatan dan prognosis jangka panjang sama pada kedua tipe.Kortikosteroid yang digunakan secara tunggal atau kombinasi azathioprine merupakan terapi pilihan yang dapat menimbulkan remisi pada lebih dari 90% kasus. Strategi terapi alternatif adalah cyclosporine. Penurunan imunosupresi dikaitkan dengan tingginya relap. Transplantasi hati dianjurkan pada penyakit hati dekom-pensata yang tidak respon dengan pengobatan medis lainnya.Kata kunci : hepatitis Autoimmune

  17. Associated Autoimmune Diseases

    Science.gov (United States)

    ... celiac disease are type 1 diabetes and autoimmune thyroid disease. The tendency to develop autoimmune diseases is believed ... confusion, weight loss, and coma (if left untreated). Thyroid Disease There are two common forms of autoimmune thyroid ...

  18. Autoimmune liver disease panel

    Science.gov (United States)

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cholangitis (formerly called primary biliary cirrhosis). This group of tests ...

  19. Update in Endocrine Autoimmunity

    OpenAIRE

    Anderson, Mark S.

    2008-01-01

    Context: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases.

  20. Association of CTLA-4 gene A/G polymorphism in Japanese type 1 diabetic patients with younger age of onset and autoimmune thyroid disease.

    Science.gov (United States)

    Takara, M; Komiya, I; Kinjo, Y; Tomoyose, T; Yamashiro, S; Akamine, H; Masuda, M; Takasu, N

    2000-07-01

    We studied the association between type 1 diabetes with autoimmune thyroid disease (AITD) and A/G allele polymorphism in exon 1 of the CTLA-4 gene in a Japanese population. We studied 74 Japanese type 1 diabetic patients with or without AITD and 107 normal subjects to identify the association between CTLA-4 polymorphism and type 1 diabetes using polymerase chain reaction-restriction fragment length polymorphism analysis. The frequency of the CTLA-4 G allele differed significantly between the type 1 diabetic patients (61%) and the normal control subjects (48%) (P = 0.016). The difference in the CTLA-4 G allele became greater between patients with a younger age of onset of type 1 diabetes (age at onset frequency of the CTLA-4 G allele did not differ between type 1 diabetic patients with younger and older age of onset (64% vs. 57%). The G allele frequencies in the patients with younger-onset type 1 diabetes and AITD increased more than in the control patients (P = 0.025). These differences reflected a significant increase in the frequency of G/G genotype--that is, 54% in those with younger-onset type 1 diabetes and AITD, 39% in those without AITD, and 28% in control subjects. An association was detected between the CTLA-4 gene polymorphism and younger-onset type 1 diabetes with AITD. The G variant was suggested to be genetically linked to AITD-associated type 1 diabetes of younger onset in this apanese population. The defect in these patients presumably lies in a T-cell-mediated autoimmune mechanism.

  1. [Autoimmune blistering diseases].

    Science.gov (United States)

    Duvert-Lehembre, S; Joly, P

    2014-03-01

    Autoimmune blistering diseases are characterized by the production of pathogenic autoantibodies that are responsible for the formation of epidermal blisters. Major advances in the understanding of the pathogenesis of these disorders have allowed the development of new therapeutic agents. Recent epidemiologic data showed that bullous pemphigoid mainly affects elderly patients. Bullous pemphigoid is often associated with degenerative neurologic disorders. A major increase in the incidence of bullous pemphigoid has been observed in France. Treatment of bullous pemphigoid is mainly based on superpotent topical corticosteroids. The role of desmosomal proteins has been demonstrated in the initiation, propagation and persistence of the autoimmune response in pemphigus. Several studies have shown a correlation between anti-desmoglein antibody titers and disease activity. Pemphigus susceptibility genes have been identified. Oral corticosteroids remain the mainstay of pemphigus treatment. Dramatic and long-lasting improvement has been recently obtained with rituximab in recalcitrant types of pemphigus. Other autoimmune junctional blistering diseases are rare entities, whose prognosis can be severe. Their diagnosis has been improved by the use of new immunological assays and immunoelectronic microscopy. Immunosupressants are widely used in severe types in order to prevent mucosal sequelae. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  2. Celiac disease and endocrine autoimmunity.

    Science.gov (United States)

    Kahaly, George J; Schuppan, Detlef

    2015-01-01

    Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives. © 2015 S. Karger AG, Basel.

  3. Homeodomain-interacting protein kinase 2, a novel autoimmune regulator interaction partner, modulates promiscuous gene expression in medullary thymic epithelial cells.

    Science.gov (United States)

    Rattay, Kristin; Claude, Janine; Rezavandy, Esmail; Matt, Sonja; Hofmann, Thomas G; Kyewski, Bruno; Derbinski, Jens

    2015-02-01

    Promiscuous expression of a plethora of tissue-restricted Ags (TRAs) by medullary thymic epithelial cells (mTECs) plays an essential role in T cell tolerance. Although the cellular mechanisms by which promiscuous gene expression (pGE) imposes T cell tolerance have been well characterized, the underlying molecular mechanisms remain poorly understood. The autoimmune regulator (AIRE) is to date the only validated molecule known to regulate pGE. AIRE is part of higher-order multiprotein complexes, which promote transcription, elongation, and splicing of a wide range of target genes. How AIRE and its partners mediate these various effects at the molecular level is still largely unclear. Using a yeast two-hybrid screen, we searched for novel AIRE-interacting proteins and identified the homeodomain-interacting protein kinase 2 (HIPK2) as a novel partner. HIPK2 partially colocalized with AIRE in nuclear bodies upon cotransfection and in human mTECs in situ. Moreover, HIPK2 phosphorylated AIRE in vitro and suppressed the coactivator activity of AIRE in a kinase-dependent manner. To evaluate the role of Hipk2 in modulating the function of AIRE in vivo, we compared whole-genome gene signatures of purified mTEC subsets from TEC-specific Hipk2 knockout mice with control mice and identified a small set of differentially expressed genes. Unexpectedly, most differentially expressed genes were confined to the CD80(lo) mTEC subset and preferentially included AIRE-independent TRAs. Thus, although it modulates gene expression in mTECs and in addition affects the size of the medullary compartment, TEC-specific HIPK2 deletion only mildly affects AIRE-directed pGE in vivo. Copyright © 2015 by The American Association of Immunologists, Inc.

  4. The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or autoimmune polyglandular syndrome type 1.

    Science.gov (United States)

    Lankisch, Tim O; Jaeckel, Elmar; Strassburg, Christian P

    2009-08-01

    Autoimmune polyglandular syndromes are rare autoimmune endocrinopathies that are associated with nonendocrine autoimmunopathies. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also named autoimmune polyglandular syndrome type 1 (APS-1), is distinguished from autoimmune polyglandular syndrome 2 (APS-2). Major disease components of APECED are adrenal insufficiency, hypoparathyroidism, and candidiasis. The diagnosis is established by the presence of two out of the three components. Minor clinical features include autoimmune hepatitis, which occurs in up to 20% of APECED patients, and ranges from a mild to a fulminant course. The disease mostly affects juvenile patients from Sardegna, Italy, Finland, and Iran (Iranian Jews), but it also occurs in other ethnic groups. The AIRE gene responsible for APECED is expressed in cells involved in induction and maintenance of immune tolerance. Genetic alterations of the single gene are associated with APECED. Because a specific therapy is not currently available, treatment consists of hormone replacement and caring for clinical symptoms. Copyright Thieme Medical Publishers.

  5. HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes.

    Science.gov (United States)

    Parkkola, Anna; Laine, Antti-Pekka; Karhunen, Markku; Härkönen, Taina; Ryhänen, Samppa J; Ilonen, Jorma; Knip, Mikael

    2017-01-01

    Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first- or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.

  6. A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan.

    Science.gov (United States)

    Sato, Kanji; Nakajima, Kishiko; Imamura, Hidehito; Deguchi, Takahisa; Horinouchi, Shuuji; Yamazaki, Kazuko; Yamada, Emiko; Kanaji, Yoshio; Takano, Kazue

    2002-12-01

    Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

  7. STAT4 confers risk for rheumatoid arthritis and systemic lupus erythematosus in Mexican patients.

    Science.gov (United States)

    Beltrán Ramírez, O; Mendoza Rincón, J F; Barbosa Cobos, R E; Alemán Ávila, I; Ramírez Bello, J

    2016-07-01

    STAT4 has been consistently associated with several autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The aim of this study was to determine whether the STAT4 rs7574865G/T polymorphism confers susceptibility for RA and SLE in a sample of Mexican patients. This study included 869 individuals: 415 patients with RA, 128 patients with SLE, and 326 controls. Genotyping using TaqMan probes showed an association between the STAT4 rs7574865G/T polymorphism and RA (GG vs. TT: OR 1.99, p=0.0009; G vs. T: OR 1.42, p=0.0009) and SLE (GG vs. TT: OR 2.98, 0.0003; G vs. T: OR 1.74, p=0.0002). Gender stratification showed an association with RA (GG vs. TT: OR 1.99, 95% CI 1.3-3.1, p=0.002; G vs. T: OR 1.42, 95% CI 1.1-1.8, p=0.002) and SLE (GG vs. TT: OR 3.3, 95% CI 1.7-6.2, p=0.0002; G vs. T: OR 1.8, 95% CI 1.3-2.4, p=0.0002) in women. Thus, the STAT4 rs7574865G/T polymorphism confers risk for RA and SLE in the Mexican population. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  8. Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor in experimental autoimmune encephalomyelitis models of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Sofia Sisay

    Full Text Available Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1 receptor and the orphan G protein receptor fifty-five (GPR55. Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational

  9. A crucial role of the thymus in induction by the lprcg gene of lymphadenopathy with autoimmunity in the mouse.

    Science.gov (United States)

    Matsuzawa, A; Moriyama, T; Ogata, Y; Katagiri, T; Kimura, M

    1992-04-01

    The new mutation at the lpr locus, lprcg, induces massive lymphoproliferation characterized by the selective expansion of CD4-, CD8-, B220+, Thy-1+ cells or double-negative T lymphocytes and production of autoantibodies as does lpr. The thymus is necessary for the induction of anomalous double-negative T lymphocytes and autoimmune symptoms by lpr. To determine whether or not the thymus is also indispensable to expression of the function of lrpcg, lprcg homozygous athymic nude mice (lprcg/lprcg nu/nu; lprcg nudes) were constructed by crossing CBA/KlJms-lprcg/lprcg (CBA-lprcg) and DDD/l-nu/nu mice and observed for lymphoid organ hyperplasia and autoantibody production with or without thymus grafts from various strains of mice including CBA-lprcg. Neither lymphoproliferation nor significantly increased production of autoantibodies was observed in unmanipulated lprcg nudes. In contrast, thymus grafts of both +/+ and lprcg/lprcg genotypes caused lymphoid organ hyperplasia composed of anomalous double-negative T lymphocytes and significantly augmented the production of antibodies against single-stranded DNA (ssDNA). Interestingly, serum Ig and anti-ssDNA antibody levels rose in response to thymus grafts only in IgG but not in IgM classes. These results indicate that the thymus plays a crucial role in the induction of abnormal T-cell differentiation by lprcg and that thymic genotype is irrelevant.

  10. Autoimmune Pancreatitis.

    Science.gov (United States)

    Majumder, Shounak; Takahashi, Naoki; Chari, Suresh T

    2017-07-01

    Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass4-related diseases (IgG4-RD) and typically presents with obstructive jaundice. Idiopathic duct-centric pancreatitis (IDCP) is a closely related but distinct disease that mimics AIP radiologically but manifests clinically most commonly as recurrent acute pancreatitis in young individuals with concurrent inflammatory bowel disease. IgG4 levels are often elevated in AIP and normal in IDCP. Histologically, lymphoplasmacytic acinar inflammation and storiform fibrosis are seen in both. In addition, the histologic hallmark of IDCP is the granulocyte epithelial lesion: intraluminal and intraepithelial neutrophils in medium-sized and small ducts with or without granulocytic acinar inflammation often associated with destruction of ductal architecture. Initial treatment of both AIP and IDCP is with oral corticosteroids for duration of 4 weeks followed by a gradual taper. Relapses are common in AIP and relatively uncommon in IDCP, a relatively rare disease for which the natural history is not well understood. For patients with relapsing AIP, treatment with immunomodulators and more recently rituximab has been recommended. Although rare instances of pancreaticobiliary malignancy has been reported in patients with AIP, overall the lifetime risk of developing pancreatic cancer does not appear to be elevated.

  11. Autoimmunity and Gastric Cancer

    Science.gov (United States)

    Bizzaro, Nicola; Antico, Antonio; Villalta, Danilo

    2018-01-01

    Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastric neoplasms: intestinal type and type I gastric carcinoid. Here, we review the association of autoimmune gastritis with gastric cancer and other autoimmune features present in gastric neoplasms. PMID:29373557

  12. Autoimmunity and Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Nicola Bizzaro

    2018-01-01

    Full Text Available Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastric neoplasms: intestinal type and type I gastric carcinoid. Here, we review the association of autoimmune gastritis with gastric cancer and other autoimmune features present in gastric neoplasms.

  13. Monogenic autoimmune diseases of the endocrine system.

    Science.gov (United States)

    Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

    2016-10-01

    The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases

    DEFF Research Database (Denmark)

    Pouget, Jennie G; Gonçalves, Vanessa F; Spain, Sarah L

    2016-01-01

    in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated...

  15. Coherent Somatic Mutation in Autoimmune Disease

    Science.gov (United States)

    Ross, Kenneth Andrew

    2014-01-01

    Background Many aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation. Results Protein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed. Conclusions The results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases. PMID:24988487

  16. Autoimmunity and Gastric Cancer

    OpenAIRE

    Nicola Bizzaro; Antonio Antico; Danilo Villalta

    2018-01-01

    Alterations in the immune response of patients with autoimmune diseases may predispose to malignancies, and a link between chronic autoimmune gastritis and gastric cancer has been reported in many studies. Intestinal metaplasia with dysplasia of the gastric corpus-fundus mucosa and hyperplasia of chromaffin cells, which are typical features of late-stage autoimmune gastritis, are considered precursor lesions. Autoimmune gastritis has been associated with the development of two types of gastri...

  17. Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Liebman, Howard A; Weitz, Ilene C

    2017-03-01

    Autoimmune hemolytic anemia is an acquired autoimmune disorder resulting in the production of antibodies directed against red blood cell antigens causing shortened erythrocyte survival. The disorders can present as a primary disorder (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immune modulation with corticosteroids and other agents. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. AIRE variations in Addison's disease and autoimmune polyendocrine syndromes (APS)

    DEFF Research Database (Denmark)

    Bøe Wolff, A S; Oftedal, B; Johansson, S

    2008-01-01

    Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms...

  19. Comparative effects of n-3, n-6 and n-9 unsaturated fatty acid-rich diet consumption on lupus nephritis, autoantibody production and CD4+ T cell-related gene responses in the autoimmune NZBWF1 mouse.

    Directory of Open Access Journals (Sweden)

    James J Pestka

    Full Text Available Mortality from systemic lupus erythematosus (SLE, a prototypical autoimmune disease, correlates with the onset and severity of kidney glomerulonephritis. There are both preclinical and clinical evidence that SLE patients may benefit from consumption of n-3 polyunsaturated fatty acids (PUFA found in fish oil, but the mechanisms remain unclear. Here we employed the NZBWF1 SLE mouse model to compare the effects of dietary lipids on the onset and severity of autoimmune glomerulonephritis after consuming: 1 n-3 PUFA-rich diet containing docosahexaenoic acid-enriched fish oil (DFO, 2 n-6 PUFA-rich Western-type diet containing corn oil (CRN or 3 n-9 monounsaturated fatty acid (MUFA-rich Mediterranean-type diet containing high oleic safflower oil (HOS. Elevated plasma autoantibodies, proteinuria and glomerulonephritis were evident in mice fed either the n-6 PUFA or n-9 MUFA diets, however, all three endpoints were markedly attenuated in mice that consumed the n-3 PUFA diet until 34 wk of age. A focused PCR array was used to relate these findings to the expression of 84 genes associated with CD4+ T cell function in the spleen and kidney both prior to and after the onset of the autoimmune nephritis. n-3 PUFA suppression of autoimmunity in NZBWF1 mice was found to co-occur with a generalized downregulation of CD4+ T cell-related genes in kidney and/or spleen at wk 34. These genes were associated with the inflammatory response, antigen presentation, T cell activation, B cell activation/differentiation and leukocyte recruitment. Quantitative RT-PCR of representative affected genes confirmed that n-3 PUFA consumption was associated with reduced expression of CD80, CTLA-4, IL-10, IL-18, CCL-5, CXCR3, IL-6, TNF-α and osteopontin mRNAs in kidney and/or spleens as compared to mice fed n-6 PUFA or n-9 MUFA diets. Remarkably, many of the genes identified in this study are currently under consideration as biomarkers and/or biotherapeutic targets for SLE and other

  20. Polyglandular autoimmune syndrome type I.

    Science.gov (United States)

    Proust-Lemoine, Emmanuelle; Saugier-Veber, Pascale; Wémeau, Jean-Louis

    2012-12-01

    Polyglandular Autoimmune Syndrom type 1 (PAS-1) or Autoimmune PolyEndocrinopathy Candidiasis-Ectodermal-Dystrophy (APECED) is a rare recessive autosomal disease related to Autoimmune Regulator (AIRE) gene mutations. AIRE is mainly implicated in central and peripheric immune tolerance. Diagnosis was classically based on presence of at least two out of three "majors" criterions of Whitaker's triad (candidiasis, autoimmune hypoparathyroidism and adrenal insufficiency). Presence of one criterion was sufficient when a sibling was previously diagnosed. However, some atypic or poorly symptomatic variants do not correspond to these criterions. As a matter of fact, digestive (malabsorption, pernicious anemia, hepatitis), cutaneous (alopecia, vitiligo, enamel dysplasia) or ophtalmological (keratitis) components could prevail. In these cases, diagnosis could be made by molecular genetics. Prognosis is influenced by genetic (AIRE mutations, HLA), hormonal and environmental (infections) factors. Potentially letal components (hepatitis and severe malabsorption) could be treated by immunosuppressors. Candidiasis and other infections should be carefully screened and treated before beginning those therapies, in order to avoid severe systemic infections. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  1. Leaky gut and autoimmune diseases.

    Science.gov (United States)

    Fasano, Alessio

    2012-02-01

    Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.

  2. Human Tregs Made Antigen Specific by Gene Modification: The Power to Treat Autoimmunity and Antidrug Antibodies with Precision

    Directory of Open Access Journals (Sweden)

    Patrick R. Adair

    2017-09-01

    Full Text Available Human regulatory CD4+ T cells (Tregs are potent immunosuppressive lymphocytes responsible for immune tolerance and homeostasis. Since the seminal reports identifying Tregs, vast research has been channeled into understanding their genesis, signature molecular markers, mechanisms of suppression, and role in disease. This research has opened the doors for Tregs as a potential therapeutic for diseases and disorders such as multiple sclerosis, type I diabetes, transplantation, and immune responses to protein therapeutics, like factor VIII. Seminal clinical trials have used polyclonal Tregs, but the frequency of antigen-specific Tregs among polyclonal populations is low, and polyclonal Tregs may risk non-specific immunosuppression. Antigen-specific Treg therapy, which uses genetically modified Tregs expressing receptors specific for target antigens, greatly mitigates this risk. Building on the principles of T-cell receptor cloning, chimeric antigen receptors (CARs, and a novel CAR derivative, called B-cell antibody receptors, our lab has developed different types of antigen-specific Tregs. This review discusses the current research and optimization of gene-modified antigen-specific human Tregs in our lab in several disease models. The preparations and considerations for clinical use of such Tregs also are discussed.

  3. Sirolimus for Autoimmune Disease of Blood Cells

    Science.gov (United States)

    2017-11-02

    Autoimmune Pancytopenia; Autoimmune Lymphoproliferative Syndrome (ALPS); Evans Syndrome; Idiopathic Thrombocytopenic Purpura; Anemia, Hemolytic, Autoimmune; Autoimmune Neutropenia; Lupus Erythematosus, Systemic; Inflammatory Bowel Disease; Rheumatoid Arthritis

  4. Galectin-3 in autoimmunity and autoimmune diseases.

    Science.gov (United States)

    de Oliveira, Felipe L; Gatto, Mariele; Bassi, Nicola; Luisetto, Roberto; Ghirardello, Anna; Punzi, Leonardo; Doria, Andrea

    2015-08-01

    Galectin-3 (gal-3) is a β-galactoside-binding lectin, which regulates cell-cell and extracellular interactions during self/non-self-antigen recognition and cellular activation, proliferation, differentiation, migration and apoptosis. It plays a significant role in cellular and tissue pathophysiology by organizing niches that drive inflammation and immune responses. Gal-3 has some therapeutic potential in several diseases, including chronic inflammatory disorders, cancer and autoimmune diseases. Gal-3 exerts a broad spectrum of functions which differs according to its intra- or extracellular localization. Recombinant gal-3 strategy has been used to identify potential mode of action of gal-3; however, exogenous gal-3 may not reproduce the functions of the endogenous gal-3. Notably, gal-3 induces monocyte-macrophage differentiation, interferes with dendritic cell fate decision, regulates apoptosis on T lymphocytes and inhibits B-lymphocyte differentiation into immunoglobulin secreting plasma cells. Considering the influence of these cell populations in the pathogenesis of several autoimmune diseases, gal-3 seems to play a role in development of autoimmunity. Gal-3 has been suggested as a potential therapeutic agent in patients affected with some autoimmune disorders. However, the precise role of gal-3 in driving the inflammatory process in autoimmune or immune-mediated disorders remains elusive. Here, we reviewed the involvement of gal-3 in cellular and tissue events during autoimmune and immune-mediated inflammatory diseases. © 2015 by the Society for Experimental Biology and Medicine.

  5. Candidate SNP Markers of Gender-Biased Autoimmune Complications of Monogenic Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

    Science.gov (United States)

    Ponomarenko, Mikhail P.; Arkova, Olga; Rasskazov, Dmitry; Ponomarenko, Petr; Savinkova, Ludmila; Kolchanov, Nikolay

    2016-01-01

    Some variations of human genome [for example, single nucleotide polymorphisms (SNPs)] are markers of hereditary diseases and drug responses. Analysis of them can help to improve treatment. Computer-based analysis of millions of SNPs in the 1000 Genomes project makes a search for SNP markers more targeted. Here, we combined two computer-based approaches: DNA sequence analysis and keyword search in databases. In the binding sites for TATA-binding protein (TBP) in human gene promoters, we found candidate SNP markers of gender-biased autoimmune diseases, including rs1143627 [cachexia in rheumatoid arthritis (double prevalence among women)]; rs11557611 [demyelinating diseases (thrice more prevalent among young white women than among non-white individuals)]; rs17231520 and rs569033466 [both: atherosclerosis comorbid with related diseases (double prevalence among women)]; rs563763767 [Hughes syndrome-related thrombosis (lethal during pregnancy)]; rs2814778 [autoimmune diseases (excluding multiple sclerosis and rheumatoid arthritis) underlying hypergammaglobulinemia in women]; rs72661131 and rs562962093 (both: preterm delivery in pregnant diabetic women); and rs35518301, rs34166473, rs34500389, rs33981098, rs33980857, rs397509430, rs34598529, rs33931746, rs281864525, and rs63750953 (all: autoimmune diseases underlying hypergammaglobulinemia in women). Validation of these predicted candidate SNP markers using the clinical standards may advance personalized medicine. PMID:27092142

  6. [Thymoma and autoimmune diseases].

    Science.gov (United States)

    Jamilloux, Y; Frih, H; Bernard, C; Broussolle, C; Petiot, P; Girard, N; Sève, P

    2018-01-01

    The association between thymoma and autoimmunity is well known. Besides myasthenia gravis, which is found in 15 to 20% of patients with thymoma, other autoimmune diseases have been reported: erythroblastopenia, systemic lupus erythematosus, inflammatory myopathies, thyroid disorders, Isaac's syndrome or Good's syndrome. More anecdotally, Morvan's syndrome, limbic encephalitis, other autoimmune cytopenias, autoimmune hepatitis, and bullous skin diseases (pemphigus, lichen) have been reported. Autoimmune diseases occur most often before thymectomy, but they can be discovered at the time of surgery or later. Two situations require the systematic investigation of a thymoma: the occurrence of myasthenia gravis or autoimmune erythroblastopenia. Nevertheless, the late onset of systemic lupus erythematosus or the association of several autoimmune manifestations should lead to look for a thymoma. Neither the characteristics of the patients nor the pathological data can predict the occurrence of an autoimmune disease after thymectomy. Thus, thymectomy usefulness in the course of the autoimmune disease, except myasthenia gravis, has not been demonstrated. This seems to indicate the preponderant role of self-reactive T lymphocytes distributed in the peripheral immune system prior to surgery. Given the high infectious morbidity in patients with thymoma, immunoglobulin replacement therapy should be considered in patients with hypogammaglobulinemia who receive immunosuppressive therapy, even in the absence of prior infection. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  7. Bistability in autoimmune diseases

    DEFF Research Database (Denmark)

    Rapin, Nicolas; Mosekilde, Erik; Lund, Ole

    2011-01-01

    Autoimmune diseases damage host tissue, which, in turn, may trigger a stronger immune response. Systems characterized by such positive feedback loops can display co-existing stable steady states. In a mathematical model of autoimmune disease, one steady state may correspond to the healthy state...... and another to an autoimmune steady state characterized by widespread tissue damage and immune activation. We show how a triggering event may move the system from the healthy to the autoimmune state and how transient immunosuppressive treatment can move the system back to the healthy state....

  8. Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand.

    Science.gov (United States)

    Aberdein, D; Munday, J S; Dittmer, K E; Heathcott, R W; Lyons, L A

    2017-11-01

    AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as

  9. American Autoimmune Related Diseases Association

    Science.gov (United States)

    ... List Common Thread Women & Autoimmunity Diagnosis Tips Coping Tools Support Groups Education Modules Caregivers Patient/Caregiver Relationship The Male Caregiver AD Knowledge Base Autoimmune Disease List Common ...

  10. THE AUTOIMMUNE ECOLOGY.

    Directory of Open Access Journals (Sweden)

    Juan-Manuel eAnaya

    2016-04-01

    Full Text Available Autoimmune diseases (ADs represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology, which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation. As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology. In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics to favor or protect against autoimmunity and its outcomes. Herein we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status, gender and sex hormones, vitamin D, organic solvents and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.

  11. Regulatory T-cells and autoimmunity.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

  12. Autoimmunity and primary immunodeficiency: two sides of the same coin?

    Science.gov (United States)

    Schmidt, Reinhold E; Grimbacher, Bodo; Witte, Torsten

    2017-12-19

    Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.

  13. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED.

    Science.gov (United States)

    Moraes-Vasconcelos, D; Costa-Carvalho, B T; Torgerson, T R; Ochs, H D

    2008-05-01

    Several primary immune deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of immune dysregulation. The concept of immune dysregulation as a direct cause of autoimmunity in primary immune deficiency disorders (PIDDs) has been strengthened by the recent discovery of distinct clinical entities linked to single-gene defects resulting in multiple autoimmune phenomena including immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, and autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome. Reviewing recent advances in our understanding of the small subgroup of PIDD patients with defined causes for autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.

  14. Autoimmune polyendocrine syndrome and thrombocytosis.

    Science.gov (United States)

    Atquet, V; Lienart, F; Vaes, M

    2015-12-01

    We describe a woman aged 37  years, affected with Hashimoto's thyroiditis, detected since the age of 17, with gonadic insufficiency with anti-ovarian antibodies since the age of 22  years and Addison's disease since 24  years old. At that moment, the diagnosis of autoimmune polyendocrine syndrome (APS) was made. Concomitant to this diagnosis, thrombocytosis was detected and aetiological assessment revealed an atrophy of the spleen. Differential diagnoses of APS and hyposplenism will be discussed. We will look at a possible association between these two pathologies. Indeed, asplenism is found in approximately 20% of adults affected by type 1 APS, also called auto-immune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome. The most likely aetiology for this atrophy of the spleen is a destruction of auto-immunological origin. However, in our patient, the search for a mutation of the autoimmune regulator (AIRE) gene proved negative. This mutation is commonly, but not systematically, present in type 1 APS. A type 2 APS should then be considered.

  15. MicroRNAs in autoimmune rheumatic diseases

    Directory of Open Access Journals (Sweden)

    G.D. Sebastiani

    2012-03-01

    Full Text Available The etiology of autoimmune diseases remains largely unknown. In recent years, besides genetic factors, several studies proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically epigenetic regulatory mechanisms comprise DNA methylation, a variety of histone modifications, and microRNA (miRNA activity, all of which act upon gene and protein expression levels. In particular it is well known that epigenetic mechanisms are important for controlling the pattern of gene expression during development, the cell cycle, and the response to biological or environmental changes. In the present review a description of the most frequent epigenetic deregulations, in particular the role of miRNA, in rheumatic autoimmune disorders will be analyzed.

  16. Celiac disease and autoimmune thyroid disease.

    Science.gov (United States)

    Ch'ng, Chin Lye; Jones, M Keston; Kingham, Jeremy G C

    2007-10-01

    Celiac disease (CD) or gluten sensitive enteropathy is relatively common in western populations with prevalence around 1%. With the recent availability of sensitive and specific serological testing, many patients who are either asymptomatic or have subtle symptoms can be shown to have CD. Patients with CD have modest increases in risks of malignancy and mortality compared to controls. The mortality among CD patients who comply poorly with a gluten-free diet is greater than in compliant patients. The pattern of presentation of CD has altered over the past three decades. Many cases are now detected in adulthood during investigation of problems as diverse as anemia, osteoporosis, autoimmune disorders, unexplained neurological syndromes, infertility and chronic hypertransaminasemia of uncertain cause. Among autoimmune disorders, increased prevalence of CD has been found in patients with autoimmune thyroid disease, type 1 diabetes mellitus, autoimmune liver diseases and inflammatory bowel disease. Prevalence of CD was noted to be 1% to 19% in patients with type 1 diabetes mellitus, 2% to 5% in autoimmune thyroid disorders and 3% to 7% in primary biliary cirrhosis in prospective studies. Conversely, there is also an increased prevalence of immune based disorders among patients with CD. The pathogenesis of co-existent autoimmune thyroid disease and CD is not known, but these conditions share similar HLA haplotypes and are associated with the gene encoding cytotoxic T-lymphocyte-associated antigen-4. Screening high risk patients for CD, such as those with autoimmune diseases, is a reasonable strategy given the increased prevalence. Treatment of CD with a gluten-free diet should reduce the recognized complications of this disease and provide benefits in both general health and perhaps life expectancy. It also improves glycemic control in patients with type 1 diabetes mellitus and enhances the absorption of medications for associated hypothyroidism and osteoporosis. It

  17. Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient

    Science.gov (United States)

    Huibregtse, Kelly Egan; Wolfgram, Peter; Winer, Karen K.; Connor, Ellen L.

    2015-01-01

    Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported. PMID:24945421

  18. Polyglandular autoimmune syndrome type I - a novel AIRE mutation in a North American patient.

    Science.gov (United States)

    Huibregtse, Kelly Egan; Wolfgram, Peter; Winer, Karen K; Connor, Ellen L

    2014-11-01

    Autoimmune polyglandular syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autoimmune disease that results from autosomal recessive mutations of the human autoimmune regulatory (AIRE) gene. We present the case of a 17-year-old North American girl of primarily Norwegian descent with a novel AIRE gene mutation causing APS-1. In addition to the classic triad of chronic candidiasis, hypoparathyoidism and autoimmune adrenocortical insufficiency, she also has vitiligo, intestinal malabsorption, autoimmune hepatitis, autoimmune hypothyroidism, myositis, myalgias, chronic fatigue, and failure to thrive. Genetic testing revealed heterozygosity for c.20_115de196 and c.967_979del13 mutations in the AIRE gene. The AIRE gene c.20_115de196 mutation has not been previously reported.

  19. Doenças reumatológicas autoimunes e sua associação com os genes killer immunoglobulin-like receptors Autoimmune rheumatic diseases and their association with killer immunoglobulin-like receptor genes

    Directory of Open Access Journals (Sweden)

    Patricia Hartstein Salim

    2011-08-01

    Full Text Available Os genes Killer Immunoglobulin-like Receptors (KIR expressam-se como receptores que estimulam ou inibem as células Natural Killer (NK. As células NK fazem parte da imunidade inata e através de seus receptores KIR identificam células-alvo que apresentam moléculas HLA (Human Leukocyte Antigen modificadas ou diferentes, induzindo à sua lise. Os receptores KIR são resultados da expressão dos genes KIR (19q13.14 na membrana celular das células NK, os quais são polimórficos e formam haplótipos. A diversidade de frequência dos haplótipos KIR em certas populações sugere que alguns indivíduos apresentam diferentes níveis de proteção contra algumas doenças e o balanço entre inibição e ativação celular mediada pelos receptores KIR e seus ligantes faz com que a célula NK possa auxiliar o organismo na vigilância imunológica. Além disso, há várias evidências da existência de associação de genótipos KIR ativadores com risco aumentado de doença autoimuneKiller Immunoglobulin-like Receptor (KIR genes express as receptors that activate or inhibit Natural Killer (NK cells. The NK cells are part of the innate immune response and, through their KIR receptors, they identify target cells that have modified or different HLA (Human Leukocyte Antigen molecules, inducing their lysis. The KIR receptors result from the expression of KIR genes (19q13.14 on the cell membrane of NK cells, which are polymorphic, and form haplotypes. The diversity of the frequency of KIR haplotypes in certain populations suggests that some individuals have different levels of protection against some diseases. The balance between cell inhibition and activation enables the NK cell to help the organism in immunological surveillance. In addition, there is evidence of the association of activating KIR genotypes with an increased risk for autoimmune disease

  20. Psoriasis and autoimmunity.

    Science.gov (United States)

    Sticherling, Michael

    2016-12-01

    Psoriasis is one of the most common chronic inflammatory human skin diseases. Though clinically well characterized, the exact etiological and pathogenic mechanisms are still not known in detail. Current knowledge indicates distinct overlap to other inflammatory as well as autoimmune disorders. However, the one or more relevant autoantigens could not be characterized so-far. On the other side, several autoimmune diseases were shown to be associated with psoriasis. In addition, serological autoimmune phenomena, namely diverse circulating specific autoantibodies could be demonstrated in the past. A matter of current debate is if psoriasis is a primary autoimmune disease or secondarily evolving into autoimmunity as seen in other chronic inflammatory diseases. Related to this aspect is the concept of autoinflammation versus autoimmunity where psoriasis shares mechanisms of both entities. Though T-cells remain among the most important cellular players in the pathogenesis of psoriasis and current therapeutic strategies successfully target these cells or their products irrespective of these concepts, autoimmunity if relevant will add to the treatment armamentarium by using protective and prophylactic antigen-specific modalities. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. The Rat Diabetes Susceptibility Locus Iddm4 And At Least One Additional Gene Are Required For Autoimmune Diabetes Induced By Viral Infection

    OpenAIRE

    Blankenhorn, Elizabeth P.; Rodemich, Lucy; Martin-Fernandez, Cristina; Leif, Jean; Greiner, Dale L.; Mordes, John P.

    2005-01-01

    BBDR rats develop autoimmune diabetes mellitus only after challenge with environmental perturbants. These include polyinosinic:polycytidylic acid (poly I:C, a ligand of toll-like receptor 3), agents that deplete regulatory T cell populations (Tregs), and a non-beta-cell-cytopathic parvovirus (Kilham rat virus, KRV). The dominant diabetes susceptibility locus Iddm4 is required for diabetes induced by treatment with poly I:C plus Treg depletion. Iddm4 is penetrant in congenic heterozygote rats ...

  2. The environment and autoimmune thyroid diseases

    NARCIS (Netherlands)

    Prummel, Mark F.; Strieder, Thea; Wiersinga, Wilmar M.

    2004-01-01

    Genetic factors play an important role in the pathogenesis of autoimmune thyroid disease (AITD) and it has been calculated that 80% of the susceptibility to develop Graves' disease is attributable to genes. The concordance rate for AITD among monozygotic twins is, however, well below I and

  3. Stress proteins, autoimmunity, and autoimmune disease.

    Science.gov (United States)

    Winfield, J B; Jarjour, W N

    1991-01-01

    At birth, the immune system is biased toward recognition of microbial antigens in order to protect the host from infection. Recent data suggest that an important initial line of defense in this regard involves autologous stress proteins, especially conserved peptides of hsp60, which are presented to T cells bearing gamma delta receptors by relatively nonpolymorphic class lb molecules. Natural antibodies may represent a parallel B cell mechanism. Through an evolving process of "physiological" autoreactivity and selection by immunodominant stress proteins common to all prokaryotes, B and T cell repertoires expand during life to meet the continuing challenge of infection. Because stress proteins of bacteria are homologous with stress proteins of the host, there exists in genetically susceptible individuals a constant risk of autoimmune disease due to failure of mechanisms for self-nonself discrimination. That stress proteins actually play a role in autoimmune processes is supported by a growing body of evidence which, collectively, suggests that autoreactivity in chronic inflammatory arthritis involves, at least initially, gamma delta cells which recognize epitopes of the stress protein hsp60. Alternate mechanisms for T cell stimulation by stress proteins undoubtedly also exist, e.g., molecular mimicry of the DR beta third hypervariable region susceptibility locus for rheumatoid arthritis by a DnaJ stress protein epitope in gram-negative bacteria. While there still is confusion with respect to the most relevant stress protein epitopes, a central role for stress proteins in the etiology of arthritis appears likely. Furthermore, insight derived from the work thus far in adjuvant-induced arthritis already is stimulating analyses of related phenomena in autoimmune diseases other than those involving joints. Only limited data are available in the area of humoral autoimmunity to stress proteins. Autoantibodies to a number of stress proteins have been identified in SLE and

  4. Vaccines, adjuvants and autoimmunity.

    Science.gov (United States)

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Type 1 diabetes and polyglandular autoimmune syndrome: A review

    Science.gov (United States)

    Hansen, Martin P; Matheis, Nina; Kahaly, George J

    2015-01-01

    Type 1 diabetes (T1D) is an autoimmune disorder caused by inflammatory destruction of the pancreatic tissue. The etiopathogenesis and characteristics of the pathologic process of pancreatic destruction are well described. In addition, the putative susceptibility genes for T1D as a monoglandular disease and the relation to polyglandular autoimmune syndrome (PAS) have also been well explored. The incidence of T1D has steadily increased in most parts of the world, especially in industrialized nations. T1D is frequently associated with autoimmune endocrine and non-endocrine diseases and patients with T1D are at a higher risk for developing several glandular autoimmune diseases. Familial clustering is observed, which suggests that there is a genetic predisposition. Various hypotheses pertaining to viral- and bacterial-induced pancreatic autoimmunity have been proposed, however a definitive delineation of the autoimmune pathomechanism is still lacking. In patients with PAS, pancreatic and endocrine autoantigens either colocalize on one antigen-presenting cell or are expressed on two/various target cells sharing a common amino acid, which facilitates binding to and activation of T cells. The most prevalent PAS phenotype is the adult type 3 variant or PAS type III, which encompasses T1D and autoimmune thyroid disease. This review discusses the findings of recent studies showing noticeable differences in the genetic background and clinical phenotype of T1D either as an isolated autoimmune endocrinopathy or within the scope of polyglandular autoimmune syndrome. PMID:25685279

  6. Eosinophils in Autoimmune Diseases.

    Science.gov (United States)

    Diny, Nicola L; Rose, Noel R; Čiháková, Daniela

    2017-01-01

    Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

  7. Prolactin and Autoimmunity

    Directory of Open Access Journals (Sweden)

    Vânia Vieira Borba

    2018-02-01

    Full Text Available The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.

  8. Eosinophils in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Daniela Čiháková

    2017-04-01

    Full Text Available Eosinophils are multifunctional granulocytes that contribute to initiation and modulation of inflammation. Their role in asthma and parasitic infections has long been recognized. Growing evidence now reveals a role for eosinophils in autoimmune diseases. In this review, we summarize the function of eosinophils in inflammatory bowel diseases, neuromyelitis optica, bullous pemphigoid, autoimmune myocarditis, primary biliary cirrhosis, eosinophilic granulomatosis with polyangiitis, and other autoimmune diseases. Clinical studies, eosinophil-targeted therapies, and experimental models have contributed to our understanding of the regulation and function of eosinophils in these diseases. By examining the role of eosinophils in autoimmune diseases of different organs, we can identify common pathogenic mechanisms. These include degranulation of cytotoxic granule proteins, induction of antibody-dependent cell-mediated cytotoxicity, release of proteases degrading extracellular matrix, immune modulation through cytokines, antigen presentation, and prothrombotic functions. The association of eosinophilic diseases with autoimmune diseases is also examined, showing a possible increase in autoimmune diseases in patients with eosinophilic esophagitis, hypereosinophilic syndrome, and non-allergic asthma. Finally, we summarize key future research needs.

  9. Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis.

    OpenAIRE

    Yao, D L; Liu, X; Hudson, L D; Webster, H D

    1995-01-01

    To compare effects of insulin-like growth factor I (IGF-I) and placebo treatment on lesions that resemble those seen during active demyelination in multiple sclerosis, we induced experimental autoimmune encephalomyelitis in Lewis rats with an emulsion containing guinea pig spinal cord and Freund's adjuvant. On day 12-13, pairs of rats with the same degree of weakness were given either IGF-I or placebo intravenously twice daily for 8 days. After 8 days of placebo or IGF-I (200 micrograms/day o...

  10. Autoimmune gastritis: Pathologist's viewpoint.

    Science.gov (United States)

    Coati, Irene; Fassan, Matteo; Farinati, Fabio; Graham, David Y; Genta, Robert M; Rugge, Massimo

    2015-11-14

    Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling.

  11. Nutrition, geoepidemiology, and autoimmunity.

    Science.gov (United States)

    Selmi, Carlo; Tsuneyama, Koichi

    2010-03-01

    As well represented by the impaired immune function of malnourished individuals encountered in developing countries and the incidence of specific diseases following local nutrient deficiencies, nutrition and immunity have been linked to each other for centuries while the specific connection between dietary factors and autoimmunity onset or modulation is a more recent acquisition. Autoimmune diseases manifest limited prevalence rates in developing countries while numerous immunity-related claims have been proposed in the field of functional foods. Nevertheless, over the past years multiple lines of evidence have supported a major role for specific dietary factors (including vitamin D, vitamin A, selenium, zinc, omega-3 fatty acids, probiotics, and flavanols) in determining the immune responses involved in infections, allergies, and autoimmune diseases. Interestingly, the link between nutrition and autoimmunity may well contribute to the geoepidemiology observed for numerous conditions. In general terms, most data that will be discussed herein were obtained in experimental or animal models while human data from real-life clinical settings or randomized clinical trials remain largely unsatisfactory. Our current knowledge on the beneficial impact of nutrition on autoimmunity prompts us to encourage the search for evidence-based nutrition to support the everyday diet choices of patients. 2009 Elsevier B.V. All rights reserved.

  12. [Autoimmune thyroid disease and other non-endocrine autoimmune diseases].

    Science.gov (United States)

    Dilas, Ljiljana Todorović; Icin, Tijana; Paro, Jovanka Novaković; Bajkin, Ivana

    2011-01-01

    Autoimmune diseases are chronic conditions initiated by the loss of immunological tolerance to self-antigens. They constitute heterogeneous group of disorders, in which multiple alterations in the immune system result in a spectrum of syndromes that either target specific organs or affect the body systematically. Recent epidemiological studies have shown a possible shift of one autoimmune disease to another or the fact that more than one autoimmune disease may coexist in a single patient or in the same family. Numerous autoimmune diseases have been shown to coexist frequently with thyroid autoimmune diseases. AUTOIMMNUNE THYROID DISEASE AND OTHER ORGAN SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: This part of the study reviews the prevalence of autoimmune thyroid disease coexisting with: pernicious anaemia, vitiligo, celiac disease, autoimmune liver disease, miastenia gravis, alopecia areata and sclerosis multiplex, and several recommendations for screening have been given. AUTOIMMUNE THYROID DISEASE AND OTHER ORGAN NON-SPECIFIC NON-ENDOCRINE AUTOIMMUNE DISEASES: Special attention is given to the correlation between autoimmune thyroid disease and rheumatoid arthritis, systemic lupus erythematosus, syndrome Sjögren, systemic sclerosis and mixed connective tissue disease. Screening for autoimmune thyroid diseases should be recommended in everyday clinical practice, in patients with primary organ-specific or organ non-specific autoimmune disease. Otherwise, in patients with primary thyroid autoimmune disease, there is no good reason of seeking for all other autoimmune diseases, although these patients have a greater risk of developing other autoimmune disease. Economic aspects of medicine require further analyzing of these data, from cost/benefit point of view to justified either mandatory screening or medical practitioner judgment.

  13. Headache in autoimmune diseases.

    Science.gov (United States)

    John, Seby; Hajj-Ali, Rula A

    2014-03-01

    Autoimmune diseases are a group of heterogeneous inflammatory disorders characterized by systemic or localized inflammation, leading to ischemia and tissue destruction. These include disorders like systemic lupus erythematosus and related diseases, systemic vasculitides, and central nervous system (CNS) vasculitis (primary or secondary). Headache is a very common manifestation of CNS involvement of these diseases. Although headache characteristics can be unspecific and often non-diagnostic, it is important to recognize because headache can be the first manifestation of CNS involvement. Prompt recognition and treatment is necessary not only to treat the headache, but also to help prevent serious neurological sequelae that frequently accompany autoimmune diseases. In this review, we discuss headache associated with autoimmune diseases along with important mimics. © 2014 American Headache Society.

  14. Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases.

    Science.gov (United States)

    Oftedal, Bergithe E; Hellesen, Alexander; Erichsen, Martina M; Bratland, Eirik; Vardi, Ayelet; Perheentupa, Jaakko; Kemp, E Helen; Fiskerstrand, Torunn; Viken, Marte K; Weetman, Anthony P; Fleishman, Sarel J; Banka, Siddharth; Newman, William G; Sewell, W A C; Sozaeva, Leila S; Zayats, Tetyana; Haugarvoll, Kristoffer; Orlova, Elizaveta M; Haavik, Jan; Johansson, Stefan; Knappskog, Per M; Løvås, Kristian; Wolff, Anette S B; Abramson, Jakub; Husebye, Eystein S

    2015-06-16

    The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity.

    OpenAIRE

    Fu, Y; Nathan, D M; Li, F; Li, X; Faustman, D L

    1993-01-01

    Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patient...

  16. Disruption of the β2-integrin CD11d (αDβ2) gene fails to protect against experimental autoimmune encephalomyelitis

    Science.gov (United States)

    Adams, Jillian E.; Webb, Matthew S.; Hu, Jane; Staunton, Don; Barnum, Scott R.

    2009-01-01

    The fourth member of the β2-integrin family of adhesion molecules, CD11d (αDβ2), is expressed on a wide variety of immune cells, however its function in autoimmune diseases, including EAE remains unknown. We induced EAE in wild type and CD11d-/- C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG35-55) peptide. The clinical course and histopathology of EAE was identical in both groups of mice throughout the disease course. There were no significant differences in the infiltration of leukocyte subsets into the central nervous system or in the production of cytokines from T cells isolated from the spleen or spinal cord from both groups of mice. Our data demonstrate that CD11d is not required for the development of EAE and, to date, is the only β2-integrin molecule whose deletion does not result in attenuated disease. PMID:17254640

  17. Bell's palsy and autoimmunity.

    Science.gov (United States)

    Greco, A; Gallo, A; Fusconi, M; Marinelli, C; Macri, G F; de Vincentiis, M

    2012-12-01

    To review our current knowledge of the etiopathogenesis of Bell's palsy, including viral infection or autoimmunity, and to discuss disease pathogenesis with respect to pharmacotherapy. Relevant publications on the etiopathogenesis, clinical presentation, diagnosis and histopathology of Bell's palsy from 1975 to 2012 were analysed. Bell's palsy is an idiopathic peripheral nerve palsy involving the facial nerve. It accounts for 60 to 75% of all cases of unilateral facial paralysis. The annual incidence of Bell's palsy is 15 to 30 per 100,000 people. The peak incidence occurs between the second and fourth decades (15 to 45 years). The aetiology of Bell's palsy is unknown but viral infection or autoimmune disease has been postulated as possible pathomechanisms. Bell's palsy may be caused when latent herpes viruses (herpes simplex, herpes zoster) are reactivated from cranial nerve ganglia. A cell-mediated autoimmune mechanism against a myelin basic protein has been suggested for the pathogenesis of Bell's palsy. Bell's palsy may be an autoimmune demyelinating cranial neuritis, and in most cases, it is a mononeuritic variant of Guillain-Barré syndrome, a neurologic disorder with recognised cell-mediated immunity against peripheral nerve myelin antigens. In Bell's palsy and GBS, a viral infection or the reactivation of a latent virus may provoke an autoimmune reaction against peripheral nerve myelin components, leading to the demyelination of cranial nerves, especially the facial nerve. Given the safety profile of acyclovir, valacyclovir, and short-course oral corticosteroids, patients who present within three days of the onset of symptoms should be offered combination therapy. However it seems logical that in fact, steroids exert their beneficial effect via immunosuppressive action, as is the case in some other autoimmune disorders. It is to be hoped that (monoclonal) antibodies and/or T-cell immunotherapy might provide more specific treatment guidelines in the

  18. Non-HLA gene polymorphisms in juvenile idiopathic arthritis

    DEFF Research Database (Denmark)

    Alberdi-Saugstrup, M.; Enevold, C.; Zak, M.

    2017-01-01

    were disease remission, actively inflamed joints and joints with limitation of motion (LOM), articular or extra-articular damage, and history of uveitis. Results: Evidence of associations between genotypes and endpoints were found for STAT4, ADAD1-IL2-IL21, PTPN2, and VTCN1 (p = 0.003–0.05). STAT4_rs......7574865 TT was associated with the presence of actively inflamed joints [odds ratio (OR) 20.6, 95% confidence interval (CI) 2.2–> 100, p = 0.003] and extra-articular damage (OR 7.9, 95% CI 1–56.6, p = 0.057). ADAD1_rs17388568 AA was associated with a lower risk of having joints with LOM (OR 0.1, 95% CI 0...

  19. Triggers and drivers of autoimmunity: lessons from coeliac disease

    Science.gov (United States)

    Sollid, Ludvig M.; Jabri, Bana

    2013-01-01

    Preface Coeliac disease, an inflammatory disease of the small intestine, shares key features with autoimmune disorders, such as susceptibility genes, presence of autoantibodies and T cell-mediated destruction of specific cells. Strikingly, however, continuous exposure to the exogenous dietary antigen gluten and gluten-specific adaptive immunity are required to maintain immunopathology. These observations challenge the notion that autoimmunity requires adaptive immune activation towards self-antigens. Using coeliac disease as an example, we propose that other exogenous factors might be identified as drivers of autoimmune processes, in particular when evidence for T cells with specificity for self-antigens is lacking. PMID:23493116

  20. Pituitary autoantibodies in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

    Science.gov (United States)

    O'Dwyer, Damien T; McElduff, Patrick; Peterson, Pärt; Perheentupa, Jaakko; Crock, Patricia A

    2007-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease due to mutations in the AIRE (AutoImmune REgulator) gene. The role of pituitary autoimmunity in APECED is not known. We determined the prevalence of pituitary autoantibodies in a cohort of 67 Finnish patients with APECED from 217 serum samples collected over 26 years by one investigator. Overall, autoantibodies to the 49 kDa cytosolic autoantigen, human pituitary enolase were detected in 39 of the 67 patients (58%). On their first sample, 25 patients had autoantibodies compared to 5 of 68 controls (chi-square, 1df=17.11, pAPECED patients.

  1. Psychosis: an autoimmune disease?

    Science.gov (United States)

    Al-Diwani, Adam A J; Pollak, Thomas A; Irani, Sarosh R; Lennox, Belinda R

    2017-11-01

    Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19 + and reduced CD3 + lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3 + and CD20 + lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated (NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis. © 2017 John Wiley & Sons Ltd.

  2. AIDBD: AUTOIMMUNE AND INFLAMMATORY DISEASES BIOMARKER DATABASE

    Directory of Open Access Journals (Sweden)

    Kulwinder Singh

    2016-09-01

    Full Text Available One of the major challenges facing the healthcare industry is how to personalize, or tailor healthcare products and services to individuals’ unique genetic and biomarker make-ups. Biomarkers provide information about normal or patho-physiological processes to detect or define disease progression or to predict or quantify therapeutic responses. Once these footprints have been identified and measured, they can then be used to personalize or tailor treatment plans, products and services to each individual’s unique makeup and background. Autoimmune and Inflammatory Diseases Biomarker Database (AIDBD is one of the first efforts to build an easily accessible and comprehensive literature-derived database covering information on known autoimmune and inflammatory diseases, biomarkers and available medications. It allows users to link autoimmune and inflammatory diseases to protein or gene biomarkers through its user interface. Currently, AIDBD integrates 206 biomarkers for 21 autoimmune and inflammatory diseases and data on 516 launched drugs for the treatment these diseases. The database is freely accessible at http://www.aidbd.in/.

  3. Recent advances in understanding autoimmune thyroid disease

    DEFF Research Database (Denmark)

    Bliddal, Sofie; Nielsen, Claus Henrik; Feldt-Rasmussen, Ulla

    2017-01-01

    Autoimmune thyroid disease (AITD) is often observed together with other autoimmune diseases. The coexistence of two or more autoimmune diseases in the same patient is referred to as polyautoimmunity, and AITD is the autoimmune disease most frequently involved. The occurrence of polyautoimmunity has...... led to the hypothesis that the affected patients suffer from a generalized dysregulation of their immune system. The present review summarizes recent discoveries unravelling the immunological mechanisms involved in autoimmunity, ranging from natural autoimmunity to disease-specific autoimmunity...

  4. Sarcoidosis and Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Piera Fazzi

    2017-08-01

    Full Text Available Most of the studies have shown a higher risk for subclinical and clinical hypothyroidism, antithyroid autoantibodies [overall antithyroid peroxidase antibodies (TPOAb], and in general, thyroid autoimmunity, overall in the female gender in patients with sarcoidosis (S. A significantly higher prevalence of clinical hypothyroidism and Graves’ disease was also described in female S patients with respect to controls. Gallium-67 (Ga-67 scyntigraphy in S patients, in the case of thyroid uptake, suggests the presence of aggressive autoimmune thyroiditis and hypothyroidism. For this reason, ultrasonography and thyroid function should be done in the case of Ga-67 thyroid uptake. In conclusion, thyroid function, TPOAb measurement, and ultrasonography should be done to assess the clinical profile in female S patients, and the ones at high risk (female individuals, with TPOAb positivity, and hypoechoic and small thyroid should have periodically thyroid function evaluations and suitable treatments.

  5. Gangliosides and autoimmune diabetes.

    Science.gov (United States)

    Misasi, R; Dionisi, S; Farilla, L; Carabba, B; Lenti, L; Di Mario, U; Dotta, F

    1997-09-01

    Gangliosides are sialic acid-containing glycolipids which are formed by a hydrophobic portion, the ceramide, and a hydrophilic part, i.e. the oligosaccharide chain. First described in neural tissue, several studies have shown that gangliosides are almost ubiquitous molecules expressed in all vertebrate tissues. Within cells, gangliosides are usually associated with plasma membranes, where they can act as receptors for a variety of molecules and have been shown to take part in cell-to-cell interaction and in signal transduction. In addition, gangliosides are expressed in cytosol membranes like those of secretory granules of some endocrine cells (adrenal medulla, pancreatic islets). As far as the role of gangliosides in diseases is concerned, there are some cases in which an aberrant ganglioside expression plays a crucial role in the disease pathogenetic process. These diseases include two major forms of ganglioside storage, namely GM2-gangliosidosis (Tay-Sachs and its beta-hexosaminidase deficiency) and GM1-gangliosidosis (beta-galactosidase deficiency), where the most prominent pathological characteristic is the lysosomal ganglioside accumulation in neurons. Other inflammatory or degenerative diseases both within and outside the nervous system have been shown to be associated with an altered pattern of ganglioside expression in the target organ. Since monoclonal antibodies have been discovered and used in immunology, a large variety of ganglioside antigens has been described both as blood group antigens and as tumour-related antigens. Several studies have also indicated that gangliosides can act not only as antigens, but also as autoantigens. As a matter of fact, auto-antibodies to gangliosides, detected by immunostaining methods performed directly on TLC plates or by ELISA, have been described in several autoimmune disorders such as Guillain-Barré syndrome, multiple sclerosis, lupus erythematosus, Hashimoto's thyroiditis and, last but not least, insulin

  6. [Oral diseases in auto-immune polyendocrine syndrome type 1].

    Science.gov (United States)

    Proust-Lemoine, Emmanuelle; Guyot, Sylvie

    2017-09-01

    Auto-immune polyendocrine syndrome type 1 (APS1) also called Auto-immune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) is a rare monogenic childhood-onset auto-immune disease. This autosomal recessive disorder is caused by mutations in the auto-immune regulator (AIRE) gene, and leads to autoimmunity targeting peripheral tissues. There is a wide variability in clinical phenotypes in patients with APSI, with auto-immune endocrine and non-endocrine disorders, and chronic mucocutaneous candidiasis. These patients suffer from oral diseases such as dental enamel hypoplasia and candidiasis. Both are frequently described, and in recent series, enamel hypoplasia and candidiasis are even the most frequent components of APS1 together with hypoparathyroidism. Both often occur during childhood (before 5 years old for canrdidiasis, and before 15 years old for enamel hypoplasia). Oral candidiasis is recurrent all life long, could become resistant to azole antifungal after years of treatment, and be carcinogenic, leading to severe oral squamous cell carcinoma. Oral components of APS1 should be diagnosed and rigorously treated. Dental enamel hypoplasia and/or recurrent oral candidiasis in association with auto-immune diseases in a young child should prompt APS1 diagnosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Thymoma and autoimmunity

    OpenAIRE

    Shelly, Shahar; Agmon-Levin, Nancy; Altman, Arie; Shoenfeld, Yehuda

    2011-01-01

    The thymus is a central lymphatic organ that is responsible for many immunological functions, including the production of mature, functional T cells and the induction of self-tolerance. Benign or malignant tumors may originate from the thymus gland, with thymoma being the most common and accounting for 50% of anterior mediastinal tumors. Malignancies linked to thymoma include the loss of self-tolerance and the presence of autoimmunity. In this review, we compiled the current scientific eviden...

  8. Autoimmune liver disease 2007.

    Science.gov (United States)

    Muratori, Paolo; Granito, Alessandro; Pappas, Georgios; Muratori, Luigi; Lenzi, Marco; Bianchi, Francesco B

    2008-01-01

    Autoimmune liver disease (ALD) includes a spectrum of diseases which comprises both cholestatic and hepatitic forms: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and the so called "overlap" syndromes where hepatitic and cholestatic damage coexists. All these diseases are characterized by an extremely high heterogeneity of presentation, varying from asymptomatic, acute (as in a subset of AIH) or chronic (with aspecific symptoms such as fatigue and myalgia in AIH or fatigue and pruritus in PBC and PSC). The detection and characterization of non organ specific autoantibodies plays a major role in the diagnostic approach of autoimmune liver disease; anti nuclear reactivities (ANA) and anti smooth muscle antibodies (SMA) mark type 1 AIH, liver kidney microsomal antibody type 1 (LKM1) and liver cytosol type 1 (LC1) are the serological markers of type 2 AIH; antimitochondrial antibodies (AMA) are associated with PBC, while no specific marker is found in PSC, since anticytoplasmic neutrophil antibodies with perinuclear pattern (atypical p-ANCA or p-ANNA) are also detected in a substantial proportion of type 1 AIH cases. Treatment options rely on immunosoppressive therapy (steroids and azathioprine) in AIH and on ursodeoxycholic acid in cholestatic conditions; in all these diseases liver transplantation remains the only therapeutical approach for the end stage of liver disease.

  9. Thymoma and autoimmunity

    Science.gov (United States)

    Shelly, Shahar; Agmon-Levin, Nancy; Altman, Arie; Shoenfeld, Yehuda

    2011-01-01

    The thymus is a central lymphatic organ that is responsible for many immunological functions, including the production of mature, functional T cells and the induction of self-tolerance. Benign or malignant tumors may originate from the thymus gland, with thymoma being the most common and accounting for 50% of anterior mediastinal tumors. Malignancies linked to thymoma include the loss of self-tolerance and the presence of autoimmunity. In this review, we compiled the current scientific evidence detailing the various interactions between thymoma and autoimmune diseases, including myasthenia gravis, systemic lupus erythematosus, inappropriate antidiuretic hormone secretion, pure red cell aplasia, pernicious anemia, pemphigus and autoimmune thyroid diseases. In recent years, several mechanisms have been proposed to explain these interactions. Most are based on the assumption that the ‘sick' thymus, like the ‘normal' thymus, can generate mature T cells; however, the T cells generated by the sick thymus are impaired and thus may exert cellular autoreactivity. Here, we present several theories that may shed light on the loss of self-tolerance associated with this epithelial tumor of the thymus. PMID:21317916

  10. The effect of 1, 25(OH)2 D3 (calcitriol) alone and in combination with all-trans retinoic acid on ROR-γt, IL-17, TGF-β, and FOXP3 gene expression in experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Parastouei, Karim; Mirshafiey, Abbas; Eshraghian, Mohammad Reza; Shiri-Shahsavar, Mohammad Reza; Solaymani-Mohammadi, Farid; Chahardoli, Reza; Alvandi, Ehsan; Saboor-Yaraghi, Ali Akbar

    2018-04-01

    It has been shown that calcitriol and all-trans retinoic acid (ATRA) have modulatory effects on the immune system. The present study investigates the synergistic effects of combination treatment of calcitriol and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The mice were allocated to four preventive groups, each consisting of eight animals, ATRA (250 μg/mouse), calcitriol (100 ng/mouse), combination of ATRA and calcitriol (125  μg/mouse and 50 ng/mouse) and vehicle groups. EAE was induced by MOG35-55 peptide in female C57BL/6 mice. Treatments were initiated at day 1 before immunization and continued every other day throughout the study until the day 21 post-immunization. Splenocytes were isolated from EAE-induced mice and the expression of retinoic acid receptor-related orphan receptor gamma t (ROR-γt), Interleukin-17 (IL-17), transforming growth factor beta (TGF-β), and forkhead box P3 (FOXP3) genes was measured using real-time polymerase chain reaction. The expression of FOXP3 and TGF-β genes in the splenocytes of combination-treated and calcitriol alone-treated mice was significantly increased compared to vehicle group (P ROR-γt and IL-17 genes in the splenocytes of ATRA, calcitriol and combination- treated mice was significantly reduced compared to those of vehicle- treated mice (P ROR-γt was significantly (P < 0.05) lower in the combination group than in the mice treated by ATRA or calcitriol alone. This study demonstrated that treatment with combination of calcitriol and ATRA can be considered as a new strategy for MS prevention and treatment.

  11. [Treatment of autoimmune hepatic diseases].

    Science.gov (United States)

    Bueverov, A O

    2004-01-01

    The immunosuppresive drugs, primarily glucocorticosteroids, serve as the basis for the pathogenetic treatment of autoimmune diseases of the liver. In autoimmune hepatitis, immunosuppressive therapy induces and maintains persistent remission in most patients while in primary biliary cirrhosis and primary sclerosing cholangitis, its capacities are substantially limited. Ursodeoxycholic acid is used as the basic drug in predominantly occurring intrahepatic cholestasis. The treatment of cross autoimmune syndromes generally requires the choice of a combination of drugs.

  12. B Cells in Autoimmune Diseases

    OpenAIRE

    Hampe, Christiane S.

    2012-01-01

    The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell...

  13. Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

    Science.gov (United States)

    Sugiura, Tomoko; Kawaguchi, Yasushi; Goto, Kanako; Hayashi, Yukiko; Gono, Takahisa; Furuya, Takefumi; Nishino, Ichizo; Yamanaka, Hisashi

    2014-01-01

    Background Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13–BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene–gene interaction between C8orf13–BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed. Methods A single-nucleotide polymorphism in C8orf13–BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects. Results The C8orf13–BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (Pdermatomyositis (Pdermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57–6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865. Conclusions This study established C8orf13–BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13–BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13–BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals. PMID:24632671

  14. [Autoimmune hemolytic anemia in children].

    Science.gov (United States)

    Becheur, M; Bouslama, B; Slama, H; Toumi, N E H

    2015-01-01

    Autoimmune hemolytic anemia is a rare condition in children which differs from the adult form. It is defined by immune-mediated destruction of red blood cells caused by autoantibodies. Characteristics of the autoantibodies are responsible for the various clinical entities. Classifications of autoimmune hemolytic anemia include warm autoimmune hemolytic anemia, cold autoimmune hemolytic anemia, and paroxysmal cold hemoglobinuria. For each classification, this review discusses the epidemiology, etiology, clinical presentation, laboratory evaluation, and treatment options. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. Autoimmune disease classification by inverse association with SNP alleles.

    Directory of Open Access Journals (Sweden)

    Marina Sirota

    2009-12-01

    Full Text Available With multiple genome-wide association studies (GWAS performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction of allele-specific disease associations for SNPs. In this work, we refine the notion of a genetic variation profile for a given disease to capture strength of association with multiple SNPs in an allele-specific fashion. We apply this method to compare genetic variation profiles of six autoimmune diseases: multiple sclerosis (MS, ankylosing spondylitis (AS, autoimmune thyroid disease (ATD, rheumatoid arthritis (RA, Crohn's disease (CD, and type 1 diabetes (T1D, as well as five non-autoimmune diseases. We quantify pair-wise relationships between these diseases and find two broad clusters of autoimmune disease where SNPs that make an individual susceptible to one class of autoimmune disease also protect from diseases in the other autoimmune class. We find that RA and AS form one such class, and MS and ATD another. We identify specific SNPs and genes with opposite risk profiles for these two classes. We furthermore explore individual SNPs that play an important role in defining similarities and differences between disease pairs. We present a novel, systematic, cross-platform approach to identify allele-specific relationships between disease pairs based on genetic variation as well as the individual SNPs which drive the relationships. While recognizing similarities between diseases might lead to identifying novel treatment options, detecting differences between diseases previously thought to be similar may point to key novel disease-specific genes and pathways.

  16. Genetics Home Reference: autoimmune Addison disease

    Science.gov (United States)

    ... of each kidney. It is classified as an autoimmune disorder because it results from a malfunctioning immune system ... disease or their family members can have another autoimmune disorder, most commonly autoimmune thyroid disease or type 1 ...

  17. [Keratitis - Infectious or Autoimmune?].

    Science.gov (United States)

    Messmer, E M

    2016-07-01

    Histopathological evaluation of ocular tissues is important in differentiating between infectious and autoimmune disease. Inflammation, necrosis and keratolysis are common to most forms of keratitis. Histopathology can be of great help in identifying the causative organism, establishing a final diagnosis and/or managing the patient with herpes simplex virus keratitis, mycotic keratitis, acanthamoeba keratitis or microsporidia keratoconjunctivitis. Important pathogenetic knowledge with therapeutic relevance has been gained from histopathological studies in nummular keratitis after epidemic keratoconjunctivitis and atopic keratoconjunctivitis. Georg Thieme Verlag KG Stuttgart · New York.

  18. Warm autoimmune hemolytic anemia.

    Science.gov (United States)

    Naik, Rakhi

    2015-06-01

    Warm autoimmune hemolytic anemia (AIHA) is defined as the destruction of circulating red blood cells (RBCs) in the setting of anti-RBC autoantibodies that optimally react at 37°C. The pathophysiology of disease involves phagocytosis of autoantibody-coated RBCs in the spleen and complement-mediated hemolysis. Thus far, treatment is aimed at decreasing autoantibody production with immunosuppression or reducing phagocytosis of affected cells in the spleen. The role of complement inhibitors in warm AIHA has not been explored. This article addresses the diagnosis, etiology, and treatment of warm AIHA and highlights the role of complement in disease pathology. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Hyposalivation in autoimmune diseases

    OpenAIRE

    Maeshima, Etsuko; Furukawa, Kanako; Maeshima, Shinichiro; Koshiba, Hiroya; Sakamoto, Wataru

    2012-01-01

    We have investigated the prevalence of dry mouth among patients with autoimmune diseases other than Sj?gren?s syndrome. One hundred and forty-four patients, excluding patients with primary Sj?gren?s syndrome, were enrolled in this study. The volume of saliva secreted was measured with the screening technique for estimation of salivary flow, which uses a filter paper for diagnosing dry mouth. Disturbed salivary secretion was observed in 84 (58.3?%) of the 144 patients. In the case of patients ...

  20. Autoimmune diseases and myelodysplastic syndromes.

    Science.gov (United States)

    Komrokji, Rami S; Kulasekararaj, Austin; Al Ali, Najla H; Kordasti, Shahram; Bart-Smith, Emily; Craig, Benjamin M; Padron, Eric; Zhang, Ling; Lancet, Jeffrey E; Pinilla-Ibarz, Javier; List, Alan F; Mufti, Ghulam J; Epling-Burnette, Pearlie K

    2016-05-01

    Immune dysregulation and altered T-cell hemostasis play important roles in the pathogenesis of myelodysplastic syndromes (MDS). Recent studies suggest an increased risk of MDS among patients with autoimmune diseases. Here, we investigated the prevalence of autoimmune diseases among MDS patients, comparing characteristics and outcomes in those with and without autoimmune diseases. From our study group of 1408 MDS patients, 391 (28%) had autoimmune disease, with hypothyroidism being the most common type, accounting for 44% (n = 171) of patients (12% among all MDS patients analyzed). Other autoimmune diseases with ≥5% prevalence included idiopathic thrombocytopenic purpura in 12% (n = 46), rheumatoid arthritis in 10% (n = 41), and psoriasis in 7% (n = 28) of patients. Autoimmune diseases were more common in female MDS patients, those with RA or RCMD WHO subtype, and those who were less dependent on red blood cell transfusion. Median overall survival (OS) was 60 months (95% CI, 50-70) for patients with autoimmune diseases versus 45 months (95% CI, 40-49) for those without (log-rank test, P = 0.006). By multivariate analysis adjusting for revised IPSS and age >60 years, autoimmune diseases were a statistically significant independent factor for OS (HR 0.78; 95% CI, 0.66-0.92; P = 0.004). The rate of acute myeloid leukemia (AML) transformation was 23% (n = 89) in MDS patients with autoimmune disease versus 30% (n = 301) in those without (P = 0.011). Patient groups did not differ in response to azacitidine or lenalidomide treatment. Autoimmune diseases are prevalent among MDS patients. MDS patients with autoimmune diseases have better OS and less AML transformation. © 2016 Wiley Periodicals, Inc.

  1. Autoimmune liver disease and concomitant extrahepatic autoimmune disease.

    Science.gov (United States)

    Muratori, Paolo; Fabbri, Angela; Lalanne, Claudine; Lenzi, Marco; Muratori, Luigi

    2015-10-01

    To assess the frequency and clinical impact of associated extrahepatic autoimmune diseases (EAD) on autoimmune liver diseases (ALD). We investigated 608 patients with ALD (327 autoimmune hepatitis - AIH and 281 primary biliary cirrhosis - PBC) for concomitant EAD. In both AIH and PBC, we observed a high prevalence of EAD (29.9 and 42.3%, respectively); both diseases showed a significant association with autoimmune thyroid disease, followed by autoimmune skin disease, celiac disease, and vasculitis in AIH patients and sicca syndrome, CREST syndrome, and celiac disease in PBC patients. At diagnosis, AIH patients with concurrent EAD were more often asymptomatic than patients with isolated AIH (Pautoimmune thyroid disease. In the light of our results, all patients with an EAD should be assessed for the concomitant presence of an asymptomatic ALD.

  2. Is Tolerance Broken in Autoimmunity?

    Directory of Open Access Journals (Sweden)

    Dama Laxminarayana

    2017-11-01

    Full Text Available Autoimmune diseases are classified into about 80 different types based on their specificity related to system, organ and/or tissue. About 5% of the western population is affected by this anomaly, but its worldwide incidence is unknown. Autoimmune diseases are heterogeneous in nature and clinical manifestations range from benign disorders to life-threatening conditions. Autoimmunity strikes at any stage of life, but age and/or gender also play role in onset of some of these anomalies. The autoimmune pathogenesis is initiated by the origination of autoantigens, which leads to the development of autoantibodies followed by auto-immunogenicity and the ultimate onset of autoimmunity. There is a lack of suitable therapies to treat autoimmune diseases, because mechanisms involved in the onset of these anomalies were poorly understood. Present therapies are limited to symptomatic treatment and come with severe side effects. Here, I described the molecular mechanisms and cellular events involved in the initiation of autoimmunity and proposed better strategies to modulate such molecular and cellular anomalies, which will help in preventing and/or controlling autoimmune pathogenesis and ultimately aid in enhancing the quality of life.

  3. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome.

    Science.gov (United States)

    Kisand, Kai; Peterson, Pärt

    2011-12-01

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene and, as a syndrome, is characterized by chronic mucocutaneous candidiasis and the presentation of various autoimmune diseases. During the last decade, research on APECED and AIRE has provided immunologists with several invaluable lessons regarding tolerance and autoimmunity. This review describes the clinical and immunological features of APECED and discusses emerging alternative models to explain the pathogenesis of the disease. © 2011 New York Academy of Sciences.

  4. Current topics in autoimmune hepatitis.

    Science.gov (United States)

    Muratori, Luigi; Muratori, Paolo; Granito, Alessandro; Pappas, Giorgios; Cassani, Fabio; Lenzi, Marco

    2010-11-01

    Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis. Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  5. Recalcitrant hypocalcaemia in autoimmune enteropathy.

    Science.gov (United States)

    Geyer, Myfanwy; Fairchild, Jan; Moore, David; Moore, Lynette; Henning, Paul; Tham, Elaine

    2014-12-01

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome is a monogenic disorder associated with autoimmune destruction of both endocrine and nonendocrine tissues. The classic triad includes candidiasis, hypoparathyroidism, and Addison disease. Up to 25% of patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome also have gastrointestinal manifestations, which can have an impact on the management of other aspects of the disease. The management of the case discussed was challenging because of the complex interplay between the manifestations and treatment of his hypoparathyroidism, Addison disease, and autoimmune enteropathy. Attempts at management of hypocalcemia were largely unsuccessful until the introduction of immunosuppressive therapy for autoimmune enteropathy. This case supports early consideration of immunosuppression in this condition. Copyright © 2014 by the American Academy of Pediatrics.

  6. Dysregulated homeostasis of target tissues or autoantigens - A novel principle in autoimmunity.

    Science.gov (United States)

    Petersen, Frank; Yue, Xiaoyang; Riemekasten, Gabriela; Yu, Xinhua

    2017-06-01

    Monogenic autoimmune disorders provide a powerful tool for our understanding of the principles of autoimmunity due to the obvious impact of a single gene on the disease. So far, approximately 100 single gene defects causing murine monogenic autoimmune disorders have been reported and the functional characterization of these genes will provide significant progress in understanding the nature of autoimmunity. According to their function, genes leading to monogenic autoimmune disorders can be categorized into two groups. An expectable first group contains genes involved in the homeostasis of the immune system, including homeostasis of immune organs and immune cells. Intriguingly, the second group consists of genes functionally involved in the homeostasis of target tissues or autoantigens. According to our novel hypothesis, we propose that autoimmunity represents a consequence of a dysregulated homeostasis of the immune system and/or its targets including autoantigens and target tissues. In this review we refer to both aspects of homeostasis in autoimmunity with a highlight on the role of the homeostasis of target tissues and autoantigens. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Smoke and autoimmunity: The fire behind the disease.

    Science.gov (United States)

    Perricone, Carlo; Versini, Mathilde; Ben-Ami, Dana; Gertel, Smadar; Watad, Abdulla; Segel, Michael J; Ceccarelli, Fulvia; Conti, Fabrizio; Cantarini, Luca; Bogdanos, Dimitrios P; Antonelli, Alessandro; Amital, Howard; Valesini, Guido; Shoenfeld, Yehuda

    2016-04-01

    The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Autoimmune comorbidity in achalasia patients.

    Science.gov (United States)

    Romero-Hernández, Fernanda; Furuzawa-Carballeda, Janette; Hernández-Molina, Gabriela; Alejandro-Medrano, Edgar; Núñez-Álvarez, Carlos A; Hernández-Ramírez, Diego F; Azamar-Llamas, Daniel; Olivares-Martínez, Elizabeth; Breña, Blanca; Palacios, Axel; Valdovinos, Miguel A; Coss-Adame, Enrique; Ramos-Ávalos, Bárbara; Torres-Landa, Samuel; Hernández-Ávila, Axel A; Flores-Nájera, Athenea; Torres-Villalobos, Gonzalo

    2018-01-01

    Idiopathic achalasia is a rare esophageal motor disorder. The disease state manifests local and systemic inflammation, and it appears that an autoimmune component and specific autoantibodies participate in the pathogenesis. The study aims to determine the prevalence of autoimmune and chronic inflammatory diseases in patients with achalasia and compare the results with those from patients with gastroesophageal reflux disease (GERD). It was a cross-sectional and included 114 patients with idiopathic achalasia and 114 age-matched and sex-matched control patients with GERD. Data on the presence of autoimmune and inflammatory diseases, the time of presentation, and any family history of autoimmune disease were obtained from the hospital's medical records. Seventy three (64%) were female patients (mean age: 42.3 ± 15.5; median disease duration: 12 months). We identified the presence of autoimmune disease in 19 patients with achalasia (16.7%), hypothyroidism was the main diagnosis, and it was present in 52.6% of patients compared with 4.2% in controls. Thirteen of the 19 achalasia patients (68.4%) with autoimmune disease had history of familial autoimmunity. We identified 11 achalasia (9.6%) and 5 GERD patients (4.16%) with an inflammatory condition. Compared with the GERD, the achalasia group was 3.8 times more likely to have an autoimmune disease (95% CI: 1.47-9.83), 3.0 times more likely to have thyroidopathies (95% CI: 1.00-9.03), and 3.02 times more likely to suffer from any chronic inflammatory disease (95% CI: 1.65-6.20). The non-negligible number of patients with autoimmune diseases identified among the patients with idiopathic achalasia supports the hypothesis that achalasia has an autoimmune component. © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  9. Autoimmune premature ovarian failure

    Directory of Open Access Journals (Sweden)

    Beata Komorowska

    2017-02-01

    Full Text Available Premature ovarian failure (POF, also termed as primary ovarian insufficiency (POI, is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system.

  10. Selfie: Autoimmunity, boon or bane.

    Science.gov (United States)

    Ahsan, Haseeb

    2017-01-01

    The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.

  11. MHC class II polymorphisms, autoreactive T-cells and autoimmunity

    Directory of Open Access Journals (Sweden)

    Sue eTsai

    2013-10-01

    Full Text Available Major histocompatibility complex (MHC genes, also known as human leukocyte antigen genes (HLA in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D, Multiple Sclerosis (MS, and Rheumatoid arthritis (RA, among others (Todd and Wicker, 2001;MacKay et al., 2002;Hafler et al., 2007. Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T cell repertoires of the host towards autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development towards a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development towards non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

  12. Insulin gene VNTR polymorphisms -2221MspI and -23HphI are associated with type 1 diabetes and latent autoimmune diabetes in adults: a meta-analysis.

    Science.gov (United States)

    Zhang, Na; Huang, Weihuang; Dong, Fang; Liu, Yang; Zhang, Baohuan; Jing, Lipeng; Wang, Man; Yang, Guang; Jing, Chunxia

    2015-12-01

    A variable number of tandem repeat (VNTRs) region in the insulin gene (INS) possibly influences the progression of type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA). However, effects of INS VNTR polymorphisms in these contexts remain inconclusive. We performed a systematic review of work on the INS VNTR -2221MspI and -23HphI polymorphisms to estimate the overall effects thereof on disease susceptibility; we included 17,498 T1D patients and 24,437 controls, and 1960 LADA patients and 5583 controls. For T1D, the C allele at -2221MspI and the A allele at -23HphI were associated with estimated relative risks of 2.13 (95 % CI 1.94, 2.35) and 0.46 (95 % CI 0.44, 0.48), which contributed to absolute increases of 46.76 and 46.98 % in the risk of all T1D, respectively. The estimated lambda values were 0.44 and 0.42, respectively, suggesting that a co-dominant model most likely explained the effects of -2221MspI and -23HphI on T1D. For -23HphI, the A allele carried an estimated relative risk of 0.55 (95 % CI 0.50, 0.61) for LADA and increased the risk of all LADA by 36.94 %. The λ value was 0.43, suggesting that a co-dominant model most likely explained the effect of -23HphI on LADA. Our results support the existence of associations of INS with T1D and LADA.

  13. New Genetic Insights from Autoimmune Thyroid Disease

    Directory of Open Access Journals (Sweden)

    Terry F. Davies

    2012-01-01

    Full Text Available The autoimmune thyroid diseases (AITDs (Graves’ disease and Hashimoto’s thyroiditis are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (including HLA, CTLA4, PTPN22, CD40, CD25, and FCRL3 and thyroid-specific genes (TG and TSHR. However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future.

  14. Scientists find link between allergic and autoimmune diseases in mouse study

    Science.gov (United States)

    Scientists at the National Institutes of Health, and their colleagues, have discovered that a gene called BACH2 may play a central role in the development of diverse allergic and autoimmune diseases, such as multiple sclerosis, asthma, Crohn's disease, ce

  15. [Stress and auto-immunity].

    Science.gov (United States)

    Delévaux, I; Chamoux, A; Aumaître, O

    2013-08-01

    The etiology of auto-immune disorders is multifactorial. Stress is probably a participating factor. Indeed, a high proportion of patients with auto-immune diseases report uncommon stress before disease onset or disease flare. The biological consequences of stress are increasingly well understood. Glucocorticoids and catecholamines released by hypothalamic-pituitary-adrenal axis during stress will alter the balance Th1/Th2 and the balance Th17/Treg. Stress impairs cellular immunity, decreases immune tolerance and stimulates humoral immunity exposing individuals to autoimmune disease among others. The treatment for autoimmune disease should include stress management. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  16. Review on thymoma and thymoma-associated autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Yue-min LI

    2014-10-01

    Full Text Available Thymic carcinomas are tumors of the anterior mediastinum derived from the epithelial cells of the thymus gland. Malignancies linked to thymoma lead to the loss of self-tolerance leading to autoimmune diseases, including myasthenia gravis, pure red cell aplastic anemia, systemic lupus erythematosus and pemphigus etc. In recent years, three main mechanisms have been proposed to elucidate these interactions, such as immature T cell theory, tumor-gene theory and the combination mechanism of cellular and humoral immunity. In fact, the resection of the thymoma is beneficial to many patients of thymoma related autoimmune diseases. DOI: 10.11855/j.issn.0577-7402.2014.08.16

  17. Psoriasis as an autoimmune disease

    OpenAIRE

    Agnieszka Owczarczyk-Saczonek; Waldemar Placek

    2014-01-01

    Nowadays it is known that psoriasis belongs to the group of autoimmune diseases and may coexist with other diseases in this group. Most often patients have psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid diseases and multiple sclerosis. The coexistence of these disorders can be a diagnostic and therapeutic problem (there is controversy over the use of corticosteroids). The common pathogenesis is still not explained. We know that the loss of immunotole...

  18. Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

    Science.gov (United States)

    Watanabe, Mitsuru; Ochi, Hirofumi; Arahata, Hajime; Matsuo, Tomohito; Nagafuchi, Seiho; Ohyagi, Yasumasa; Kira, Jun-Ichi

    2012-06-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. Progressive myopathy involvement could be a hitherto unknown manifestation of APECED. Copyright © 2012 Wiley Periodicals, Inc.

  19. [Smoking and chronic autoimmune thyroiditis].

    Science.gov (United States)

    Buzoianu, Ioana Cristina; Arghir, Oana Cristina; Circo, E

    2010-01-01

    The chronic autoimmune thyroiditis are heterogeneous entities by the functional, lesional and evolutive point of view. Ethiopathogenic factors involved in chronic autoimmune thyroiditis are genetical factors, combines with environmental factors, hormonal factors, infectious factors etc. The exact role of smoking on the autoimmune mechanism is unclear, but smoking is known to have an antithyroid effect. Our study tries to estimate the influence of smoking on serum levels of antithyroid peroxidase antibodies and antithyroglobulin antibodies, in a group of patients with various clinical forms of chronic autoimmune thyroiditis. We studied a group consists of 310 patients with chronic autoimmune thyroiditis, hospitalised in the Endocrinology Department of Constanta County Hospital, between January 2006 - December 2009. We detected serum values of antithyroidperoxidase antibodies and antithyroglobulin antibodies of our patients. We also followed the age, sex and presence of smoking in our study group. For statistical processing of the data we use Student's t-test. In our study group 24.28% of patients were smokers. Serum levels of antithyroid peroxidase antibodies were significantly increased (p < 0.001) in the smokers patients, compared with the nonsmokers patients. Serum levels of antithyroglobulin antibodies were significantly increased (p < 0.01) in smokers patients, compared with those who were nonsmokers. Smoking increased the serum levels of antithyroid antibodies in patients with chronic autoimmune thyroiditis.

  20. Autoimmune hepatitis: a classic autoimmune liver disease.

    Science.gov (United States)

    Moy, Libia; Levine, Jeremiah

    2014-12-01

    AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis. Copyright © 2014 Mosby, Inc. All rights reserved.

  1. HLA-G Molecules in Autoimmune Diseases and Infections

    Science.gov (United States)

    Rizzo, Roberta; Bortolotti, Daria; Bolzani, Silvia; Fainardi, Enrico

    2014-01-01

    Human leukocyte antigen (HLA)-G molecule, a non-classical HLA-Ib molecule, is less polymorphic when compared to classical HLA class I molecules. Human leukocyte antigen-G (HLA-G) was first detected on cytotrophoblast cells at the feto-maternal interface but its expression is prevalent during viral infections and several autoimmune diseases. HLA-G gene is characterized by polymorphisms at the 3′ un-translated region and 5′ upstream regulatory region that regulate its expression and are associated with autoimmune diseases and viral infection susceptibility, creating an unbalanced and pathologic environment. This review focuses on the role of HLA-G genetic polymorphisms, mRNA, and protein expression in autoimmune conditions and viral infections. PMID:25477881

  2. Autoimmunity in Wiskott-Aldrich Syndrome: an unsolved enigma

    Directory of Open Access Journals (Sweden)

    Marco eCatucci

    2012-07-01

    Full Text Available Wiskott-Aldrich Syndrome (WAS is a severe X-linked Primary Immunodeficiency (PID that affects 1 to 10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was-/- mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22% to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.

  3. Toward molecular pathogenesis of an autoimmune disease: Refined genetic mapping of autoimmune polyglandular disease type I (APECED)

    Energy Technology Data Exchange (ETDEWEB)

    Aaltonen, J.; Bjoerses, P.; Peltonen, L. [National Public Health Institute, Helsinki (Finland)] [and others

    1994-09-01

    Autoimmune reactions encoupled to many human diseases are still only partially understood. Unravelling the molecular pathogenesis of inherited diseases with a strong autoimmune component in their clinical expression could help to dissect individual components in the molecular background of abnormal immune response. One such genetic disorder is autosomal recessive autoimmune polyglandular disease type I (PGD I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, MIM 240300). The disease is especially enriched in the genetically isolated population of Finland and we have assigned the APECED locus to human chromosome 21q22.3 in 14 Finnish families by linkage analyses. The best positional lod score of 6.49 was observed with marker D21S49. Based on the history of the Finns, the gene pool of this population clearly demonstrates the consequences of a founder effect and consequent isolation. In the Finnish population, we can take advantage of linkage disequilibrium and allelic association studies to more precisely define the critical DNA region for our disease gene of interest than would be possible by linkage analyses alone. We are now able to define the chromosomal region of interest between two flanking markers locating 1 cM apart. Linkage disequilibrium is observed with three of the markers used in the analyses and this suggests a distance of less than 500 kb to the disease locus, well approachable with molecular cloning techniques. Overlapping YAC and cosmid clones spanning our region of interest will facilitate the cloning of APECED gene in the near future.

  4. AUTOIMMUNE EPIDERMAL BLISTERING DISEASES

    Directory of Open Access Journals (Sweden)

    Ana Maria Abreu Velez

    2013-11-01

    Full Text Available Autoimmune bullous skin diseases (ABDs are uncommon, potentially fatal diseases of skin and mucous membranes which are associated with deposits of autoantibodies and complement against distinct molecules of the epidermis and dermal/epidermal basement membrane zone (BMZ. These autoantibodies lead to a loss in skin molecular integrity, which manifests clinically as formation of blisters or erosions. In pemphigus vulgaris, loss of adhesion occurs within the epidermis. The pioneering work of Ernst H. Beutner, Ph.D. and Robert E. Jordon, M.D. confirmed the autoimmune nature of these diseases. Walter F. Lever, M.D. contributed significantly to our understanding of the histopathologic features of these diseases. Walter Lever, M.D. and Ken Hashimoto, M.D. contributed electron microscopic studies of these diseases, especially in pemphigus vulgaris and bullous pemphigoid. In bullous pemphigoid (BP, linear IgA bullous dermatosis, epidermolysis bullosa acquisita (EBA and dermatitis herpetiformis (DH, loss of adhesion takes place within or underneath the BMZ. Classic EBA demonstrates extensive skin fragility; DH is commonly associated with gluten-sensitive enteropathy, and manifests clinically with pruritic papulovesicles on the extensor surfaces of the extremities and the lumbosacral area. The clinical spectrum of bullous pemphigoid includes tense blisters, urticarial plaques, and prurigo-like eczematous lesions. Pemphigoid gestationis mostly occurs during the last trimester of pregnancy, and mucous membrane pemphigoid primarily involves the oral mucosa and conjunctivae and leads to scarring. Linear IgA bullous dermatosis manifests with tense blisters in a „cluster of jewels”-like pattern in childhood (chronic bullous disease of childhood and is more clinically heterogeneous in adulthood. Many of the autoantigens in these disorders are known and have been well characterized. ABDs may be influenced by both genetic and exogenous factors. The diagnoses of

  5. Autoimmune hepatitis in association with lymphocytic colitis.

    LENUS (Irish Health Repository)

    Cronin, Edmond M

    2012-02-03

    Autoimmune hepatitis is a rare, chronic inflammatory disorder which has been associated with a number of other auto-immune conditions. However, there are no reports in the medical literature of an association with microscopic (lymphocytic) colitis. We report the case of a 53-year-old woman with several autoimmune conditions, including lymphocytic colitis, who presented with an acute hepatitis. On the basis of the clinical features, serology, and histopathology, we diagnosed autoimmune hepatitis. To our knowledge, this is the first report of autoimmune hepatitis in association with lymphocytic colitis, and lends support to the theory of an autoimmune etiology for lymphocytic colitis.

  6. Immunogenetics and genetic susceptibility in the pathogenesis of autoimmune hepatitis

    Directory of Open Access Journals (Sweden)

    Das Anup K

    2014-11-01

    Full Text Available vAutoimmune hepatitis is a progressive liver disease. Its pathogenesis is unclear, but needs a ‘trigger’ to initiate the disease in a genetically susceptible person. The susceptibility is partly related to MHCII class genes, and more so with human leukocyte antigen (HLA. Several mechanisms have been proposed which, however, cannot fully explain the immunologic findings in autoimmune hepatitis. The susceptibility to any autoimmune disease is determined by several factors where genetic and immunological alterations, along with, environmental factor are active. MHCII antigens as a marker for AIH, or a predictor of treatment response and prognosis has been investigated. Since MHCII antigens show significant ethnic heterogeneity, mutations in MHCII may merely act as only precursors of the surface markers of immune cells, which can be of significance, because the changes in HLA and MHC are missing in certain populations. One such marker is the CTLA-4 (CD152 gene mutation, reported in the phenotypes representing susceptibility to AIH. Other candidate genes of cytokines, TNF, TGF-beta1 etc, have also been investigated but with unvalidated results. Paediatric AIH show differences in genetic susceptibility. Genetic susceptibility or resistance to AIH may be associated with polypeptides in DRB1 with certain amino-acid sequences. Understanding which genes are implicated in genesis and/or disease progression will obviously help to identify key pathways in AIH and provide better insights into its pathogenesis. But studies to identify responsible genes are complex because of the complex trait of AIH.

  7. The critical role of epigenetics in systemic lupus erythematosus and autoimmunity.

    Science.gov (United States)

    Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M Eric; Lu, Qianjin

    2016-11-01

    One of the major disappointments in human autoimmunity has been the relative failure on genome-wide association studies to provide "smoking genetic guns" that would explain the critical role of genetic susceptibility to loss of tolerance. It is well known that autoimmunity refers to the abnormal state that the dysregulated immune system attacks the healthy cells and tissues due to the loss of immunological tolerance to self-antigens. Its clinical outcomes are generally characterized by the presence of autoreactive immune cells and (or) the development of autoantibodies, leading to various types of autoimmune disorders. The etiology and pathogenesis of autoimmune diseases are highly complex. Both genetic predisposition and environmental factors such as nutrition, infection, and chemicals are implicated in the pathogenic process of autoimmunity, however, how much and by what mechanisms each of these factors contribute to the development of autoimmunity remain unclear. Epigenetics, which refers to potentially heritable changes in gene expression and function that do not involve alterations of the DNA sequence, has provided us with a brand new key to answer these questions. In the recent decades, increasing evidence have demonstrated the roles of epigenetic dysregulation, including DNA methylation, histone modification, and noncoding RNA, in the pathogenesis of autoimmune diseases, especially systemic lupus erythematosus (SLE), which have shed light on a new era for autoimmunity research. Notably, DNA hypomethylation and reactivation of the inactive X chromosome are two epigenetic hallmarks of SLE. We will herein discuss briefly how genetic studies fail to completely elucidate the pathogenesis of autoimmune diseases and present a comprehensive review on landmark epigenetic findings in autoimmune diseases, taking SLE as an extensively studied example. The epigenetics of other autoimmune diseases such as rheumatic arthritis, systemic sclerosis and primary biliary

  8. Type 1 autoimmune pancreatitis.

    Science.gov (United States)

    Zen, Yoh; Bogdanos, Dimitrios P; Kawa, Shigeyuki

    2011-12-07

    Before the concept of autoimmune pancreatitis (AIP) was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP) has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney) and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of regulatory T-cells are assumed

  9. Type 1 autoimmune pancreatitis

    Directory of Open Access Journals (Sweden)

    Zen Yoh

    2011-12-01

    Full Text Available Abstract Before the concept of autoimmune pancreatitis (AIP was established, this form of pancreatitis had been recognized as lymphoplasmacytic sclerosing pancreatitis or non-alcoholic duct destructive chronic pancreatitis based on unique histological features. With the discovery in 2001 that serum IgG4 concentrations are specifically elevated in AIP patients, this emerging entity has been more widely accepted. Classical cases of AIP are now called type 1 as another distinct subtype (type 2 AIP has been identified. Type 1 AIP, which accounts for 2% of chronic pancreatitis cases, predominantly affects adult males. Patients usually present with obstructive jaundice due to enlargement of the pancreatic head or thickening of the lower bile duct wall. Pancreatic cancer is the leading differential diagnosis for which serological, imaging, and histological examinations need to be considered. Serologically, an elevated level of IgG4 is the most sensitive and specific finding. Imaging features include irregular narrowing of the pancreatic duct, diffuse or focal enlargement of the pancreas, a peri-pancreatic capsule-like rim, and enhancement at the late phase of contrast-enhanced images. Biopsy or surgical specimens show diffuse lymphoplasmacytic infiltration containing many IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. A dramatic response to steroid therapy is another characteristic, and serological or radiological effects are normally identified within the first 2 or 3 weeks. Type 1 AIP is estimated as a pancreatic manifestation of systemic IgG4-related disease based on the fact that synchronous or metachronous lesions can develop in multiple organs (e.g. bile duct, salivary/lacrimal glands, retroperitoneum, artery, lung, and kidney and those lesions are histologically identical irrespective of the organ of origin. Several potential autoantigens have been identified so far. A Th2-dominant immune reaction and the activation of

  10. Autoimmune pancreatitis. An update

    International Nuclear Information System (INIS)

    Helmberger, T.

    2016-01-01

    Autoimmune pancreatitis (AIP) is a rare disease, the pathophysiological understanding of which has been greatly improved over the last years. The most common form, type 1 AIP belongs to the IgG4-related diseases and must be distinguished from type 2 AIP, which is a much rarer entity associated with chronic inflammatory bowel disease. Clinically, there is an overlap with pancreatic cancer. Imaging and further criteria, such as serological and histological parameters are utilized for a differentiation between both entities in order to select the appropriate therapy and to avoid the small but ultimately unnecessary number of pancreatectomies. The diagnostics of AIP are complex, whereby the consensus criteria of the International Association of Pancreatology have become accepted as the parameters for discrimination. These encompass five cardinal criteria and one therapeutic criterion. By applying these criteria AIP can be diagnosed with a sensitivity of 84.9 %, a specificity of 100 % and an accuracy of 93.8 %. The diagnosis of AIP is accomplished by applying several parameters of which two relate to imaging. As for the routine diagnostics of the pancreas these are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Important for the differential diagnosis is the exclusion of signs of local and remote tumor spread for which CT and MRI are established. The essential diagnostic parameter of histology necessitates sufficient sample material, which cannot usually be acquired by a fine needle biopsy. CT or MRI are the reference standard methods for identification of the optimal puncture site and imaging-assisted (TruCut) biopsy. In patients presenting with unspecific upper abdominal pain, painless jaundice combined with the suspicion of a pancreatic malignancy in imaging but a mismatch of secondary signs of malignancy, AIP should also be considered as a differential diagnosis. As the diagnosis of AIP only partially relies on imaging radiologists also

  11. Development of autoantibodies precedes clinical manifestations of autoimmune diseases: A comprehensive review.

    Science.gov (United States)

    Ma, Wen-Tao; Chang, Christopher; Gershwin, M Eric; Lian, Zhe-Xiong

    2017-09-01

    The etiology of autoimmune diseases is due to a combination of genetic predisposition and environmental factors that alter the expression of immune regulatory genes through various mechanisms including epigenetics. Both humoral and cellular elements of the adaptive immune system play a role in the pathogenesis of autoimmune diseases and the presence of autoantibodies have been detected in most but not all autoimmune diseases before the appearance of clinical symptoms. In some cases, the presence or levels of these autoantibodies portends not only the risk of developing a corresponding autoimmune disease, but occasionally the severity as well. This observation is intriguing because it suggests that we can, to some degree, predict who may or may not develop autoimmune diseases. However, the role of autoantibodies in the pathogenesis of autoimmune diseases, whether they actually affect disease progression or are merely an epiphenomenon is still not completely clear in many autoimmune diseases. Because of these gaps in our knowledge, the ability to accurately predict a future autoimmune disease can only be considered a relative risk factor. Importantly, it raises the critical question of defining other events that may drive a patient from a preclinical to a clinical phase of disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Shaking Out Clues to Autoimmune Disease

    Science.gov (United States)

    ... into how an immune cell involved in several autoimmune disorders is regulated. Among their findings was a potential ... but they’ve also been linked with several autoimmune disorders. Th17 cells, along with other types of helper ...

  13. Multiple autoimmune syndrome with celiac disease.

    Science.gov (United States)

    Harpreet, Singh; Deepak, Jain; Kiran, B

    Multiple autoimmune syndrome (MAS) is a condition characterised by three or more autoimmune disorders in a same individual. Familial, immunologic and infectious factors are implicated in the development of MAS. Here we report a case of a 32-year-old woman with co-existence of four auto-immune diseases, namely autoimmune hypothyroidism, Sjögren's syndrome, systemic lupus erythematosus (SLE) and celiac disease which leads to the final diagnosis of multiple autoimmune syndrome type 3 with celiac disease. Patients with single autoimmune disorder are at 25% risk of developing other autoimmune disorders. The present case emphasises to clinicians that there is a need for continued surveillance for the development of new autoimmune disease in predisposed patients.

  14. [Therapeutic options for autoimmune encephalomyelitis].

    Science.gov (United States)

    Borisow, N; Prüss, H; Paul, F

    2013-04-01

    Autoantibodies to neuronal tissue are becoming increasingly more important in the evaluation and classification of several neurological diseases, e.g. neuromyelitis optica, paraneoplastic syndromes of the central nervous system (CNS), stiff person syndrome or autoimmune epilepsy. As these disorders are rare, no evidence-based recommendations for therapy are available. Currently, immunomodulating or immunosuppressive drugs are administered in most cases. In paraneoplastic syndromes treatment of the underlying cancer is of considerable importance. This overview summarizes current experiences and recommendations in the treatment of autoimmune neurological disorders.

  15. Psoriasis is not an autoimmune disease?

    Science.gov (United States)

    Fry, Lionel; Baker, Barbara S; Powles, Anne V; Engstrand, Lars

    2015-04-01

    The concept that psoriasis is an autoimmune disease needs to be questioned. The autoimmune label has been based on molecular mimicry between streptococcal and keratin proteins and the existence of homologous peptides between these proteins. However, it is only peripheral blood CD8, and not CD4, T lymphocytes that respond to the homologous peptides. This ignores the fact that it is CD4 T cells which are necessary to initiate psoriasis. Recent studies on skin bacterial microbiota have found a variety of bacteria in both normal skin and psoriatic lesions. In biopsy specimens, the most common phylum was Firmicutes and the most common genus streptococcus in both psoriasis and normal skin. The innate immune system is activated in psoriasis, and recent genetic findings have shown the majority of susceptibility loci are associated with innate immunity. There is a known clinical relationship between both Crohn's disease (CD) and periodontitis, and psoriasis, and patients with psoriasis share mutations in some innate immunity genes with individuals with CD. It is now accepted that CD is due to a breakdown of immune tolerance (dysbiosis) to bacteria in the intestine. These findings suggest that psoriasis is initiated by an abnormal response to bacteria in the skin due to genetic factors. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Endocrine autoimmune diseases and female infertility.

    Science.gov (United States)

    Sen, Aritro; Kushnir, Vitaly A; Barad, David H; Gleicher, Norbert

    2014-01-01

    An increasing body of evidence suggests that immune-mediated processes affect female reproductive success at multiple levels. Crosstalk between endocrine and immune systems regulates a large number of biological processes that affect target tissues, and this crosstalk involves gene expression, cytokine and/or lymphokine release and hormone action. In addition, endocrine-immune interactions have a major role in the implantation process of the fetal (paternally derived) semi-allograft, which requires a reprogramming process of the maternal immune system from rejection to temporary tolerance for the length of gestation. Usually, the female immune system is supportive of all of these processes and, therefore, facilitates reproductive success. Abnormalities of the female immune system, including autoimmunity, potentially interfere at multiple levels. The relevance of the immune system to female infertility is increasingly recognized by investigators, but clinically is often not adequately considered and is, therefore, underestimated. This Review summarizes the effect of individual autoimmune endocrine diseases on female fertility, and points towards selected developments expected in the near future.

  17. An autosomal locus causing autoimmune disease: Autoimmune polyglandular disease type I assigned to chromosome 21

    NARCIS (Netherlands)

    J. Aaltonen (Johanna); P. Björses (Petra); L.A. Sandkuijl (Lodewijk); J. Perheentupa (Jaakko); L. Peltonen (Leena Johanna)

    1994-01-01

    textabstractAutoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does

  18. A minimum number of autoimmune T cells to induce autoimmunity?

    Czech Academy of Sciences Publication Activity Database

    Bosch, A.J.T.; Bolinger, B.; Keck, S.; Štěpánek, Ondřej; Ozga, A.J.; Galati-Fournier, V.; Stein, J.V.; Palmer, E.

    2017-01-01

    Roč. 316, jaro (2017), s. 21-31 ISSN 0008-8749 R&D Projects: GA ČR GJ16-09208Y Institutional support: RVO:68378050 Keywords : T cell * Tolerance * Autoimmunity Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Immunology Impact factor: 3.172, year: 2016

  19. Recombinant Protein Production from TPO Gen Cloning and Expression for Early Detection of Autoimmune Thyroid Diseases

    Science.gov (United States)

    Aulanni'am, Aulanni'am; Kinasih Wuragil, Dyah; Wahono Soeatmadji, Djoko; Zulkarnain; Marhendra, Agung Pramana W.

    2018-01-01

    Autoimmune Thyroid Disease (AITD) is an autoimmune disease that has many clinical symptoms but is difficult to detect at the onset of disease progression. Most thyroid autoimmune disease patients are positive with high titre of thyroid autoantibodies, especially thyroid peroxidase (TPO). The detection AITD are still needed because these tests are extremely high cost and have not regularly been performed in most of clinical laboratories. In the past, we have explored the autoimmune disease marker and it has been developed as source of polyclonal antibodies from patient origin. In the current study, we develop recombinant protein which resulted from cloning and expression of TPO gene from normal person and AITD patients. This work flows involves: DNA isolation and PCR to obtain TPO gene from human blood, insertion of TPO gene to plasmid and transformation to E. coli BL21, Bacterial culture to obtain protein product, protein purification and product analysis. This products can use for application to immunochromatography based test. This work could achieved with the goal of producing autoimmune markers with a guaranteed quality, sensitive, specific and economically. So with the collaboration with industries these devices could be used for early detection. Keywords: recombinant protein, TPO gene, Autoimmune thyroid diseases (AITD)ction of the diseases in the community.

  20. Multiplex autoantibody detection for autoimmune liver diseases and autoimmune gastritis.

    Science.gov (United States)

    Vanderlocht, Joris; van der Cruys, Mart; Stals, Frans; Bakker-Jonges, Liesbeth; Damoiseaux, Jan

    2017-09-01

    Autoantibody detection for autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and autoimmune gastritis (AIG) is traditionally performed by IIF on a combination of tissues. Multiplex line/dot blots (LIA/DIA) offer multiple advantages, i.e. automation, objective reading, no interfering reactivities, no coincidental findings. In the current study we evaluated automated DIA (D-Tek) for detecting autoantibodies related to autoimmune diseases of the gastrointestinal tract. We tested samples of the Dutch EQC program and compared the results with the consensus of the participating labs. For the autoimmune liver diseases and AIG, respectively, 64 and 36 samples were tested. For anti-mitochondrial and anti-smooth muscle antibodies a concordance rate of 97% and 88% was observed, respectively. The concordance rate for anti-parietal cell antibodies was 92% when samples without EQC consensus (n=15) were excluded. For antibodies against intrinsic factor a concordance of 96% was observed. For all these antibodies discrepancies were identified that relate to the different test characteristics and the preponderance of IIF utilizing labs in the EQC program. In conclusion, we observed good agreement of the tested DIA blots with the consensus results of the Dutch EQC program. Taken together with the logistic advantages these blots are a good alternative for autoantibody detection in the respective diseases. A large prospective multicenter study is warranted to position these novel tests further in the whole spectrum of assays for the detection of these antibodies in a routine autoimmune laboratory. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Pathogenic and Protective Autoantibodies in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED

    Directory of Open Access Journals (Sweden)

    Sakeen W. Kashem

    2017-01-01

    Full Text Available Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED is a rare disorder caused by mutations in the autoimmune regulator (AIRE gene, leading to defects in T cell selection. The disease manifestations include both autoimmune tissue destruction and immunodeficiency, with specific susceptibility to chronic mucocutaneous candidiasis. Studies have demonstrated a wide repertoire of high affinity tissue- and cytokine-specific antibodies in patients with APECED. Here, we review the antigenic targets and function of these disease-causing and disease-ameliorating antibodies.

  2. Autoimmune polyendocrine syndrome type 1: case report and review of literature.

    Science.gov (United States)

    Weiler, Fernanda Guimarães; Dias-da-Silva, Magnus R; Lazaretti-Castro, Marise

    2012-02-01

    Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the classic triad is composed by mucocutaneous candidiasis, hypoparathyroidism and adrenal failure, many other components may develop. Treatment is based on supplementation of the various deficiencies, and patients require regular follow-up throughout their lifespan. This article describes the case of a patient with the disease, and reviews literature data on the epidemiology, clinical course, immunogenetic aspects, diagnosis and treatment of the syndrome.

  3. [One case of type 1 auto-immune polyendocrinopathy or APECED].

    Science.gov (United States)

    Puzenat, E; Pepin, L; Bertrand, A-M; Pelletier, F; Monnier, D; Levang, J; Mermet, I; Humbert, P; Aubin, F

    2010-12-01

    autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). We report the case of a young girl with APECED. an 18 year-old girl born to consanguineous parents consulted for diffuse alopecia. Dermatological examination showed nail and dental enamel dystrophy and angular cheilitis. She had a history of mineralocorticoid deficiency (Addison's disease), hypoparathyroidism, hypogonadism and Biermer's disease, and she had also had chronic mucocutaneous candidiasis since childhood. She was presenting APECED with autoimmune endocrine failure, chronic mucocutaneous candidiasis and abnormalities of ectoderm-derived tissue. Analysis of mutation in the AIRE gene showed the c.769C>T homozygous mutation in exon 6. APECED, a rare autosomal recessive disorder, is a potentially life-threatening autoimmune disease. Chronic mucocutaneous candidiasis is a common and early feature in children. Dermatologists are likely to be the first physicians to diagnose this syndrome. 2010. Published by Elsevier Masson SAS.

  4. Rebooting autoimmunity with autologous HSCT.

    Science.gov (United States)

    Snowden, John A

    2016-01-07

    Autologous hematopoietic stem cell transplantation (HSCT) is increasingly used for severe autoimmune and inflammatory diseases, but the mechanisms involved have yet to be elucidated. In this issue of Blood, Delemarre et al report their findings in both animal and human models which provide insights into restoration of functionality and diversity within the regulatory T-cell (Treg) compartment following HSCT.

  5. Vitiligo and Autoimmune Thyroid Disorders

    Directory of Open Access Journals (Sweden)

    Enke Baldini

    2017-10-01

    Full Text Available Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5–1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves’ disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s.

  6. Hemophagocytosis in Cutaneous Autoimmune Disease.

    Science.gov (United States)

    Kerl, Katrin; Wolf, Ingrid H; Cerroni, Lorenzo; Wolf, Peter; French, Lars E; Kerl, Helmut

    2015-07-01

    The significance of the histological visualization of hemophagocytosis in tissues depends on the context, varying from a nonspecific phenomenon to a characteristic or diagnostic feature for certain disease entities. Hemophagocytosis is also one of the key features of macrophage activation syndrome (MAS) (hemophagocytic syndrome) a potentially life-threatening complication of underlying conditions such as infections, malignancy, and autoimmune disorders. Clinical manifestations of MAS are high fever, pancytopenia, liver dysfunction, and coagulopathy. These clinical symptoms are due to an abnormal activation of the immune system in a strong association with the cytokine milieu. The diagnosis of MAS may be easily missed; it is usually detected in the bone marrow, lymph node, liver, and spleen. Only few reports exist in the literature with histological description of cutaneous hemophagocytosis as a sign for MAS in patients with lymphoma and infection. In this report, the authors present the clinicopathological and immunohistochemical features of 3 patients with cutaneous hemophagocytosis, specifically erythrophagocytosis, associated with autoimmune disease, and discuss the relevance of these findings. The authors report 3 patients who developed cutaneous hemophagocytosis during the course of an underlying autoimmune disorder. One patient suffered from dermatomyositis, the other 2 patients from systemic lupus erythematosus, whereby one of them was a 3-month old girl with neonatal lupus erythematosus. The patient with dermatomyositis developed MAS according to the current diagnostic criteria. Although the 2 other patients had an acute flare of their autoimmune disease with histological signs of cutaneous hemophagocytosis, they did not fulfill the complete criteria for a diagnosis of MAS. Histiocyte proliferation and activation with increase of cytokines could be demonstrated by immunohistology. This report is the first to describe hemophagocytosis in cutaneous biopsies

  7. [Type 2 autoimmune polyendocrine syndromes (APS-2)].

    Science.gov (United States)

    Vialettes, Bernard; Dubois-Leonardon, Noémie

    2013-01-01

    Type 2 autoimmune polyendocrine syndromes (APS-2) are the most frequent disorders associating several organ-specific autoimmune diseases. Their high prevalence is due to the fact that the main manifestations of APS-2, such as thyroidal autoimmunity, type 1 diabetes, autoimmune gastric atrophy and vitiligo, are common diseases. APS-2 represents a clinical model that can serve to help unravel the mechanisms underlying autoimmunity. Diagnosis of APS-2 is a challenge for the clinician, especially in poorly symptomatic forms, and may require systematic screening based on measurement of autoantibodies and functional markers.

  8. The role of the autoimmunity laboratory in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    SS Hasson

    2012-04-01

    Full Text Available Laboratory testing is of great value when evaluating a patient with a suspected autoimmune disease. The results can confirm a diagnosis, estimate disease severity, aid in assessing prognosis and are useful to follow disease activity. Components of the laboratory exam include complete blood count with differential, comprehensive metabolic panel, inflammatory markers, autoantibodies, and flow cytometry. Currently, autoimmunity laboratories are very vibrant owing to the constant and increasing availability of new tests, mainly due to the detection of new autoantibodies. The main characteristic that differentiates the autoimmunity laboratory from other laboratories is the use of immunoassays such as enzyme-linked immunosorbent assay (ELISA, as basic techniques which determines antibodies (autoantibodies and not antigens. For this reason, immunoassay techniques must employ antigens as reagents. However, over the last few years, a significant trend at autoimmunity laboratories has been the gradual replacement of immunofluorescence microscopy by immunoassay. Nowadays the revolution of new technology has taken place significantly, for examples; recombinant DNA technology has allowed the production of large quantities of antigens for autoantibody analysis. Flow cytometry for the analysis of microsphere-based immunoassays allows the simultaneous measurement of several autoantibodies. In the same way, autoantigen microarrays provide a practical means to analyse biological fluids in the search for a high number of autoantibodies. We are now at the beginning of an era of multiplexed analysis, with a high capacity of autoantibody specificities. The future tendency in this field will include immunoassays with greater analytical sensitivity, specificity, simultaneous multiplexed capability, the use of protein microarrays, and the use of other technologies such as microfluidics.

  9. Expression of long non-coding RNAs in autoimmunity and linkage to enhancer function and autoimmune disease risk genetic variants.

    Science.gov (United States)

    Aune, T M; Crooke, P S; Patrick, A E; Tossberg, J T; Olsen, N J; Spurlock, C F

    2017-07-01

    Genome-wide association studies have identified numerous genetic variants conferring autoimmune disease risk. Most of these genetic variants lie outside protein-coding genes hampering mechanistic explorations. Numerous mRNAs are also differentially expressed in autoimmune disease but their regulation is also unclear. The majority of the human genome is transcribed yet its biologic significance is incompletely understood. We performed whole genome RNA-sequencing [RNA-seq] to categorize expression of mRNAs, known and novel long non-coding RNAs [lncRNAs] in leukocytes from subjects with autoimmune disease and identified annotated and novel lncRNAs differentially expressed across multiple disorders. We found that loci transcribing novel lncRNAs were not randomly distributed across the genome but co-localized with leukocyte transcriptional enhancers, especially super-enhancers, and near genetic variants associated with autoimmune disease risk. We propose that alterations in enhancer function, including lncRNA expression, produced by genetics and environment, change cellular phenotypes contributing to disease risk and pathogenesis and represent attractive therapeutic targets. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Management strategies for autoimmune pancreatitis.

    Science.gov (United States)

    Kamisawa, Terumi; Takuma, Kensuke; Hara, Seiichi; Tabata, Taku; Kuruma, Sawako; Inaba, Yoshihiko; Gopalakrishna, Rajesh; Egawa, Naoto; Itokawa, Fumihide; Itoi, Takao

    2011-10-01

    Autoimmune pancreatitis (AIP) is a newly developed concept for a peculiar type of pancreatitis, and at present is recognized as a pancreatic lesion reflecting IgG4-related systemic disease. It is of utmost importance to differentiate AIP from pancreatic cancer to avoid unnecessary surgery. The current management strategies for AIP, including its clinical features, diagnostic criteria, clinical subtypes, steroid therapy and prognosis are discussed, based on our 66 AIP cases and papers searched in PubMed from 1992 to March 2011, using the term 'autoimmune pancreatitis'. A new clinicopathological entity, an 'IgG4-related sclerosing disease' is also mentioned. AIP should be considered in the differential diagnosis in elderly male patients presented with obstructive jaundice and pancreatic mass. Steroids are a standard therapy for AIP, but their regimen including maintenance therapy should be evaluated in prospective trials.

  11. [Latent autoimmune diabetes in adults].

    Science.gov (United States)

    Pollak, Felipe; Vásquez, Tatiana

    2012-11-01

    Latent Autoimmune Diabetes in Adults (LADA) is the term used to describe adults who have a slowly progressive form of diabetes mellitus (DM) of autoimmune etiology, but that may be treated initially without insulin. Although it shares some immunological and genetic aspects with type 1 DM, it affects an age group that is typically affected by type 2 DM. Therefore, it could be considered an intermediate type. Diagnosis is based on clinical and laboratory criteria: age of onset, initial response to oral hypoglycemic agents and the presence of specific antibodies for diabetes. Although the definitive treatment is insulin, glitazones may be useful in early stages of the disease. Currently, its management represents a challenge for the physician, including specialists, and it is a form of DM to keep in mind.

  12. Autoimmune encephalitis and sleep disorders

    Directory of Open Access Journals (Sweden)

    Yan HUANG

    2017-10-01

    Full Text Available Research shows that autoimmune encephalitis is associated with sleep disorders. Paraneoplastic neurological syndrome (PNS with Ma2 antibodies can cause sleep disorders, particularly narcolepsy and rapid eye movement sleep behavior disorder (RBD. Limbic encephalitis (LE and Morvan syndrome, associated with voltage - gated potassium channel (VGKC-complex antibodies, which include leucine-rich glioma-inactivated 1 (LGI1 antibody and contactin-associated protein 2 (Caspr2, can result in profound insomnia and other sleep disorders. Central neurogenic hypoventilation are found in patients with anti-N-methyl-D-aspartate (NMDA receptor encephalitis, whereas obstructive sleep apnea (OSA, stridor and parasomnia are prominent features of encephalopathy associated with IgLON5 antibodies. Sleep disorders are cardinal manifestations in patients with autoimmune encephalitis. Immunotherapy possiblely can improve clinical symptoms and prognosis in a positive way. DOI: 10.3969/j.issn.1672-6731.2017.10.004

  13. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Science.gov (United States)

    Shi, Juan; Chi, Shuhong; Xue, Jing; Yang, Jiali; Li, Feng; Liu, Xiaoming

    2016-01-01

    The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases. PMID:27110577

  14. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Juan Shi

    2016-01-01

    Full Text Available The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs, a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

  15. Vitamin D in autoimmune liver disease.

    Science.gov (United States)

    Smyk, Daniel S; Orfanidou, Timoklia; Invernizzi, Pietro; Bogdanos, Dimitrios P; Lenzi, Marco

    2013-11-01

    The development of autoimmune disease is based on the interaction of genetic susceptibility and environmental causes. Environmental factors include infectious and non-infectious agents, with some of these factors being implicated in several autoimmune diseases. Vitamin D is now believed to play a role in the development (or prevention) of several autoimmune diseases, based on its immunomodulatory properties. As well, the increasing incidence of autoimmune disease as one moves away from the equator, may be due to the lack of sunlight, which is crucial for the maintenance of normal vitamin D levels. A deficiency in vitamin D levels or vitamin D receptors is commonly indicated in autoimmune diseases, with multiple sclerosis (MS) being one of the best-studied and well-known examples. However, the role of vitamin D in other autoimmune diseases is not well defined, including autoimmune liver diseases such as primary biliary cirrhosis, autoimmune hepatitis, and primary sclerosing cholangitis. This review will examine the role of vitamin D as an immunomodulator, followed by a comparison of vitamin D in MS versus autoimmune liver disease. From this comparison, it will become clear that vitamin D likely plays a role in the development of autoimmune liver disease, but this area requires further investigation. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  16. Psoriasis as an autoimmune disease

    Directory of Open Access Journals (Sweden)

    Agnieszka Owczarczyk-Saczonek

    2014-09-01

    Full Text Available Nowadays it is known that psoriasis belongs to the group of autoimmune diseases and may coexist with other diseases in this group. Most often patients have psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid diseases and multiple sclerosis. The coexistence of these disorders can be a diagnostic and therapeutic problem (there is controversy over the use of corticosteroids. The common pathogenesis is still not explained. We know that the loss of immunotolerance leads to formation of autoreactive Th1 and Th17 lymphocytes which recognize self-antigens and lead to their destruction in the target organ. Some features of immune mechanisms, observed in psoriasis, suggest its autoimmune background. In psoriasis the main role is played by the activation of the axis IL-12/Th1/IFN- and Th17/Il-23. Il-12 probably acts on naive T cells and the Th1 response is initiated. Il-23 maintains the Th1-mediated inflammatory reaction, stimulates maturation and effects of Th17, and maintains a certain amount of memory cells. We also observe dysfunction of Treg cells, which are responsible for the destruction of autoreactive lymphocytes. In addition, psoriatic keratinocytes have increased resistance to apoptosis, which eliminate damaged cells so that they cannot be recognized as a foreign antigen. However, researchers have suggested that initially the polyclonal activation of T lymphocytes is induced by superantigens (e.g. streptococcal M protein, peptidoglycan or skin trauma (Koebner phenomenon, whereas in the later phase self-antigens in the epidermis are recognized by autoreactive T cells (keratin K 17, HPV 5 proteins L1, Pso p27, leading to autoimmunity.

  17. Helminth Immunomodulation in Autoimmune Disease

    OpenAIRE

    John J. Miles; John J. Miles; John J. Miles; John J. Miles; Taylor B. Smallwood; Paul R. Giacomin; Alex Loukas; Jason P. Mulvenna; Jason P. Mulvenna; Jason P. Mulvenna; Richard J. Clark

    2017-01-01

    Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating “talents” of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models ...

  18. Autoimmune diseases and reproductive aging

    OpenAIRE

    Bove, Riley

    2013-01-01

    As the population ages, more individuals with autoimmune diseases are experiencing reproductive senescence. Understanding the impact of menopause and age-related androgen decline on disease onset and course, as well as the potential for hormonal interventions, is critically important. In men, lupus erythematosis (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS) are associated with lower androgen levels. However, the impact of age-related declines in testosterone, as well as of tes...

  19. Autoimmune Thyroiditis and Myasthenia Gravis

    Directory of Open Access Journals (Sweden)

    Angela Lopomo

    2017-07-01

    Full Text Available Autoimmune diseases (AIDs are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as “self” are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto’s thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG. In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed.

  20. Vitamin D and autoimmune diseases

    Directory of Open Access Journals (Sweden)

    E. A. Potrokhova

    2017-01-01

    Full Text Available The review discusses the effect of vitamin D on the tolerogenic modulation of an immune response, its relationship to cells of the monocyte-macrophage series, including dendritic cells, monocytes, and macrophages, in the context of the impact of the expression of anti-inflammatory proinflammatory cytokines in some autoimmune diseases (rheumatoid arthritis, systemic scleroderma, multiple sclerosis, type 1 diabetes mellitus, systemic lupus erythematosus, and Crohn`s disease. It discusses the role of vitamin D in the development of innate and adaptive immunity. Despite some conflicting evidence, the immune regulatory function of vitamin D is generally directed toward inhibition of the components of innate and acquired immunity, which are responsible for the induction of autoimmune reactions; in this connection there are a growing number of publications devoted to the issues of vitamin D supplementation in patients with autoimmune diseases, the preventive effect of vitamin D intake on the risk of an abnormality and that of therapeutic doses of the vitamin on its course. The maintenance of the threshold value for serum 25(OHD3 at least 30 ng/ml, which is achieved by the intake of about 2000 IU of vitamin D, is shown to be required for its immune regulatory function. The data given raise the question as to whether it is necessity to revise the Russian recommended daily dietary allowances for vitamin D through its infant food fortification.

  1. Stochastic Effects in Autoimmune Dynamics

    Directory of Open Access Journals (Sweden)

    Farzad Fatehi

    2018-02-01

    Full Text Available Among various possible causes of autoimmune disease, an important role is played by infections that can result in a breakdown of immune tolerance, primarily through the mechanism of “molecular mimicry”. In this paper we propose and analyse a stochastic model of immune response to a viral infection and subsequent autoimmunity, with account for the populations of T cells with different activation thresholds, regulatory T cells, and cytokines. We show analytically and numerically how stochasticity can result in sustained oscillations around deterministically stable steady states, and we also investigate stochastic dynamics in the regime of bi-stability. These results provide a possible explanation for experimentally observed variations in the progression of autoimmune disease. Computations of the variance of stochastic fluctuations provide practically important insights into how the size of these fluctuations depends on various biological parameters, and this also gives a headway for comparison with experimental data on variation in the observed numbers of T cells and organ cells affected by infection.

  2. Autoimmune Thyroiditis and Myasthenia Gravis

    Science.gov (United States)

    Lopomo, Angela; Berrih-Aknin, Sonia

    2017-01-01

    Autoimmune diseases (AIDs) are the result of specific immune responses directed against structures of the self. In normal conditions, the molecules recognized as “self” are tolerated by immune system, but when the self-tolerance is lost, the immune system could react against molecules from the body, causing the loss of self-tolerance, and subsequently the onset of AID that differs for organ target and etiology. Autoimmune thyroid disease (ATD) is caused by the development of autoimmunity against thyroid antigens and comprises Hashimoto’s thyroiditis and Graves disease. They are frequently associated with other organ or non-organ specific AIDs, such as myasthenia gravis (MG). In fact, ATD seems to be the most associated pathology to MG. The etiology of both diseases is multifactorial and it is due to genetic and environmental factors, and each of them has specific characteristics. The two pathologies show many commonalities, such as the organ-specificity with a clear pathogenic effect of antibodies, the pathological mechanisms, such as deregulation of the immune system and the implication of the genetic predisposition. They also show some differences, such as the mode of action of the antibodies and therapies. In this review that focuses on ATD and MG, the common features and the differences between the two diseases are discussed. PMID:28751878

  3. Human Cytomegalovirus and Autoimmune Disease

    Science.gov (United States)

    2014-01-01

    Human cytomegalovirus (HCMV) represents a prototypic pathogenic member of the β-subgroup of the herpesvirus family. A range of HCMV features like its lytic replication in multiple tissues, the lifelong persistence through periods of latency and intermitting reactivation, the extraordinary large proteome, and extensive manipulation of adaptive and innate immunity make HCMV a high profile candidate for involvement in autoimmune disorders. We surveyed the available literature for reports on HCMV association with onset or exacerbation of autoimmune disease. A causative linkage between HCMV and systemic lupus erythematosus (SLE), systemic sclerosis (SSc), diabetes mellitus type 1, and rheumatoid arthritis (RA) is suggested by the literature. However, a clear association of HCMV seroprevalence and disease could not be established, leaving the question open whether HCMV could play a coresponsible role for onset of disease. For convincing conclusions population-based prospective studies must be performed in the future. Specific immunopathogenic mechanisms by which HCMV could contribute to the course of autoimmune disease have been suggested, for example, molecular mimicry by UL94 in SSc and UL83/pp65 in SLE patients, as well as aggravation of joint inflammation by induction and expansion of CD4+/CD28− T-cells in RA patients. Further studies are needed to validate these findings and to lay the grounds for targeted therapeutic intervention. PMID:24967373

  4. Epigenetics as biomarkers in autoimmune diseases.

    Science.gov (United States)

    Wu, Haijing; Liao, Jieyue; Li, Qianwen; Yang, Ming; Zhao, Ming; Lu, Qianjin

    2018-03-21

    Autoimmune diseases are immune system disorders in which immune cells cannot distinguish self-antigens from foreign ones. The current criteria for autoimmune disease diagnosis are based on clinical manifestations and laboratory tests. However, none of these markers shows both high sensitivity and specificity. In addition, some autoimmune diseases, for example, systemic lupus erythematosus (SLE), are highly heterogeneous and often exhibit various manifestations. On the other hand, certain autoimmune diseases, such as Sjogren's syndrome versus SLE, share similar symptoms and autoantibodies, which also causes difficulties in diagnosis. Therefore, biomarkers that have both high sensitivity and high specificity for diagnosis, reflect disease activity and predict drug response are necessary. An increasing number of publications have proposed the abnormal epigenetic modifications as biomarkers of autoimmune diseases. Therefore, this review will comprehensively summarize the epigenetic progress in the pathogenesis of autoimmune disorders and unearth potential biomarkers that might be appropriate for disease diagnosis and prediction. Copyright © 2018. Published by Elsevier Inc.

  5. Autoimmune diseases in adults with atopic dermatitis

    DEFF Research Database (Denmark)

    Andersen, Yuki M F; Egeberg, Alexander; Gislason, Gunnar H.

    2017-01-01

    Background: An increased susceptibility to autoimmune disease has been shown in patients with atopic dermatitis (AD), but data remain scarce and inconsistent. Objective: We examined the co-occurrence of selected autoimmune diseases in adult patients with AD. Methods: Nationwide health registers...... were used. Adult patients with a hospital diagnosis of AD in Denmark between 1997 and 2012 were included as cases (n = 8112) and matched with controls (n = 40,560). The occurrence of autoimmune diseases was compared in the 2 groups. Logistic regression was used to estimate odds ratios. Results: AD...... was significantly associated with 11 of 22 examined autoimmune diseases. In addition, AD was associated with having multiple autoimmune comorbidities. Patients with a history of smoking had a significantly higher occurrence of autoimmune comorbidities compared to nonsmokers. Limitations: This study was limited...

  6. [Pulmonary arterial hypertension: a flavor of autoimmunity].

    Science.gov (United States)

    Perros, Frédéric; Humbert, Marc; Cohen-Kaminsky, Sylvia

    2013-01-01

    It is admitted that autoimmunity results from a combination of risks such as genetic background, environmental triggers, and stochastic events. Pulmonary arterial hypertension (PAH) shares with the so-called prototypic autoimmune diseases, genetic risk factors, female predominance and sex hormone influence, association with other chronic inflammatory and autoimmune diseases, defects in regulatory T cells function, and presence of autoantibodies. Case reports have been published indicating the beneficial effect of some immunosuppressive and anti-inflammatory therapies in PAH, supporting the potential role of immune mechanisms in the pathophysiology of the disease. In this review, we discuss the current knowledge on autoimmune mechanisms operating in PAH, especially mounting a local autoimmune response inside the pulmonary tissue, namely pulmonary lymphoid neogenesis. A better understanding of the role of autoimmunity in pulmonary vascular remodelling may help develop targeted immunomodulatory strategies in PAH. © 2013 médecine/sciences – Inserm.

  7. Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

    Science.gov (United States)

    Gutierrez-Arcelus, Maria; Rich, Stephen S.; Raychaudhuri, Soumya

    2016-01-01

    Genome-wide strategies have driven the discovery of more than 300 susceptibility loci for autoimmune diseases. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in non-coding regions of the genome. A critical next step will be to identify the in vivo and ex vivo immunophenotypes that are affected by risk variants. To do this, key cell types and cell states that are implicated in autoimmune diseases will need to be defined. Functional genomic annotations from these cell types and states can then be used to resolve candidate genes and causal variants. Together with longitudinal studies, this approach may yield pivotal insights into how autoimmunity is triggered. PMID:26907721

  8. Silicosis and Silica-Induced Autoimmunity in the Diversity Outbred Mouse

    Directory of Open Access Journals (Sweden)

    Jessica M. Mayeux

    2018-04-01

    Full Text Available Epidemiological studies have confidently linked occupational crystalline silica exposure to autoimmunity, but pathogenic mechanisms and role of genetic predisposition remain poorly defined. Although studies of single inbred strains have yielded insights, understanding the relationships between lung pathology, silica-induced autoimmunity, and genetic predisposition will require examination of a broad spectrum of responses and susceptibilities. We defined the characteristics of silicosis and autoimmunity and their relationships using the genetically heterogeneous diversity outbred (DO mouse population and determined the suitability of this model for investigating silica-induced autoimmunity. Clinically relevant lung and autoimmune phenotypes were assessed 12 weeks after a transoral dose of 0, 5, or 10 mg crystalline silica in large cohorts of DO mice. Data were further analyzed for correlations, hierarchical clustering, and sex effects. DO mice exhibited a wide range of responses to silica, including mild to severe silicosis and importantly silica-induced systemic autoimmunity. Strikingly, about half of PBS controls were anti-nuclear antibodies (ANA positive, however, few had disease-associated specificities, whereas most ANAs in silica-exposed mice showed anti-ENA5 reactivity. Correlation and hierarchical clustering showed close association of silicosis, lung biomarkers, and anti-ENA5, while other autoimmune characteristics, such as ANA and glomerulonephritis, clustered separately. Silica-exposed males had more lung inflammation, bronchoalveolar lavage fluid cells, IL-6, and autoantibodies. DO mice are susceptible to both silicosis and silica-induced autoimmunity and show substantial individual variations reflecting their genetic diverseness and the importance of predisposition particularly for autoimmunity. This model provides a new tool for deciphering the relationship between silica exposure, genes, and disease.

  9. Microbiota and Autoimmunity: exploring new avenues

    OpenAIRE

    Yurkovetskiy, Leonid; Pickard, Joseph M.; Chervonsky, Alexander V.

    2015-01-01

    Given the recognized role of the commensal microbiota in regulating host immunity to pathogens, it is not surprising that microbiota are also capable of regulating autoimmune responses. The underlying mechanisms of autoimmune regulation by the microbiota are just beginning to emerge. Here, we discuss possible pressure points towards the development of autoimmune diseases that can be influenced by the microbiota. Besides acting on the adaptive and innate arms of the immune response, the microb...

  10. Severe autoimmune hemolytic anemia with renal neoplasm.

    Science.gov (United States)

    Rhodes, Emily C; Parikh, Sahil P; Bhattacharyya, Nishith

    2014-02-01

    Autoimmune hemolytic anemia is a type of hemolytic anemia characterized by autoantibodies directed against red blood cells shortening their survival. When autoimmune hemolytic anemia is secondary to a paraneoplastic process, severe anemia can occur leading to significant morbidity and even mortality. Here we discuss the literature and present the case of a child with autoimmune hemolytic anemia from a paraneoplastic syndrome secondary to a renal tumor.

  11. Recurrent Oral Inflammation in Autoimmune Lymphoproliferative Syndrome

    OpenAIRE

    Pac, Malgorzata; Olczak-Kowalczyk, Dorota; Wolska-Kuśnierz, Beata; Piątosa, Barbara; Górska, Renata; Bernatowska, Ewa

    2014-01-01

    Abstract   Background and aim: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. In ALPS defective lymphocyte apoptosis manifests as a chronic, nonmalignant lymphadenopathy and/or splenomegaly/hepatosplenomegaly, expansion of double negative T cell (DNTC) – CD4-CD8-TCRαβ+ T cells, autoimmune cytopenias and other autoimmune diseases.  Patients demonstrate oral lesions which have not yet been repo...

  12. Role of Complement in Autoimmune Hemolytic Anemia

    OpenAIRE

    Berentsen, Sigbj?rn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorder...

  13. Diagnosing autoimmune pancreatitis with the Unifying-Autoimmune-Pancreatitis-Criteria.

    Science.gov (United States)

    Schneider, Alexander; Michaely, Henrik; Rückert, Felix; Weiss, Christel; Ströbel, Philipp; Belle, Sebastian; Hirth, Michael; Wilhelm, Torsten J; Haas, Stephan L; Jesenofsky, Ralf; Schönberg, Stefan; Marx, Alexander; Singer, Manfred V; Ebert, Matthias P; Pfützer, Roland H; Löhr, J Matthias

    We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  14. A new combination of multiple autoimmune syndrome? Coexistence of vitiligo, autoimmune thyroid disease and ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Firdevs Topal

    2011-09-01

    Full Text Available The occurrence of three or more autoimmune disorders in one patient defines multiple autoimmune syndrome. The pathogenesis of multiple autoimmune syndrome is not known yet and environmental triggers and genetic susceptibility have been suggested to be involved. Herein, we report a 47-year-old woman who had Hashimoto’s thyroiditis, vitiligo and newly diagnosed ulcerative colitis. Diagnosis of ulcerative colitis was confirmed with histopathologic examination. This case presents a new combination of multiple autoimmune syndrome.

  15. sirt1-null mice develop an autoimmune-like condition

    International Nuclear Information System (INIS)

    Sequeira, Jedon; Boily, Gino; Bazinet, Stephanie; Saliba, Sarah; He Xiaohong; Jardine, Karen; Kennedy, Christopher; Staines, William; Rousseaux, Colin; Mueller, Rudi; McBurney, Michael W.

    2008-01-01

    The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals. Some of the sirt1-null animals develop a disease resembling diabetes insipidus when they approach 2 years of age although the relationship to the autoimmunity remains unclear. We interpret these observations as consistent with a role for SIRT1 in sustaining normal immune function and in this way delaying the onset of autoimmune disease

  16. Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases.

    Science.gov (United States)

    Witoelar, Aree; Jansen, Iris E; Wang, Yunpeng; Desikan, Rahul S; Gibbs, J Raphael; Blauwendraat, Cornelis; Thompson, Wesley K; Hernandez, Dena G; Djurovic, Srdjan; Schork, Andrew J; Bettella, Francesco; Ellinghaus, David; Franke, Andre; Lie, Benedicte A; McEvoy, Linda K; Karlsen, Tom H; Lesage, Suzanne; Morris, Huw R; Brice, Alexis; Wood, Nicholas W; Heutink, Peter; Hardy, John; Singleton, Andrew B; Dale, Anders M; Gasser, Thomas; Andreassen, Ole A; Sharma, Manu

    2017-07-01

    Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. The study findings provide novel mechanistic

  17. Autoimmune atrophic gastritis: current perspectives

    Directory of Open Access Journals (Sweden)

    Minalyan A

    2017-02-01

    Full Text Available Artem Minalyan,1 Jihane N Benhammou,1 Aida Artashesyan,1 Michael S Lewis,2 Joseph R Pisegna1 1Division of Gastroenterology, Hepatology and Parenteral Nutrition, 2Department of Pathology and Laboratory Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA Abstract: At present there is no universally accepted classification for gastritis. The first successful classification (The Sydney System that is still commonly used by medical professionals was first introduced by Misiewicz et al in Sydney in 1990. In fact, it was the first detailed classification after the discovery of Helicobacter pylori by Warren and Marshall in 1982. In 1994, the Updated Sydney System was proposed during the International Workshop on the Histopathology of Gastritis followed by the publication in The American Journal of Surgical Pathology by Dixon et al. Using the new classification, distinction between atrophic and nonatrophic gastritis was revised, and the visual scale grading was incorporated. According to the Updated Sydney System Classification, atrophic gastritis is categorized into multifocal (H. pylori, environmental factors, specific diet and corpus-predominant (autoimmune. Since metaplasia is a key histological characteristic in patients with atrophic gastritis, it has been recommended to use the word “metaplastic” in both variants of atrophic gastritis: autoimmune metaplastic atrophic gastritis (AMAG and environmental metaplastic atrophic gastritis. Although there are many overlaps in the course of the disease and distinction between those two entities may be challenging, the aim of this review article was to describe the etiology, epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment in patients with AMAG. However, it is important to mention that H. pylori is the most common etiologic factor for the development of gastritis in the world. Keywords: autoimmune gastritis, pernicious anemia, gastric carcinoid

  18. Immunoglobulin E-Mediated Autoimmunity

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    Marcus Maurer

    2018-04-01

    Full Text Available The study of autoimmunity mediated by immunoglobulin E (IgE autoantibodies, which may be termed autoallergy, is in its infancy. It is now recognized that systemic lupus erythematosus, bullous pemphigoid (BP, and chronic urticaria, both spontaneous and inducible, are most likely to be mediated, at least in part, by IgE autoantibodies. The situation in other conditions, such as autoimmune uveitis, rheumatoid arthritis, hyperthyroid Graves’ disease, autoimmune pancreatitis, and even asthma, is far less clear but evidence for autoallergy is accumulating. To be certain of an autoallergic mechanism, it is necessary to identify both IgE autoantibodies and their targets as has been done with the transmembrane protein BP180 and the intracellular protein BP230 in BP and IL-24 in chronic spontaneous urticaria. Also, IgE-targeted therapies, such as anti-IgE, must have been shown to be of benefit to patients as has been done with both of these conditions. This comprehensive review of the literature on IgE-mediated autoallergy focuses on three related questions. What do we know about the prevalence of IgE autoantibodies and their targets in different diseases? What do we know about the relevance of IgE autoantibodies in different diseases? What do we know about the cellular and molecular effects of IgE autoantibodies? In addition to providing answers to these questions, based on a broad review of the literature, we outline the current gaps of knowledge in our understanding of IgE autoantibodies and describe approaches to address them.

  19. Helminth Immunomodulation in Autoimmune Disease.

    Science.gov (United States)

    Smallwood, Taylor B; Giacomin, Paul R; Loukas, Alex; Mulvenna, Jason P; Clark, Richard J; Miles, John J

    2017-01-01

    Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

  20. Endocrine autoimmune disease: genetics become complex.

    Science.gov (United States)

    Wiebolt, Janneke; Koeleman, Bobby P C; van Haeften, Timon W

    2010-12-01

    The endocrine system is a frequent target in pathogenic autoimmune responses. Type 1 diabetes and autoimmune thyroid disease are the prevailing examples. When several diseases cluster together in one individual, the phenomenon is called autoimmune polyglandular syndrome. Progress has been made in understanding the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases such as autoimmune polyglandular syndrome type 1, immunodysregulation, polyendocrinopathy, enteropathy, X-linked and primary immune deficiencies helped uncover the role of key regulators in the preservation of immune tolerance. Alleles of the major histocompatibility complex have been known to contribute to the susceptibility to most forms of autoimmunity for more than 3 decades. Furthermore, sequencing studies revealed three non-major histocompatibility complex loci and some disease specific loci, which control T lymphocyte activation or signalling. Recent genome-wide association studies (GWAS) have enabled acceleration in the identification of novel (non-HLA) loci and hence other relevant immune response pathways. Interestingly, several loci are shared between autoimmune diseases, and surprisingly some work in opposite direction. This means that the same allele which predisposes to a certain autoimmune disease can be protective in another. Well powered GWAS in type 1 diabetes has led to the uncovering of a significant number of risk variants with modest effect. These studies showed that the innate immune system may also play a role in addition to the adaptive immune system. It is anticipated that next generation sequencing techniques will uncover other (rare) variants. For other autoimmune disease (such as autoimmune thyroid disease) GWAS are clearly needed. © 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.

  1. Autoimmunity as a Driving Force of Cognitive Evolution

    Directory of Open Access Journals (Sweden)

    Serge Nataf

    2017-10-01

    Full Text Available In the last decades, increasingly robust experimental approaches have formally demonstrated that autoimmunity is a physiological process involved in a large range of functions including cognition. On this basis, the recently enunciated “brain superautoantigens” theory proposes that autoimmunity has been a driving force of cognitive evolution. It is notably suggested that the immune and nervous systems have somehow co-evolved and exerted a mutual selection pressure benefiting to both systems. In this two-way process, the evolutionary-determined emergence of neurons expressing specific immunogenic antigens (brain superautoantigens has exerted a selection pressure on immune genes shaping the T-cell repertoire. Such a selection pressure on immune genes has translated into the emergence of a finely tuned autoimmune T-cell repertoire that promotes cognition. In another hand, the evolutionary-determined emergence of brain-autoreactive T-cells has exerted a selection pressure on neural genes coding for brain superautoantigens. Such a selection pressure has translated into the emergence of a neural repertoire (defined here as the whole of neurons, synapses and non-neuronal cells involved in cognitive functions expressing brain superautoantigens. Overall, the brain superautoantigens theory suggests that cognitive evolution might have been primarily driven by internal cues rather than external environmental conditions. Importantly, while providing a unique molecular connection between neural and T-cell repertoires under physiological conditions, brain superautoantigens may also constitute an Achilles heel responsible for the particular susceptibility of Homo sapiens to “neuroimmune co-pathologies” i.e., disorders affecting both neural and T-cell repertoires. These may notably include paraneoplastic syndromes, multiple sclerosis as well as autism, schizophrenia and neurodegenerative diseases. In the context of this theoretical frame, a specific

  2. Neuromyelitis optica spectrum disorders without and with autoimmune diseases

    OpenAIRE

    Zhang, Bingjun; Zhong, Yi; Wang, Yanqiang; Dai, Yongqiang; Qiu, Wei; Zhang, Lei; Li, Haiyan; Lu, Zhengqi

    2014-01-01

    Background Neuromyelitis optica spectrum disorder (NMOSD) can coexist with non-organ-specific or organ-specific autoimmune diseases. The aim of this study was to investigate and compare the features between NMOSD without and with autoimmune diseases, and NMOSD with non-organ-specific and organ-specific autoimmune diseases. Methods One hundred and fifty five NMOSD patients without autoimmune diseases (n = 115) and with autoimmune diseases (n = 40) were enrolled. NMOSD with autoimmune diseases ...

  3. Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease.

    Science.gov (United States)

    Nabhani, Schafiq; Ginzel, Sebastian; Miskin, Hagit; Revel-Vilk, Shoshana; Harlev, Dan; Fleckenstein, Bernhard; Hönscheid, Andrea; Oommen, Prasad T; Kuhlen, Michaela; Thiele, Ralf; Laws, Hans-Jürgen; Borkhardt, Arndt; Stepensky, Polina; Fischer, Ute

    2015-09-01

    Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. Copyright© Ferrata Storti

  4. Lupus-like panniculitis in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

    Science.gov (United States)

    Füchtenbusch, M; Vogel, A; Achenbach, P; Gummer, M; Ziegler, A G; Albert, E; Standl, E; Manns, M P

    2003-08-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder, characterised by a loss of self-tolerance to endocrine tissues, chronic candidiasis and ectodermal disorders. APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). We describe a 31-year-old APECED patient with non-traumatic, cutaneous ulcers on both forearms with features of a lupus-like panniculitis. On admission to the ICU in September 2001, the patient suffered from a ketoacidotic, hyperglycemic coma and adrenal crisis due to an Enterobacter-cloacae sepsis, originating from multiple, necrotising deep cutaneous ulcers. These ulcers spontaneously developed on both forearms, some of which were just emerging, full blown or healing with scars. Histological examination showed signs of a scarring panniculitis and vasculitis. Immunohistochemistry and direct immunofluorescence with characterisation of immunoglobulin and complement-factor binding pattern revealed features of a lupus-like panniculitis. Sequence analysis of all 14 exons of the AIRE gene revealed a R257 X mutation in exon 6 resulting in a nonsense mutation at codon 257 confirming the diagnosis of APECED. Oral treatment with 60 mg/day corticosteroids for two weeks led to complete resolution of all ulcers. In conclusion, mutations in the AIRE gene may provide the genetic background against which additional factors can initiate an autoimmune process. Here, autoimmune panniculitis appears to be an associated feature of the APECED syndrome. Our findings support the use of immunosuppressive therapy for autoimmune disease components of the APECED syndrome.

  5. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders

    Science.gov (United States)

    Miller, Frederick W.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy; Isenberg, David A.; Chinoy, Hector; Ollier, William E. R.; O’Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.

    2014-01-01

    Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID:23983088

  6. Estrogen receptor alpha dinucleotide repeat polymorphism in Japanese patients with autoimmune thyroid diseases

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    Tozaki Teruaki

    2000-11-01

    Full Text Available Abstract Background The autoimmune thyroid diseases (AITDs, comprising Graves' disease (GD and Hashimoto's thyroiditis (HT, appear to develop as a result of complex interactions between predisposing genes and environmental triggers. Susceptibility to AITDs is conferred by genes in the human leukocyte antigen (HLA and genes unlinked to HLA, including the CTLA-4 gene. Recently, an association to some estrogen receptor (ERα genotypes with breast cancer, hypertension, osteoporosis, generalized osteoarthritis, and some autoimmune diseases such as rheumatoid arthritis has been reported. We have analyzed a dinucleotide (TAn repeat polymorphism lying upstream of the human ERα gene in patients with AITDs and in normal subjects. Results Seventeen different alleles were found in 130 patients with GD, 93 patients with HT, and 190 control subjects. There was no significant difference in the distributions of ERα alleles between patients and controls. Conclusions The present results do not support an association between the ERα gene and AITD in the Japanese population.

  7. The mechanism of tissue-restricted antigen gene expression by AIRE.

    Science.gov (United States)

    Zumer, Kristina; Saksela, Kalle; Peterlin, B Matija

    2013-03-15

    The autoimmune regulator is a critical transcription factor for generating central tolerance in the thymus. Recent studies have revealed how the autoimmune regulator targets many otherwise tissue-restricted Ag genes to enable negative selection of autoreactive T cells.

  8. AIRE genetic variants and predisposition to polygenic autoimmune disease: The case of Graves' disease and a systematic literature review.

    Science.gov (United States)

    Colobran, Roger; Giménez-Barcons, Mireia; Marín-Sánchez, Ana; Porta-Pardo, Eduard; Pujol-Borrell, Ricardo

    2016-08-01

    Autoimmune Regulator (AIRE) is a transcriptional regulator that is crucial for establishing central tolerance as illustrated by the Mendelian Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome associated with AIRE-inactivating recessive or dominant mutations. Polymorphisms in AIRE have been proposed to be implicated in genetic susceptibility to non-Mendelian organ specific autoimmune diseases. Because there is evidence that in predisposition to Graves' disease (GD) central tolerance is crucial, we investigated whether AIRE polymorphisms could modulate risk of GD. A case-control association study using 29 variants and conducted in 150 GD patients and 200 controls did not detect any significant association. This result is not exceptional: a systematic review of the literature, including GWAS, on the association of AIRE variants with organ specific autoimmune diseases did not show clear associations; similarly heterozygous recessive mutations are not associated to non-Mendelian autoimmunity. Dominant negative mutations of AIRE are associated to autoimmunity but as mild forms of APECED rather than to non-Mendelian organ specific autoimmunity. The lack of association of common AIRE polymorphisms with polygenic autoimmune diseases is counterintuitive as many other genes less relevant for immunological tolerance have been found to be associated. These findings give rise to the intriguing possibility that evolution has excluded functionally modifying polymorphisms in AIRE. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  9. Interferon-¿ regulates oxidative stress during experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C.; Penkowa, Milena; Saez-Torres, I.

    2002-01-01

    Neurobiology, experimental autoimmune encephalomyelitis IFN-d, multiple sclerosis, neurodegeneration, oxidative stress......Neurobiology, experimental autoimmune encephalomyelitis IFN-d, multiple sclerosis, neurodegeneration, oxidative stress...

  10. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

    NARCIS (Netherlands)

    Cavalli, G.; Hayashi, M.; Jin, Y.; Yorgov, D.; Santorico, S.A.; Holcomb, C.; Rastrou, M.; Erlich, H.; Tengesdal, I.W.; Dagna, L.; Neff, C.P.; Palmer, B.E.; Spritz, R.A.; Dinarello, C.A.

    2016-01-01

    Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart,

  11. Kaleidoscope of autoimmune diseases in HIV infection.

    Science.gov (United States)

    Roszkiewicz, Justyna; Smolewska, Elzbieta

    2016-11-01

    Within the last 30 years, the human immunodeficiency virus (HIV) infection has changed its status from inevitably fatal to chronic disorder with limited impact on life span. However, this breakthrough was mainly the effect of introduction of the aggressive antiviral treatment, which has led to the clinically significant increase in CD4+ cell count, resulting in fewer cases of the acquired immunodeficiency syndrome (AIDS) and improved management of opportunistic infections occurring in the course of the disease. The occurrence of a particular autoimmune disease depends on degree of immunosuppression of the HIV-positive patient. In 2002, four stages of autoimmunity were proposed in patients infected by HIV, based on the absolute CD4+ cell count, feature of AIDS as well as on the presence of autoimmune diseases. Spectrum of autoimmune diseases associated with HIV infection seems to be unexpectedly wide, involving several organs, such as lungs (sarcoidosis), thyroid gland (Graves' disease), liver (autoimmune hepatitis), connective tissue (systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa and other types of vasculitis, antiphospholipid syndrome) or hematopoietic system (autoimmune cytopenias). This paper contains the state of art on possible coincidences between HIV infection and a differential types of autoimmune diseases, including the potential mechanisms of this phenomenon. As the clinical manifestations of autoimmunization often mimic those inscribed in the course of HIV infection, health care providers should be aware of this rare but potentially deadly association and actively seek for its symptoms in their patients.

  12. Gender and autoimmune comorbidity in multiple sclerosis

    DEFF Research Database (Denmark)

    Magyari, Melinda; Koch-Henriksen, Nils; Pfleger, Claudia C

    2014-01-01

    BACKGROUND: The female preponderance in incidence of multiple sclerosis (MS) calls for investigations into sex differences in comorbidity with other autoimmune diseases (ADs). OBJECTIVES: To determine whether male and female patients with MS have a higher frequency of autoimmune comorbidity than...

  13. Autoimmune hepatitis and juvenile systemic lupus erythematosus

    NARCIS (Netherlands)

    Deen, M. E. J.; Porta, G.; Fiorot, F. J.; Campos, L. M. A.; Sallum, A. M. E.; Silva, C. A. A.

    Juvenile systemic lupus erythematosus (JSLE) and autoimmune hepatitis (AIH) are both autoimmune disorders that are rare in children and have a widespread clinical manifestation. A few case reports have shown a JSLE-AIH associated disorder. To our knowledge, this is the first study that

  14. Autoimmune diseases in women with Turner's syndrome

    DEFF Research Database (Denmark)

    Jørgensen, Kristian T; Rostgaard, Klaus; Bache, Iben

    2010-01-01

    OBJECTIVE: In terms of number of X chromosomes, women with Turner's syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turner's syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with T...

  15. Cardiovascular Involvement in Autoimmune Diseases

    Science.gov (United States)

    Amaya-Amaya, Jenny

    2014-01-01

    Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetics factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD. PMID:25177690

  16. Cystic Lesions in Autoimmune Pancreatitis

    Directory of Open Access Journals (Sweden)

    Macarena Gompertz

    2015-11-01

    Full Text Available Autoimmune pancreatitis (AIP can be chronic or recurrent, but frequently completely reversible after steroid treatment. A cystic lesion in AIP is a rare finding, and it can mimic a pancreatic cystic neoplasm. Difficulties in an exact diagnosis interfere with treatment, and surgery cannot be avoided in some cases. We report the history of a 63-year-old male presenting with jaundice and pruritus. AIP was confirmed by imaging and elevated IgG4 blood levels, and the patient completely recovered after corticosteroid therapy. One year later, he presented with a recurrent episode of AIP with elevated IgG4 levels, accompanied by the appearance of multiple intrapancreatic cystic lesions. All but 1 of these cysts disappeared after steroid treatment, but the remaining cyst in the pancreatic head was even somewhat larger 1 year later. Pancreatoduodenectomy was finally performed. Histology showed the wall of the cystic lesion to be fibrotic; the surrounding pancreatic tissue presented fibrosis, atrophy and lymphoplasmacytic infiltration by IgG4-positive cells, without malignant elements. Our case illustrates the rare possibility that cystic lesions can be part of AIP. These pseudocysts appear in the pancreatic segments involved in the autoimmune disease and can be a consequence of the local inflammation or related to ductal strictures. Steroid treatment should be initiated, after which these cysts can completely disappear with recovery from AIP. Surgical intervention may be necessary in some exceptional cases.

  17. Autoimmunity, infectious immunity, and atherosclerosis.

    Science.gov (United States)

    Matsuura, Eiji; Kobayashi, Kazuko; Matsunami, Yukana; Shen, Lianhua; Quan, Nanhu; Makarova, Marina; Suchkov, Sergey V; Ayada, Kiyoshi; Oguma, Keiji; Lopez, Luis R

    2009-11-01

    Vascular inflammation is common in certain systemic autoimmune diseases and contributes to the oxidation of low-density lipoprotein (oxLDL) and oxLDL/beta2-glycoprotein I (beta2GPI) complex formation. These complexes have been implicated as proatherogenic autoantigens that participate in the development of atherosclerotic disease. We have demonstrated that the in vitro macrophage uptake of oxLDL/beta2GPI complexes increases in the presence of IgG anti-beta2GPI antibodies and that IgG immune complexes containing oxLDL/beta2GPI upregulate the expression of both scavenger and Fcgamma receptors to activate beta2GPI specific T cells. Some persistent infections may cause immune responses that promote atherogenesis. Cellular immunity (Th1) against Helicobacter pylori (H. pylori) derived heat shock protein 60 (Hp-HSP60) cross-reacts with endogenous HSP60 to cause cardiovascular disease likely by molecular mimicry. Infectious cellular response may be proatherogenic,while the humoral response (antibody production) maybe protective. We review the recent progress in our understanding of autoimmunity and infectious immunity that promote atherosclerosis.

  18. Warm antibody autoimmune hemolytic anemia.

    Science.gov (United States)

    Kalfa, Theodosia A

    2016-12-02

    Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disease that affects 1 to 3/100 000 patients per year. AIHA caused by warm autoantibodies (w-AIHA), ie, antibodies that react with their antigens on the red blood cell optimally at 37°C, is the most common type, comprising ∼70% to 80% of all adult cases and ∼50% of pediatric cases. About half of the w-AIHA cases are called primary because no specific etiology can be found, whereas the rest are secondary to other recognizable underlying disorders. This review will focus on the postulated immunopathogenetic mechanisms in idiopathic and secondary w-AIHA and report on the rare cases of direct antiglobulin test-negative AIHA, which are even more likely to be fatal because of inherent characteristics of the causative antibodies, as well as because of delays in diagnosis and initiation of appropriate treatment. Then, the characteristics of w-AIHA associated with genetically defined immune dysregulation disorders and special considerations on its management will be discussed. Finally, the standard treatment options and newer therapeutic approaches for this chronic autoimmune blood disorder will be reviewed. © 2016 by The American Society of Hematology. All rights reserved.

  19. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept.

    Science.gov (United States)

    Altieri, Barbara; Muscogiuri, Giovanna; Barrea, Luigi; Mathieu, Chantal; Vallone, Carla V; Mascitelli, Luca; Bizzaro, Giorgia; Altieri, Vincenzo M; Tirabassi, Giacomo; Balercia, Giancarlo; Savastano, Silvia; Bizzaro, Nicola; Ronchi, Cristina L; Colao, Annamaria; Pontecorvi, Alfredo; Della Casa, Silvia

    2017-09-01

    In the last few years, more attention has been given to the "non-calcemic" effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1α-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the VDR or the CYP27B1 gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison's disease, Hashimoto's thyroiditis, Graves' disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases.

  20. The normally expressed kappa immunoglobulin light chain gene repertoire and somatic mutations studied by single-sided specific polymerase chain reaction (PCR); frequent occurrence of features often assigned to autoimmunity

    DEFF Research Database (Denmark)

    Juul, L; Hougs, L; Andersen, V

    1997-01-01

    . V genes from the Jkappa-proximal duplication unit of the kappa locus were almost exclusively used. A total of 65% of the sequences could be assigned to four or five genes: A27 (humkv325), L6 (Vg), L2 (humkv328), and A3 and/or A19. N additions and P nucleotides were quite common and found in 32......The expressed human kappa light chain gene repertoire utilized by healthy individuals was studied by two different single-sided specific PCR techniques to avoid bias for certain V genes. A total of 103 rearranged kappa sequences from peripheral blood mononuclear cells from healthy individuals were...... agreement with those of previous repertoire studies using potentially V-gene-biased techniques. Thus, it is clear that restricted V-gene usage, common N and P additions, and extended CDR3 regions are normal features and not, as has been claimed, characteristics of pathological autoantibodies....

  1. DNA mismatch repair enzymes: genetic defects and autoimmunity.

    Science.gov (United States)

    Muro, Yoshinao; Sugiura, Kazumitsu; Mimori, Tsuneyo; Akiyama, Masashi

    2015-03-10

    DNA mismatch repair (MMR) is one of the several DNA repair pathways conserved from bacteria to humans. The primary function of MMR is to eliminate the mismatch of base-base insertions and deletions that appear as a consequence of DNA polymerase errors at DNA synthesis. The genes encoding the DNA MMR enzymes (MMREs) are highly conserved throughout evolution. In humans, there are two sets of MMREs, corresponding to homologues of the bacterial MutLS systems. The human MutS enzymes consist of MSH2, MSH3 and MSH6, and the human MutL enzymes include MLH1, MLH3, PMS1 and PMS2. Since the beginning of this century, a few reports on autoantibodies to some MMREs have been reported in autoimmune inflammatory myopathy, cancer and hematological disorders. This review charts the functional structures of MMREs, their genetic defects and associated disorders, and autoimmunity to MMREs, including our recent data that was the first to analyze autoantibodies against all seven kinds of MMREs in systemic autoimmune diseases, including idiopathic inflammatory myopathies. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Oral microbiota in autoimmune polyendocrine syndrome type 1

    Science.gov (United States)

    Bruserud, Øyvind; Siddiqui, Huma; Marthinussen, Mihaela Cuida; Chen, Tsute; Jonsson, Roland; Oftedal, Bergithe Eikeland; Olsen, Ingar; Husebye, Eystein Sverre; Wolff, Anette Bøe

    2018-01-01

    ABSTRACT Background: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, childhood onset disease caused by mutations in the Autoimmune Regulator gene. The phenotypic expression is highly variable and includes disease manifestations in the oral cavity, including mucocutaneous candidiasis. Increasing evidence suggests a potential role of the skin, oral and gut microbiotas in the pathogenesis of autoimmunity. To date, no information exists regarding the oral microbiota in APS-1. Objective: To assess the bacterial microbiota of whole saliva in APS-1 patients by using high throughput sequencing. Design: Whole unstimulated saliva was collected from 10 APS-1 patients and 17 healthy controls and examined by high throughput sequencing of the hypervariable region V1-V2 of 16S rRNA using the 454 GS Junior system. Metastats (http://cbcb.umd.edu/software/metastats) was used to analyse the pyrosequencing reads. Results: A reduction in the total number of bacterial genera and species was detected in APS-1 compared to healthy controls. The proportion of the major phyla Firmicutes was higher (60% vs 41%, p = 0.002) and Bacteroidetes lower (15% vs 28%, p = 0.007) in APS-1 compared to healthy controls. On the genus level, Streptococcus and Gemella were prevalent in APS-1. Conclusion: Our findings indicate a significantly altered oral microbiota in APS-1. PMID:29503707

  3. Suppression of systemic autoimmunity by the innate immune adaptor STING

    Science.gov (United States)

    Sharma, Shruti; Campbell, Allison M.; Chan, Jennie; Schattgen, Stefan A.; Orlowski, Gregory M.; Nayar, Ribhu; Huyler, Annie H.; Nündel, Kerstin; Mohan, Chandra; Berg, Leslie J.; Shlomchik, Mark J.; Marshak-Rothstein, Ann; Fitzgerald, Katherine A.

    2015-01-01

    Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies. PMID:25646421

  4. Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED)--a diagnostic and therapeutic challenge.

    Science.gov (United States)

    Jääskeläinen, J; Perheentupa, J

    2009-12-01

    Autoimmune polyendocrinopathy - candidosis - ectodermal dystrophy (APECED), also known as autoimmune polyendocrine/polyglandular syndrome type 1 (APS1), is a rare disease caused by mutations in the autoimmune regulator (AIRE) gene pair resulting in absence of active AIRE protein, which is essential for both central and peripheral self-tolerance. The phenotype is widely variable. Apart from the classical triad of mucocutaneous candidosis, hypoparathyroidism and adrenal failure, several other components, some of which are potentially life-threatening, may develop. Due to the unpredictable clinical course, the patients need regular follow-up by a clinician familiar with the disease. Diagnosis is often possible by clinical diagnostic criteria, but in many cases the early clinical picture does not bring it to mind. A novel tool, search for autoantibodies against interferon-omega, enables proof or exclusion of APECED with more certainty than gene analysis. It is highly specific and sensitive for APECED if thymoma and myasthenia gravis are excluded.

  5. Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

    Science.gov (United States)

    Kreiner, Eskil; Waage, Johannes; Standl, Marie; Brix, Susanne; Pers, Tune H; Couto Alves, Alexessander; Warrington, Nicole M; Tiesler, Carla M T; Fuertes, Elaine; Franke, Lude; Hirschhorn, Joel N; James, Alan; Simpson, Angela; Tung, Joyce Y; Koppelman, Gerard H; Postma, Dirkje S; Pennell, Craig E; Jarvelin, Marjo-Riitta; Custovic, Adnan; Timpson, Nicholas; Ferreira, Manuel A; Strachan, David P; Henderson, John; Hinds, David; Bisgaard, Hans; Bønnelykke, Klaus

    2017-09-01

    The relationship between allergy and autoimmune disorders is complex and poorly understood. We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

  6. Novel associations for hypothyroidism include known autoimmune risk loci.

    Directory of Open Access Journals (Sweden)

    Nicholas Eriksson

    Full Text Available Hypothyroidism is the most common thyroid disorder, affecting about 5% of the general population. Here we present the current largest genome-wide association study of hypothyroidism, in 3,736 cases and 35,546 controls. Hypothyroidism was assessed via web-based questionnaires. We identify five genome-wide significant associations, three of which are well known to be involved in a large spectrum of autoimmune diseases: rs6679677 near PTPN22, rs3184504 in SH2B3, and rs2517532 in the HLA class I region (p-values 2.8·10(-13, 2.6·10(-12, and 1.3·10(-8, respectively. We also report associations with rs4915077 near VAV3 (p-value 7.5·10(-10 and rs925489 near FOXE1 (p value 2.4·10(-19. VAV3 is involved in immune function, and FOXE1 and PTPN22 have previously been associated with hypothyroidism. Although the HLA class I region and SH2B3 have previously been linked with a number of autoimmune diseases, this is the first report of their association with thyroid disease. The VAV3 association is also novel. We also show suggestive evidence of association for hypothyroidism with a SNP in the HLA class II region (independent of the other HLA association as well as SNPs in CAPZB, PDE8B, and CTLA4. CAPZB and PDE8B have been linked to TSH levels and CTLA4 to a variety of autoimmune diseases. These results suggest heterogeneity in the genetic etiology of hypothyroidism, implicating genes involved in both autoimmune disorders and thyroid function. Using a genetic risk profile score based on the top association from each of the five genome-wide significant regions in our study, the relative risk between the highest and lowest deciles of genetic risk is 2.0.

  7. Expansion of CD8+ cells in autoimmune hemolytic anemia.

    Science.gov (United States)

    Smirnova, S Ju; Sidorova, Ju V; Tsvetaeva, N V; Nikulina, O F; Biderman, B V; Nikulina, E E; Kulikov, S M; Sudarikov, A B

    2016-01-01

    Autoimmune hemolytic anemia (AIHA) is a rare blood disease associated with the production of auto-antibodies and autoimmune hemolysis. A critical role of B-cells in the development of AIHA has been demonstrated before. Here, we present the analysis of the clonal T-cell populations in patients with AIHA. Thirty-three patients with AIHA were included in this study. Thirteen patients with other anemias, 14 patients with other autoimmune conditions (SLE - 6, RA - 8) and 20 healthy donors were included in the study as a control group. The clonality of T-cell was evaluated by the assessment of the T-cell receptor gamma and beta chain gene rearrangements (TCRG and TCRB). The incidence of T-cell monoclonality detected in patients with AIHA was significantly higher compared to the control group. The persistence of T-cell clones did not correlate with the level of hemoglobin and other signs of remission or relapse and did not disappear after the therapy and clinical improvement (observation period was between 1 and 10 years). There was no correlation between the T-cell clonality and the gender, age, splenectomy, duration or severity of the disease. Fractionation of T-lymphocytes (CD4+, CD8+, CD4+25+) revealed that the monoclonal T-cells belonged to the CD8+ sub-population. We assume that besides a possible causative role of the T-cell clones in AIHA to autoimmune process, these clones do not directly participate in the development and maintenance of hemolysis. Most of the AIHA patients (48.5%) demonstrated a T-cell monoclonality, which requires monitoring and should be distinguished from T-cell tumors.

  8. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective.

    Science.gov (United States)

    Capalbo, D; Improda, N; Esposito, A; De Martino, L; Barbieri, F; Betterle, C; Pignata, C; Salerno, M

    2013-11-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator gene. The clinical spectrum of the disease encompasses several autoimmune endocrine and non-endocrine manifestations, which may lead to acute metabolic alterations and eventually life-threatening events. The clinical diagnosis is defined by the presence of at least two components of the classic triad including chronic mucocoutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), Addison's disease (AD). Other common features of the disease are hypergonadotropic hypogonadism, alopecia, vitiligo, autoimmune hepatitis, Type 1 diabetes, gastrointestinal dysfunction. APECED usually begins in childhood. CMC is the first manifestation to appear, usually before the age of 5 yr, followed by CH and then by AD. The clinical phenotype may evolve over several years and many components of the disease may not appear until the 4th or 5th decade of life. The phenotypical expression of the syndrome shows a wide variability even between siblings with the same genotype. In view of this heterogeneity, an early diagnosis of APECED can be very challenging often leading to a considerable diagnostic delay. Therefore, clinicians should be aware that the presence of even a minor component of APECED in children should prompt a careful investigation for other signs and symptoms of the disease, thus allowing an early diagnosis and prevention of severe and life-threatening events. Aim of this review is to focus on clinical presentation, diagnosis and management of the major components of APECED in children particularly focusing on endocrine features of the disease.

  9. Toxicogenomic analysis reveals profibrogenic effects of trichloroethylene in autoimmune-mediated cholangitis in mice.

    Science.gov (United States)

    Kopec, Anna K; Sullivan, Bradley P; Kassel, Karen M; Joshi, Nikita; Luyendyk, James P

    2014-10-01

    Epidemiological studies suggest that exposure to environmental chemicals increases the risk of developing autoimmune liver disease. However, the identity of specific chemical perpetrators and the mechanisms whereby environmental chemicals modify liver disease is unclear. Previous studies link exposure to trichloroethylene (TCE) with the development of autoimmune liver disease and exacerbation of autoimmunity in lupus-prone MRL mice. In this study, we utilized NOD.c3c4 mice, which spontaneously develop autoimmune cholangitis bearing resemblance to some features of primary biliary cirrhosis. Nine-week-old female NOD.c3c4 mice were given TCE (0.5 mg/ml) or its vehicle (1% Cremophor-EL) in drinking water for 4 weeks. TCE had little effect on clinical chemistry, biliary cyst formation, or hepatic CD3+ T-cell accumulation. Hepatic microarray profiling revealed a dramatic suppression of early growth response 1 (EGR1) mRNA in livers of TCE-treated mice, which was verified by qPCR and immunohistochemical staining. Consistent with a reported link between reduced EGR1 expression and liver fibrosis, TCE increased hepatic type I collagen (COL1A1) mRNA and protein levels in livers of NOD.c3c4 mice. In contrast, TCE did not increase COL1A1 expression in NOD.ShiLtJ mice, which do not develop autoimmune cholangitis. These results suggest that in the context of concurrent autoimmune liver disease with a genetic basis, modification of hepatic gene expression by TCE may increase profibrogenic signaling in the liver. Moreover, these studies suggest that NOD.c3c4 mice may be a novel model to study gene-environment interactions critical for the development of autoimmune liver disease. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  10. Helminth Immunomodulation in Autoimmune Disease

    Directory of Open Access Journals (Sweden)

    John J. Miles

    2017-04-01

    Full Text Available Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating “talents” of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

  11. Pemphigus autoimmunity: Hypotheses and realities

    Science.gov (United States)

    Grando, Sergei A

    2011-01-01

    The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients. PMID:21939410

  12. Adaptive immunity in autoimmune hepatitis.

    Science.gov (United States)

    Longhi, Maria Serena; Ma, Yun; Mieli-Vergani, Giorgina; Vergani, Diego

    2010-01-01

    The histological lesion of interface hepatitis, with its dense portal cell infiltrate consisting of lymphocytes, monocytes/macrophages and plasma cells, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of autoimmune hepatitis (AIH). Immunohistochemical studies, focused on the phenotype of inflammatory cells infiltrating the liver parenchyma, have shown a predominance of alphabeta-T cells. Amongst these cells, the majority have been CD4 helper/inducers, while a sizeable minority have consisted of CD8 cytotoxic/suppressors. Lymphocytes on non-T cell lineage included natural killer cells, monocytes/macrophages and B lymphocytes. For autoimmunity to arise, the self-antigenic peptide, embraced by an human leukocyte antigen (HLA) class II molecule, must be presented to an uncommitted T helper (T(H)0) lymphocyte by professional antigen-presenting cells. Once activated and according to the presence in the milieu of interleukin 12 (IL-12) or IL-4, T(H)0 lymphocytes can differentiate into T(H)1 cells, which are pivotal to macrophage activation; enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack; and induce HLA class II expression on hepatocytes; or they can differentiate into T(H)2 cells, which produce IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25(high) regulatory T cells. Numerical and functional regulatory T cell impairment characterises AIH and permits the perpetuation of effector immune responses with ensuing persistent liver destruction. Advances in the study of autoreactive T cells stem mostly from AIH type 2, where the main autoantigen, cytochrome P450IID6 (CYP2D6), is known to enable characterisation of antigen-specific immune responses. Copyright 2010 S. Karger AG, Basel.

  13. Criteria for Environmentally Associated Autoimmune Diseases

    Science.gov (United States)

    Pollard, K. Michael; Parks, Christine G.; Germolec, Dori R.; Leung, Patrick S.C.; Selmi, Carlo; Humble, Michael C.; Rose, Noel R.

    2012-01-01

    Increasing evidence supports a role for the environment in the development of autoimmune diseases, as reviewed in the accompanying three papers from the National Institute of Environmental Health Sciences Expert Panel Workshop. An important unresolved issue, however, is the development of criteria for identifying autoimmune disease phenotypes for which the environment plays a causative role, herein referred to as environmentally associated autoimmune diseases. There are several different areas in which such criteria need to be developed, including: 1) identifying the necessary and sufficient data to define environmental risk factors for autoimmune diseases meeting current classification criteria; 2) establishing the existence of and criteria for new environmentally associated autoimmune disorders that do not meet current disease classification criteria; and 3) identifying in clinical practice specific environmental agents that induce autoimmune disease in individual patients. Here we discuss approaches that could be useful for developing criteria in these three areas, as well as factors that should be considered in evaluating the evidence for criteria that can distinguish individuals with such disorders from individuals without such disorders with high sensitivity and specificity. Current studies suggest that multiple lines of complementary evidence will be important and that in many cases there will be clinical, serologic, genetic, epigenetic, and/or other laboratory features that could be incorporated as criteria for environmentally associated autoimmune diseases to improve diagnosis and treatment and possibly allow for preventative strategies in the future. PMID:22771005

  14. Presence of Autoimmune Antibody in Chikungunya Infection

    Directory of Open Access Journals (Sweden)

    Wirach Maek-a-nantawat

    2009-01-01

    Full Text Available Chikungunya infection has recently re-emerged as an important arthropod-borne disease in Thailand. Recently, Southern Thailand was identified as a potentially endemic area for the chikungunya virus. Here, we report a case of severe musculoskeletal complication, presenting with muscle weakness and swelling of the limbs. During the investigation to exclude autoimmune muscular inflammation, high titers of antinuclear antibody were detected. This is the report of autoimmunity detection associated with an arbovirus infection. The symptoms can mimic autoimmune polymyositis disease, and the condition requires close monitoring before deciding to embark upon prolonged specific treatment with immunomodulators.

  15. liver cirrhosis from autoimmune hepatitis in a nigerian woman

    African Journals Online (AJOL)

    like autoimmune thyroiditis, celiac disease and ulcerative colitis, with about 25% having cirrhosis at ... to immunosuppressive therapy. Keywords: Autoimmune hepatitis, Autoimmune liver disease, Chronic liver disease, Nigeria ... who is also exposed to environmental triggering factors.2,5,8 Subsequently, the autoimmune.

  16. Exome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease.

    Science.gov (United States)

    Andreoletti, Gaia; Ashton, James J; Coelho, Tracy; Willis, Claire; Haggarty, Rachel; Gibson, Jane; Holloway, John; Batra, Akshay; Afzal, Nadeem A; Beattie, Robert Mark; Ennis, Sarah

    2015-06-01

    Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients.

  17. A role for VAV1 in experimental autoimmune encephalomyelitis and multiple sclerosis

    DEFF Research Database (Denmark)

    Jagodic, Maja; Colacios, Celine; Nohra, Rita

    2009-01-01

    region on rat chromosome 9 regulates experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Using interval-specific congenic rat lines and association of single-nucleotide polymorphisms with inflammatory phenotypes, we localized the gene of influence to Vav1, which codes for a signal...

  18. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    NARCIS (Netherlands)

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W. J.; Abecasis, Goncalo; Becker, Jessica; Boeckxstaens, Guy E.; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D.; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P.; Noethen, Markus M.; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapaa-Dahlqvist, Solbritt; Stuart, Philip E.; Tsoi, Lam C.; van Heel, David A.; Worthington, Jane; Wouters, Mira M.; Klareskog, Lars; Elder, James T.; Gregersen, Peter K.; Schumacher, Johannes; Rich, Stephen S.; Wijmenga, Cisca; Sunyaev, Shamil R.; de Bakker, Paul I. W.; Raychaudhuri, Soumya

    Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the

  19. Cyclosporine Treatment in a Patient with Concurrent Autoimmune Urticaria and Autoimmune Hepatitis

    OpenAIRE

    Ju, Hye Young; Kim, Hei Sung; Kim, Hyung Ok; Park, Young Min

    2009-01-01

    Patients with autoimmune urticaria show a higher rate of seropositivity for other autoantibodies and often have a history of autoimmune conditions. They also tend to have more severe symptoms and to have a poor response to conventional antihistamine treatment. Autoimmune hepatitis is a chronic inflammatory disorder in which progressive liver injury is thought to be the result of a T-cell-mediated immunologic attack against liver cells in genetically predisposed individuals. While the associat...

  20. [Autoimmune diseases of the thyroid gland].

    Science.gov (United States)

    Allelein, S; Feldkamp, J; Schott, M

    2017-01-01

    Autoimmune diseases of the thyroid gland are considered to be the most frequent cause of thyroid gland disorders. Autoimmune thyroid diseases consist of two subgroups: autoimmune thyroiditis (AIT) and Graves' disease. The AIT is the most common human autoimmune disease. Infiltration of the thyroid gland with cytotoxic T‑cells can lead to an initial thyrotoxicosis und during the course to hypothyroidism due to destruction of the thyroid gland. Substitution with Levothyroxine is indicated for manifest hypothyroidism and subclinical hypothyroidism with increased thyroid antibodies with the intention of normalizing the serum thyroid stimulating hormone (TSH). Graves' disease is characterized by the appearance of stimulating TSH receptor antibodies leading to hyperthyroidism. Endocrine ophthalmopathy may also occur. Ablative therapy with radioiodine therapy or thyroidectomy is administered to patients with Graves' disease without remission after at least 1 year of antithyroid drug therapy.

  1. Autoimmune pancreatitis : Diagnostic and immunological aspects

    NARCIS (Netherlands)

    M.J. van Heerde (Marianne)

    2013-01-01

    textabstractAutoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic fibro- inflammatory disease, characterized by infiltration with lymphoplasmacytic cells and extensive fibrosis, which leads to morphological changes (swelling, mass forming) and organ dysfunction. Often, but

  2. Role of Complement in Autoimmune Hemolytic Anemia

    Science.gov (United States)

    Berentsen, Sigbjørn

    2015-01-01

    Summary The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed. PMID:26696798

  3. Th17 Response and Inflammatory Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Janelle C. Waite

    2012-01-01

    Full Text Available The proinflammatory activity of T helper 17 (Th17 cells can be beneficial to the host during infection. However, uncontrolled or inappropriate Th17 activation has been linked to several autoimmune and autoinflammatory pathologies. Indeed, preclinical and clinical data show that Th17 cells are associated with several autoimmune diseases such as arthritis, multiple sclerosis, psoriasis, and lupus. Furthermore, targeting the interleukin-17 (IL-17 pathway has attenuated disease severity in preclinical models of autoimmune diseases. Interestingly, a recent report brings to light a potential role for Th17 cells in the autoinflammatory disorder adult-onset Still's disease (AOSD. Whether Th17 cells are the cause or are directly involved in AOSD remains to be shown. In this paper, we discuss the biology of Th17 cells, their role in autoimmune disease development, and in AOSD in particular, as well as the growing interest of the pharmaceutical industry in their use as therapeutic targets.

  4. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available The clinical course of chronic lymphocytic leukemia (CLL may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Pure red cell aplasia (PRCA and autoimmune agranulocytosis (AG are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

  5. Autoimmune hepatitis: an uncommon presentation of thymoma.

    Science.gov (United States)

    Mendogni, Paolo; Rosso, Lorenzo; Tosi, Davide; Palleschi, Alessandro; Righi, Ilaria; Minonzio, Francesca; Fusco, Nicola; Nosotti, Mario

    2016-11-11

    In a substantial proportion of patients with thymoma, many different types of paraneoplastic syndromes are observed. The association between thymoma and autoimmune liver diseases, however, has been found in very few cases. We report the case of a 31-year-old man affected by autoimmune hepatitis associated with myasthenia gravis and thymoma, successfully treated with extended thymectomy. The patient is free from neoplastic and hepatic disease 4 years after surgery. Eighteen months after thymectomy, an exacerbation of hepatitis was successfully treated with steroids. To the authors' knowledge, only 7 cases of myasthenia gravis associated with thymoma and autoimmune hepatitis have been reported in the English-language literature. The exact role of thymoma in immune-mediated hepatitis is unclear. It seems likely that thymoma-associated T-cell abnormalities, due to the presence of thymoma, may have a role in the development of this rare clinical triad of autoimmune hepatitis, thymoma and myasthenia gravis.

  6. Role of Complement in Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Berentsen, Sigbjørn

    2015-09-01

    The classification of autoimmune hemolytic anemias and the complement system are reviewed. In autoimmune hemolytic anemia of the warm antibody type, complement-mediated cell lysis is clinically relevant in a proportion of the patients but is hardly essential for hemolysis in most patients. Cold antibody-mediated autoimmune hemolytic anemias (primary cold agglutinin disease, secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria) are entirely complement-mediated disorders. In cold agglutinin disease, efficient therapies have been developed in order to target the pathogenic B-cell clone, but complement modulation remains promising in some clinical situations. No established therapy exists for secondary cold agglutinin syndrome and paroxysmal cold hemoglobinuria, and the possibility of therapeutic complement inhibition is interesting. Currently, complement modulation is not clinically documented in any autoimmune hemolytic anemia. The most relevant candidate drugs and possible target levels of action are discussed.

  7. Cardiovascular disease biomarkers across autoimmune diseases.

    Science.gov (United States)

    Ahearn, Joseph; Shields, Kelly J; Liu, Chau-Ching; Manzi, Susan

    2015-11-01

    Cardiovascular disease is increasingly recognized as a major cause of premature mortality among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic intervention and ultimately prevention. Accurate identification, monitoring and stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease. This review will discuss some of the most recent biomarkers of cardiovascular diseases in autoimmune disease, including lipid oxidation, imaging biomarkers to characterize coronary calcium, plaque, and intima media thickness, biomarkers of inflammation and activated complement, genetic markers, endothelial biomarkers, and antiphospholipid antibodies. Clinical implementation of these biomarkers will not only enhance patient care but also likely accelerate the pharmaceutical pipeline for targeted intervention to reduce or eliminate cardiovascular disease in the setting of autoimmunity. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Overexpression of the Cytokine BAFF and Autoimmunity Risk.

    Science.gov (United States)

    Steri, Maristella; Orrù, Valeria; Idda, M Laura; Pitzalis, Maristella; Pala, Mauro; Zara, Ilenia; Sidore, Carlo; Faà, Valeria; Floris, Matteo; Deiana, Manila; Asunis, Isadora; Porcu, Eleonora; Mulas, Antonella; Piras, Maria G; Lobina, Monia; Lai, Sandra; Marongiu, Mara; Serra, Valentina; Marongiu, Michele; Sole, Gabriella; Busonero, Fabio; Maschio, Andrea; Cusano, Roberto; Cuccuru, Gianmauro; Deidda, Francesca; Poddie, Fausto; Farina, Gabriele; Dei, Mariano; Virdis, Francesca; Olla, Stefania; Satta, Maria A; Pani, Mario; Delitala, Alessandro; Cocco, Eleonora; Frau, Jessica; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Ferrigno, Paola; Ban, Maria; Barizzone, Nadia; Leone, Maurizio; Guerini, Franca R; Piga, Matteo; Firinu, Davide; Kockum, Ingrid; Lima Bomfim, Izaura; Olsson, Tomas; Alfredsson, Lars; Suarez, Ana; Carreira, Patricia E; Castillo-Palma, Maria J; Marcus, Joseph H; Congia, Mauro; Angius, Andrea; Melis, Maurizio; Gonzalez, Antonio; Alarcón Riquelme, Marta E; da Silva, Berta M; Marchini, Maurizio; Danieli, Maria G; Del Giacco, Stefano; Mathieu, Alessandro; Pani, Antonello; Montgomery, Stephen B; Rosati, Giulio; Hillert, Jan; Sawcer, Stephen; D'Alfonso, Sandra; Todd, John A; Novembre, John; Abecasis, Gonçalo R; Whalen, Michael B; Marrosu, Maria G; Meloni, Alessandra; Sanna, Serena; Gorospe, Myriam; Schlessinger, David; Fiorillo, Edoardo; Zoledziewska, Magdalena; Cucca, Francesco

    2017-04-27

    Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).

  9. Autoimmunity against INS-IGF2 expressed in human pancreatic islets.

    OpenAIRE

    Kanatsuna, Norio; Taneera, Jalal; Vaziri Sani, Fariba; Wierup, Nils; Larsson, Helena; Delli, Ahmed; Skärstrand, Hanna; Balhuizen, Alexander; Bennet, Hedvig; Steiner, Donald F; Törn, Carina; Fex, Malin; Lernmark, Åke

    2013-01-01

    Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine 1) expression of INS-IGF2 in human pancreatic islets and 2) autoantibodies in newly diagnosed type 1 diabetes chil...

  10. Treatment of patients with severe autoimmune hepatitis

    DEFF Research Database (Denmark)

    Larsen, Finn Stolze

    2008-01-01

    Autoimmune hepatitis (AIH) is a progressive inflammatory diseases of unknown origin that is characterised by a necro-inflammatory and fibrotic process and may result in liver failure or uncompensated liver cirrhosis. Normally AIH is responsive to immunosuppressive therapy, and treatment aims...... and tacrolimus) might salvage patients from transplantation. Mycophenolate mofetil may also improve liver tests and reduce the requirement for corticosteroids. Besides, sirolimus is effective for treatment of de novo autoimmune hepatitis that sometimes develops after liver transplantation. Initial experience...

  11. Encephalopathy Associated With Autoimmune Thyroid Disease

    OpenAIRE

    li A. Raouf; Gianluca Tamagno

    2014-01-01

    Autoimmune thyroid diseases (ATDs) are immune-endocrine disorders affecting the thyroid gland and, eventually, also a number of other systemic targets, including the brain and the nervous system. Encephalopathy associated with autoimmune thyroid disease (EAATD) is a rare, heterogeneous condition arising from the background of an ATD. It is characterised by neurological and/or psychiatric symptoms with acute or sub-acute onset, and virtually any neurological or psychiatric symptom can appear. ...

  12. Automation, consolidation, and integration in autoimmune diagnostics

    OpenAIRE

    Tozzoli, Renato; D?Aurizio, Federica; Villalta, Danilo; Bizzaro, Nicola

    2015-01-01

    Over the past two decades, we have witnessed an extraordinary change in autoimmune diagnostics, characterized by the progressive evolution of analytical technologies, the availability of new tests, and the explosive growth of molecular biology and proteomics. Aside from these huge improvements, organizational changes have also occurred which brought about a more modern vision of the autoimmune laboratory. The introduction of automation (for harmonization of testing, reduction of human error, ...

  13. Humanized in vivo Model for Autoimmune Diabetes

    Science.gov (United States)

    2010-05-07

    guinea - pig polyclonal anti-insulin (1:100 dilution, Abcam Ab7842-500, Cambridge, MA) and a secondary goat anti- guinea - pig Alexa-fluor 568 (1:100 dilu...which is reported to accelerate experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis). Our reasoning was that, as T cells...HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4

  14. Allelic and copy-number variations of Fc gamma Rs affect granulocyte function and susceptibility for autoimmune blistering diseases

    NARCIS (Netherlands)

    Recke, Andreas; Vidarsson, Gestur; Ludwig, Ralf J.; Freitag, Miriam; Möller, Steffen; Vonthein, Reinhard; Schellenberger, Julia; Haase, Ozan; Görg, Siegfried; Nebel, Almut; Flachsbart, Friederike; Schreiber, Stefan; Lieb, Wolfgang; Gläser, Regine; Benoit, Sandrine; Sárdy, Miklós; Eming, Rüdiger; Hertl, Michael; Zillikens, Detlef; König, Inke R.; Schmidt, Enno; Ibrahim, Saleh; Däschlein, Georg; Goebeler, Mattias; Goetze, Steven; Günther, Claudia; Hadaschik, Eva; Homey, Bernhard; Hunzelmann, Nicolas; Kreuter, Andreas; Kunz, Manfred; Lippert, Undine; Ludwig-Peitsch, Wiebke; Pföhler, Claudia; Sticherling, Michael; Worm, Margitta

    2015-01-01

    Low-affinity Fc gamma receptors (Fc gamma R) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding Fc gamma R exhibit frequent variations in sequence and gene copy number that

  15. Autoimmune channelopathies in paraneoplastic neurological syndromes.

    Science.gov (United States)

    Joubert, Bastien; Honnorat, Jérôme

    2015-10-01

    Paraneoplastic neurological syndromes and autoimmune encephalitides are immune neurological disorders occurring or not in association with a cancer. They are thought to be due to an autoimmune reaction against neuronal antigens ectopically expressed by the underlying tumour or by cross-reaction with an unknown infectious agent. In some instances, paraneoplastic neurological syndromes and autoimmune encephalitides are related to an antibody-induced dysfunction of ion channels, a situation that can be labelled as autoimmune channelopathies. Such functional alterations of ion channels are caused by the specific fixation of an autoantibody upon its target, implying that autoimmune channelopathies are usually highly responsive to immuno-modulatory treatments. Over the recent years, numerous autoantibodies corresponding to various neurological syndromes have been discovered and their mechanisms of action partially deciphered. Autoantibodies in neurological autoimmune channelopathies may target either directly ion channels or proteins associated to ion channels and induce channel dysfunction by various mechanisms generally leading to the reduction of synaptic expression of the considered channel. The discovery of those mechanisms of action has provided insights on the regulation of the synaptic expression of the altered channels as well as the putative roles of some of their functional subdomains. Interestingly, patients' autoantibodies themselves can be used as specific tools in order to study the functions of ion channels. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Updates on GMSCs treatment for autoimmune diseases.

    Science.gov (United States)

    Huang, Feng; Liu, Zhong-Min; Zheng, Song Guo

    2018-02-20

    Autoimmune disease is a refractory disease. Accumulating Evidence has revealed that the manipulation of mesenchymal stem cells may have the potential to control or even treat autoimmune diseases. Human gingiva-derived mesenchymal stem cells (GMSCs) are emerging as a new line of mesenchymal stem cells that have displayed some potential advantages in controlling and treating autoimmune diseases. In this review, we briefly update the current understanding on the biology of GMSCs and their effects on preventing and treating autoimmune diseases. The availability of gingival mesenchymal stem cells (GMSCs), together with their potent capacity of multi-directional differentiation and inflammatory modulation, making GMSCs an ideal subtype of MSCs in treating autoimmune disease. Our and other studies have launched the earliest appraisal on GMSCs and carried out a lot of biological researches. The clinical trial of GMSCs on patients with autoimmune diseases will further approve their therapeutic effects, as well as its cellular and molecular mechanisms. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Autoimmune connective tissue diseases and vaccination

    Directory of Open Access Journals (Sweden)

    Ewa Więsik-Szewczyk

    2015-12-01

    Full Text Available The idea that infectious agents can induce autoimmune diseases in genetically susceptible subjects has been a matter of discussion for years. Moreover, increased incidence of autoimmune diseases and introduction of prophylactic vaccinations from early childhood suggest that these two trends are linked. In the medical literature and even non-professional media, case reports or events temporally related to vaccination are reported. It raises the issue of vaccination safety. In everyday practice medical professionals, physicians, rheumatologists and other specialists will be asked their opinion of vaccination safety. The decision should be made according to evidence-based medicine and the current state of knowledge. The purpose of this paper is to discuss a potential mechanism which links infections, vaccinations and autoimmunity. We present an overview of published case reports, especially of systemic connective tissue diseases temporally related to vaccination and results from case-nested studies. As yet, no conclusive evidence supports a causal relationship between vaccination and autoimmune diseases. It has to be determined whether the performed studies are sufficiently Epsteinasensitive to detect the link. The debate is ongoing, and new data may be required to explain the pathogenesis of autoimmunity. We would like to underscore the need for prophylactic vaccination in patients with autoimmune rheumatic diseases and to break down the myth that the vaccines are contraindicated in this target group.

  18. Autoimmune cytopenias related to common variable immunodeficiency

    Directory of Open Access Journals (Sweden)

    Vlasta Petric

    2011-09-01

    Full Text Available Background: Common variable immunodeficiency disorders are characterised by defective antibody production leading to recurrent infections. Noninfective complications are a consequence of autoimmunity, granuloma and polyclonal lymphoid infiltration. We often detect autoimmune cytopenias before primary immunodefciency is confirmed. Patients and methods: We report a case of 39-year old man with recurrent respiratory infections, autoimmune thrombocytopenia and haemolytic anemia who had common varible immunodeficiency confirmed. He had a lack of serum IgG, IgA and IgM, bronchiectasis, lymphadenopathy, splenomegaly, hepatic granuloma, autoimmune gastritis with B12 deficiency and Evans syndrome. We treated autoimmune cytopenias with methylprednisolon and cyclosporine. After substitution therapy with intravenous immunoglobulin the frequency of espiratory infections decreased. Occurrence of diarrhea is suspected for enteropathy, however, hystologic identification is required. Because of patologically changed gastric mucosa and signs of polyclonal lymphoid infiltration, the patient is at high risk for malignancy and the outcome of the disease remains unpredictable. Conclusions: Generally, we discover common variable immunodeficiency at management of noninfective complications, in wich intravenous immunoglobulin are not effective. Autoimmune cytopenias and some other complications are successfully treated with glucocorticoids. Careful monitorig of these patients is important because of a high risk for malignancy.

  19. Clinical aspects of autoimmune rheumatic diseases.

    Science.gov (United States)

    Goldblatt, Fiona; O'Neill, Sean G

    2013-08-31

    Multisystem autoimmune rheumatic diseases are heterogeneous rare disorders associated with substantial morbidity and mortality. Efforts to create international consensus within the past decade have resulted in the publication of new classification or nomenclature criteria for several autoimmune rheumatic diseases, specifically for systemic lupus erythematosus, Sjögren's syndrome, and the systemic vasculitides. Substantial progress has been made in the formulation of new criteria in systemic sclerosis and idiopathic inflammatory myositis. Although the autoimmune rheumatic diseases share many common features and clinical presentations, differentiation between the diseases is crucial because of important distinctions in clinical course, appropriate drugs, and prognoses. We review some of the dilemmas in the diagnosis of these autoimmune rheumatic diseases, and focus on the importance of new classification criteria, clinical assessment, and interpretation of autoimmune serology. In this era of improvement of mortality rates for patients with autoimmune rheumatic diseases, we pay particular attention to the effect of leading complications, specifically cardiovascular manifestations and cancer, and we update epidemiology and prognosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Thyroid Autoimmunity in Girls with Turner Syndrome.

    Science.gov (United States)

    Witkowska-Sędek, Ewelina; Borowiec, Ada; Kucharska, Anna; Chacewicz, Karolina; Rumińska, Małgorzata; Demkow, Urszula; Pyrżak, Beata

    2017-01-01

    Turner syndrome is associated with increased incidence of autoimmune diseases, especially those of the thyroid gland. The aim of this study was to assess the prevalence of thyroid autoimmunity among pediatric patients with Turner syndrome. The study was retrospective and included 41 girls with Turner syndrome aged 6-18 years. Free thyroxine (FT4), thyroid stimulating hormone (TSH), anti-thyroid peroxidase (TPO-Ab) antibodies, anti-thyroglobulin (TG-Ab) antibodies, and karyotype were investigated. The correlation between karyotype and incidence of thyroid autoimmunity was also examined. Eleven patients (26.8%) were positive for TPO-Ab and/or TG-Ab. Three girls from that subgroup were euthyroid, 5 had subclinical hypothyroidism, and 3 were diagnosed with overt hypothyroidism. Out of these 11 patients affected by thyroid autoimmunity, 6 girls had mosaic karyotype with X-isochromosome (n = 4) or with deletions (n = 2), and 5 had the 45,X karyotype. The study findings confirmed a high incidence of thyroid autoimmunity in girls with Turner syndrome, but we failed to observe an association between the incidence of thyroid autoimmunity and karyotype. We conclude that it is important to monitor thyroid function in patients with Turner syndrome because they are prone to develop hypothyroidism.

  1. Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

    Science.gov (United States)

    Teixeira, Antonio R. L.; Hecht, Mariana M.; Guimaro, Maria C.; Sousa, Alessandro O.; Nitz, Nadjar

    2011-01-01

    Summary: Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8+ γδ, and CD8α+ T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease. PMID:21734249

  2. [Autoimmune thyroiditis and thyroid cancer].

    Science.gov (United States)

    Krátký, Jan; Jiskra, Jan

    2015-10-01

    Association between autoimmune thyroiditis (CLT) and thyroid cancer remains not clear. Although both diseases often occur simultaneously in histological samples, it is not yet clear whether CLT can be regarded as a risk factor for thyroid malignancy. This review focus on the known epidemiological and molecular genetics links between both diseases. Most studies have shown a significant association between thyroid cancer and positive antibodies to thyroglobulin and histological evidence of CLT, as well. Both disorders share some risk factors (greater incidence in women, in areas with adequate supply of iodine and in patients after radiotherapy of the neck) and molecular genetics linkage. For example: RET/PTC rearrangements could be more often found in carcinomas associated with CLT, but this mutation could be found in benign lesions such as CLT, as well. CLT seems to be a positive prognostic factor in patients with differentiated thyroid cancer. It is associated with less invasive forms of tumor, lower occurrence of infiltrated lymphatic nodes and a lower risk of recurrence.

  3. The potential for induction of autoimmune disease by a randomly-mutated self-antigen

    DEFF Research Database (Denmark)

    Pedersen, Anders Elm

    2007-01-01

    -antigens can be immunogenic and lead to autoimmunity against wildtype self-antigens. In theory, modified self-antigens can arise by random errors and mutations during protein synthesis and would be recognized as foreign antigens by naïve B and T lymphocytes. Here, it is postulated that the initial auto......-antigen is not a germline self-antigen, but rather a mutated self-antigen. This mutated self-antigen might interfere with peripheral tolerance if presented to the immune system during an infection. The infection lead to bystander activation of naïve T and B cells with specificity for mutated self-antigen and this can lead......The pathology of most autoimmune diseases is well described. However, the exact event that triggers the onset of the inflammatory cascade leading to disease is less certain and most autoimmune diseases are complex idiopathic diseases with no single gene known to be causative. In many cases...

  4. Clinical Significance of Autoantibodies to P53 Protein in Patients with Autoimmune Liver Diseases

    Directory of Open Access Journals (Sweden)

    Takashi Himoto

    2012-01-01

    Full Text Available Mutations in the p53 gene leading to conformational changes in the p53 protein have been well established in many human cancers. Conformational changes and/or cellular accumulation of the protein may induce an immune response, resulting in circulating autoantibodies to p53, which have been documented in several types of cancers. Although rarely associated with autoimmune disease, a few reports have documented titres of anti-p53 autoantibodies in patients with autoimmune hepatitis and primary biliary cirrhosis. The clinical relevance of circulating autoantibodies to p53, therefore, remains unclear. Accordingly, this study aimed to examine the prevalence and clinical relevance of anti-p53 autoantibodies in patients with selected autoimmune liver diseases.

  5. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: report of three cases from Iran.

    Science.gov (United States)

    Seifi-Alan, Mahnaz; Shamsi, Roshanak; Setoodeh, Aria; Sayarifard, Fatemeh; Aghasi, Parisa; Kompani, Farzad; Ghafouri-Fard, Soudeh; Abbasi, Farzaneh

    2016-08-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also named as autoimmune polyglandular syndrome (APS) type 1, is a rare autosomal recessive disorder caused by mutations in autoimmune regulator (AIRE) gene. It is distinguished by an immune-mediated damage of endocrine tissues, chronic candidiasis, and ectodermal disorder. APECED has been shown to be frequent in some populations including Iranian Jews. Here we report three cases of APECED from two independent Iranian Muslim families. Addison's disease, hypoparathyroidismand mucocutaneous candidiasis were shared clinical manifestations in all patients. Mutational analyses have demonstrated a novel homozygous splice site mutation (c.1095+2T>A) in intron 9 and a previously identified homozygous nonsense mutation (c.415C>T) in exon 3 of patients respectively. Future studies are needed to evaluate the frequency of these variants in Iranian APECED patients which would facilitate genetic counseling as well as prenatal diagnosis.

  6. How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

    Directory of Open Access Journals (Sweden)

    Manuel J. Amador-Patarroyo

    2012-01-01

    Full Text Available The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs, these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE, rheumatoid arthritis (RA, multiple sclerosis (MS, type 1 diabetes mellitus (T1D, Sjögren's syndrome, and autoimmune thyroiditis (AITD. Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D, while for others it does not have a significant influence on the course of disease (i.e., SS or no unanimous consensus exists (i.e., RA and MS.

  7. The Footprints of Poly-Autoimmunity: Evidence for Common Biological Factors Involved in Multiple Sclerosis and Hashimoto’s Thyroiditis

    Science.gov (United States)

    Perga, Simona; Martire, Serena; Montarolo, Francesca; Giordani, Ilaria; Spadaro, Michela; Bono, Gabriele; Corvisieri, Stefania; Messuti, Ilaria; Panzica, Giancarlo; Orlandi, Fabio; Bertolotto, Antonio

    2018-01-01

    Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS) have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto’s thyroiditis (HT), suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg) percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity. PMID:29527211

  8. The Footprints of Poly-Autoimmunity: Evidence for Common Biological Factors Involved in Multiple Sclerosis and Hashimoto’s Thyroiditis

    Directory of Open Access Journals (Sweden)

    Simona Perga

    2018-02-01

    Full Text Available Autoimmune diseases are a diverse group of chronic disorders and affect a multitude of organs and systems. However, the existence of common pathophysiological mechanisms is hypothesized and reports of shared risk are emerging as well. In this regard, patients with multiple sclerosis (MS have been shown to have an increased susceptibility to develop chronic autoimmune thyroid diseases, in particular Hashimoto’s thyroiditis (HT, suggesting an autoimmune predisposition. However, studies comparing such different pathologies of autoimmune origin are still missing till date. In the present study, we sought to investigate mechanisms which may lead to the frequent coexistence of MS and HT by analyzing several factors related to the pathogenesis of MS and HT in patients affected by one or both diseases, as well as in healthy donors. In particular, we analyzed peripheral blood mononuclear cell gene-expression levels of common candidate genes such as TNFAIP3, NR4A family, BACH2, FOXP3, and PDCD5, in addition to the regulatory T cell (Treg percentage and the 25-hydroxy vitamin D serum levels. Our findings support the plausibility of the existence of common deregulated mechanisms shared by MS and HT, such as BACH2/PDCD5-FOXP3 pathways and Tregs. Although the biological implications of these data need to be further investigated, we have highlighted the relevance of studies comparing different autoimmune pathologies for the understanding of the core concepts of autoimmunity.

  9. Autoimmune and Neoplastic Thyroid Diseases Associated with Hepatitis C Chronic Infection

    Directory of Open Access Journals (Sweden)

    Poupak Fallahi

    2014-01-01

    Full Text Available Frequently, patients with hepatitis C virus (HCV chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographic signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender versus healthy controls, or hepatitis B virus infected patients. In patients with “HCV-associated mixed cryoglobulinemia” (MC + HCV, a higher prevalence of thyroid autoimmune disorders was shown not only compared to controls, but also versus HCV patients without cryoglobulinemia. Patients with MC + HCV or HCV chronic infection show a higher prevalence of papillary thyroid cancer than controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC + HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th1 (C-X-C motif ligand 10 (CXCL10 chemokine, but normal levels of Th2 (C-C motif ligand 2 chemokine, than patients without thyroiditis. HCV thyroid infection could act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete interferon-γ and tumor necrosis factor-α. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function, particularly where nodules occur, is recommended in HCV patients.

  10. The immunobiology and clinical features of type 1 autoimmune polyglandular syndrome (APS-1).

    Science.gov (United States)

    Guo, Can-Jie; Leung, Patrick S C; Zhang, Weici; Ma, Xiong; Gershwin, M Eric

    2018-01-01

    Autoimmune Polyglandular Syndrome type 1 (APS-1) is a subtype of the autoimmune polyendocrine syndrome characterized by the simultaneous or sequential dysfunction of multiple endocrine or non-endocrine glands. A clinical diagnosis of APS-1 is typically based on the presence of at least two of three following criteria: chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. The first identified causative mutated gene for APS-1 is autoimmune regulator (AIRE) encoding a critical transcription factor, which is primarily expressed in the medullary thymic epithelial cells (mTECs) for generating central immune tolerance. A wide range of chronic, debilitating complications, with no obvious correlation with genetics, makes a diagnosis of APS-1 challenging early in the disease course. Managing APS-1 is difficult due to its complexity, especially the intricate relationships within manifestations and genetic mutations. The past decades have witnessed dramatic progress in elucidating the function of AIRE and conducting large-scale cohort studies in APS-1. However, no clear evidence-based guidelines have been established in APS-1. In this review, we provide a detailed critical overview of the study history, epidemiology, clinical features, and related mechanisms of autoimmunity in APS-1, as well as currently available therapies for this autoimmune disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Association of severe myoclonic epilepsy of infancy (SMEI with probable autoimmune lymphoproliferative syndrome-variant

    Directory of Open Access Journals (Sweden)

    A. Berio

    2014-12-01

    Full Text Available The paper reported on a case of severe myoclonic epilepsy of infancy (SMEI associated with a probable autoimmune lymphoproliferative syndrome variant (Dianzani autoimmune lymphoproliferative disease (DALD. A male patient with typical features of SMEI and a SCN1A gene variant presented in the first year of life with multiple lymph nodes, palpable liver at 2 cm from the costal margin, neutropenia, dysgammaglobulinemia, relative and sometimes absolute lymphocytosis. Subsequently the patient presented with constantly raised IgA in serum and positive antinuclear and thyroid antimicrosomal antibodies. The diagnosis of probable autoimmune lymphoproliferative syndrome was made; arthritis, skin and throat blisters, which appeared subsequently led to the diagnosis of linear IgA disease. On the basis of these unique associations, the Authors hypothesized that autoimmunity may be partly responsible of the severe epileptic symptomatology, perhaps mediated by autoantibodies against sodium channels or by accompanying cytotoxic T-lymphocytes. Corticosteroid treatment ameliorated the epilepsy and laboratory tests. Future studies will be necessary to evaluate the relevance of autoimmunity in SMEI.

  12. [Auto-immune disorders as a possible cause of neuropsychiatric syndromes].

    Science.gov (United States)

    Martinez-Martinez, P; Molenaar, P C; Losen, M; Hoffmann, C; Stevens, J; de Witte, L D; van Amelsvoort, T; van Os, J; Rutten, B P F

    2015-01-01

    Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear. To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes. Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes. Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis. Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

  13. Dietary naringenin supplementation attenuates experimental autoimmune encephalomyelitis by modulating autoimmune inflammatory responses in mice

    Science.gov (United States)

    Autoimmune disease is prevalent in humans. Since conventional therapies have limited efficacy and often come with significant side effects, nutrition may provide an alternative and complementary approach to improving the autoimmune disorders. Naringenin, a flavonoid found in citrus fruits, has been ...

  14. Autoimmunity, Not a Developmental Defect, is the Cause for Subfertility of Autoimmune Regulator (Aire) Deficient Mice.

    Science.gov (United States)

    Kekäläinen, E; Pöntynen, N; Meri, S; Arstila, T P; Jarva, H

    2015-05-01

    Autoimmune regulator's (AIRE) best characterized role is in the generation immunological tolerance, but it is also involved in many other processes such as spermatogenesis. Loss-of-function mutations in AIRE cause a disease called autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED; also called autoimmune polyendocrinopathy syndrome type 1, APS-1) that is dominated by various autoimmune manifestations, mainly endocrinopathies. Both patients with APECED and Aire(-/-) mice suffer from varying levels of infertility, but it is not clear if it is a result of an autoimmune tissue damage or more of a developmental defect. In this study, we wanted to resolve whether or not the reduced fertility of Aire(-/-) mice is dependent on the adaptive immune system and therefore a manifestation of autoimmunity in these mice. We generated lymphopenic mice without Aire expression that were devoid of the autoimmune manifestations previously reported in immunocompetent Aire(-/-) mice. These Aire(-/-) Rag1(-/-) mice regained full fertility. This confirms that the development of infertility in Aire(-/-) mice requires a functional adaptive immune system. We also show that only the male Aire(-/-) mice are subfertile, whereas Aire(-/-) females produce litters normally. Moreover, the male subfertility can be adoptively transferred with lymphocytes from Aire(-/-) donor mice to previously fertile lymphopenic Aire(-/-) recipients. Our data show that subfertility in Aire(-/-) mice is dependent on a functional adaptive immune system thus confirming its autoimmune aetiology. © 2015 John Wiley & Sons Ltd.

  15. Genetic basis of altered central tolerance and autoimmune diseases: a lesson from AIRE mutations.

    Science.gov (United States)

    Capalbo, Donatella; Giardino, Giuliana; Martino, Lucia De; Palamaro, Loredana; Romano, Rosa; Gallo, Vera; Cirillo, Emilia; Salerno, Mariacarolina; Pignata, Claudio

    2012-10-01

    The thymus is a specialized organ that provides an inductive environment for the development of T cells from multipotent hematopoietic progenitors. Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic nonresponsiveness in the presence of a particular antigen. The immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. Central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self-antigens, which are potentially autoreactive, are eliminated through so-called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue-specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease-modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome contributed enormously to unraveling several issues of the molecular basis of autoimmunity. This review focuses on the developmental, functional, and molecular events governing central tolerance and on the clinical implication of its failure.

  16. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  17. Context-specific effects of genetic variants associated with autoimmune disease.

    Science.gov (United States)

    Jonkers, Iris H; Wijmenga, Cisca

    2017-10-01

    Autoimmune diseases such as rheumatoid arthritis and coeliac disease are typical examples of complex genetic diseases caused by a combination of genetic and non-genetic risk factors. Insight into the genetic risk factors (single nucleotide polymorphisms (SNPs)) has increased since genome-wide association studies (GWAS) became possible in 2007 and, for individual diseases, SNPs can now explain some 15-50% of genetic risk. GWAS have also shown that some 50% of the genetic risk factors for individual autoimmune diseases overlap between different diseases. Thus, shared risk factors may converge to pathways that, when perturbed by genetic variation, predispose to autoimmunity in general. This raises the question of what determines disease specificity, and suggests that identical risk factors may have different effects in various autoimmune diseases. Addressing this question requires translation of genetic risk factors to causal genes and then to molecular and cellular pathways. Since >90% of the genetic risk factors are found in the non-coding part of the genome (i.e. outside the exons of protein-coding genes) and can have an impact on gene regulation, there is an urgent need to better understand the non-coding part of the genome. Here, we will outline the methods being used to unravel the gene regulatory networks perturbed in autoimmune diseases and the importance of doing this in the relevant cell types. We will highlight findings in coeliac disease, which manifests in the small intestine, to demonstrate how cell type and disease context can impact on the consequences of genetic risk factors. © The Author 2017. Published by Oxford University Press.

  18. Context-specific effects of genetic variants associated with autoimmune disease

    Science.gov (United States)

    Jonkers, Iris H.; Wijmenga, Cisca

    2017-01-01

    Abstract Autoimmune diseases such as rheumatoid arthritis and coeliac disease are typical examples of complex genetic diseases caused by a combination of genetic and non-genetic risk factors. Insight into the genetic risk factors (single nucleotide polymorphisms (SNPs)) has increased since genome-wide association studies (GWAS) became possible in 2007 and, for individual diseases, SNPs can now explain some 15–50% of genetic risk. GWAS have also shown that some 50% of the genetic risk factors for individual autoimmune diseases overlap between different diseases. Thus, shared risk factors may converge to pathways that, when perturbed by genetic variation, predispose to autoimmunity in general. This raises the question of what determines disease specificity, and suggests that identical risk factors may have different effects in various autoimmune diseases. Addressing this question requires translation of genetic risk factors to causal genes and then to molecular and cellular pathways. Since >90% of the genetic risk factors are found in the non-coding part of the genome (i.e. outside the exons of protein-coding genes) and can have an impact on gene regulation, there is an urgent need to better understand the non-coding part of the genome. Here, we will outline the methods being used to unravel the gene regulatory networks perturbed in autoimmune diseases and the importance of doing this in the relevant cell types. We will highlight findings in coeliac disease, which manifests in the small intestine, to demonstrate how cell type and disease context can impact on the consequences of genetic risk factors. PMID:28977443

  19. Complicating autoimmune diseases in myasthenia gravis: a review

    Science.gov (United States)

    Nacu, Aliona; Andersen, Jintana Bunpan; Lisnic, Vitalie; Owe, Jone Furlund; Gilhus, Nils Erik

    2015-01-01

    Abstract Myasthenia gravis (MG) is a rare autoimmune disease of skeletal muscle endplates. MG subgroup is relevant for comorbidity, but usually not accounted for. MG patients have an increased risk for complicating autoimmune diseases, most commonly autoimmune thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. In this review, we present concomitant autoimmune disorders associated with the different MG subgroups, and show how this influences treatment and prognosis. Concomitant MG should always be considered in patients with an autoimmune disorder and developing new neuromuscular weakness, fatigue or respiratory failure. When a second autoimmune disorder is suspected, MG should be included as a differential diagnosis. PMID:25915571

  20. Models of Aire-Dependent Gene Regulation for Thymic Negative Selection

    OpenAIRE

    Danso-Abeam, Dina; Humblet-Baron, Stephanie; Dooley, James; Liston, Adrian

    2011-01-01

    Mutations in the autoimmune regulator (AIRE) gene lead to autoimmune polyendocrinopathy syndrome type 1 (APS1), characterized by the development of multi-organ autoimmune damage. The mechanism by which defects in AIRE result in autoimmunity has been the subject of intense scrutiny. At the cellular level, the working model explains most of the clinical and immunological characteristics of APS1, with AIRE driving the expression of tissue-restricted antigens (TRAs) in the epithelial cells of the...

  1. Unusual pediatric co-morbility: autoimmune thyroiditis and cortico-resistant nephrotic syndrome in a 6-month-old Italian patient

    Directory of Open Access Journals (Sweden)

    Urbano Flavia

    2012-10-01

    Full Text Available Abstract We report on a case of autoimmune thyroiditis in a 6-month-old patient with cortico-resistant nephrotic syndrome. Normal serum levels of thyroid hormons and thyroid-stimulating hormone were detected with high titers of circulant antithyroid antibodies and a dysomogeneous ultrasound appearance of the gland, typical of autoimmune thyroiditis. The research of maternal thyroid antibodies was negative. This is the first case of autoimmune thyroiditis found in such a young patient with pre-existing nephrotic syndrome ever described in literature. This association is random because nephrotic syndrome does not have an autoimmune pathogenesis and the genes involved in autoimmune thyroiditis are not related to those of nephrotic syndrome.

  2. Autoimmune diseases and infections: controversial issues.

    Science.gov (United States)

    Baio, P; Brucato, A; Buskila, D; Gershwin, M E; Giacomazzi, D; Lopez, L R; Luzzati, R; Matsuura, E; Selmi, C; Sarzi-Puttini, P; Atzeni, F

    2008-01-01

    The etiology and pathogenesis of certain types of disease remain controversial and stand like a bridge that crosses infectious, autoimmune and autoinflammatory pathways. Infection, for example, may initiate a disease, although it is the genetic regulation in the host, the interplay between virus or bacteria persistence and autoimmunity that produces the later phases of disease, the antigenic determinants responsible for inducing autoimmune disease, and the pathogenetic effector mechanisms. Infections agents cause pericarditis, but in 85% of cases it is "idiopathic". It has also been shown that persistent Clamydia pneumoniae, Porphyromonas gingivalis, and Helicobacter pylori infections cause host immunity and promote atherogenesis. A number of infectious agents have been suggested as potential triggers for primary biliary cirrhosis. Infections and vaccinations have also been linked to the pathogenesis of fibromyalgia syndrome, a common, chronic syndrome of widespread pain. Many factors are also responsible for fever of unknown origin such as: infections, autoimmunity disease, etc. However, it is difficult to determine a direct correlation between the infections agents in such a large group of diseases. The aim of this review is to analyze some of the controversies about the role of infections in autoimmune diseases.

  3. Menopause in patients with autoimmune diseases.

    Science.gov (United States)

    Sammaritano, Lisa R

    2012-05-01

    Menopause represents a time of significant clinical and hormonal change. Given the incompletely understood interrelationship between gonadal hormones and the immune system, it is possible that menopause may affect, or be affected by, the presence of autoimmune disease. Menopause has significant effects on a number of organ systems including the cardiovascular, skeletal, central nervous and genitourinary systems. Premature ovarian failure is related to autoimmune factors in a proportion of cases, but is not generally associated with systemic autoimmune disorders unless secondary to treatment with alkylating agents such as cyclophosphamide. Gonadal hormones have been suggested to relate to both onset and activity in certain autoimmune diseases. For patients with systemic lupus erythematosus, disease activity is lower, and damage accrual higher, in the postmenopausal years, but the mechanisms responsible may relate to age, duration of disease, menopause changes, long-term effects of therapy, or some combination of these factors. Early menopause is a risk factor for rheumatoid arthritis, and post-menopausal status in RA is associated with greater damage and disability. Systemic sclerosis and giant cell arteritis may also be adversely affected by onset of menopause. Importantly, autoimmune disease and menopause may have an additive effect on risk for common comorbidities such as cardiovascular disease and osteoporosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Autoimmune hepatitis in Italy: the Bologna experience.

    Science.gov (United States)

    Muratori, Paolo; Granito, Alessandro; Quarneti, Chiara; Ferri, Silvia; Menichella, Rita; Cassani, Fabio; Pappas, Georgios; Bianchi, Francesco B; Lenzi, Marco; Muratori, Luigi

    2009-06-01

    Autoimmune hepatitis affects mainly women. It is subdivided into type 1 and type 2 according to the autoantibody profile and without immunosuppression usually evolves to cirrhosis and end-stage liver failure. We evaluated clinical, biochemical, immunological and genetic features and treatment response of 163 consecutive Italian patients with autoimmune hepatitis. At diagnosis, type 1 autoimmune hepatitis showed more inflamed liver histology and more pronounced cholestasis, whereas type 2 was more common in children. Male and female patients shared similar clinical, biochemical and immunological features. Of 89 patients with 5-year follow-up or longer, 23 patients irrespective of presenting clinical, biochemical and immunological features achieved complete remission (normal transaminases and gammaglobulin levels) which was maintained with minimal steroid dosage; attempt at treatment withdrawal led to disease exacerbation. Complete responders had more often HLA DRB1*0401 (p = 0.011) and their risk of disease progression was lower (p < 0.0001). Type 1 and type 2 autoimmune hepatitis is one and the same disease. Autoimmune hepatitis has similar features in male and female patients. HLA DRB1*0401 positive patients are more likely to achieve complete remission. Continuous low-dose steroids are necessary to maintain remission, significantly reducing the risk of disease progression.

  5. Upper gastrointestinal symptoms in autoimmune gastritis

    Science.gov (United States)

    Carabotti, Marilia; Lahner, Edith; Esposito, Gianluca; Sacchi, Maria Carlotta; Severi, Carola; Annibale, Bruno

    2017-01-01

    Abstract Autoimmune gastritis is often suspected for its hematologic findings, and rarely the diagnosis is made for the presence of gastrointestinal symptoms. Aims of this cross-sectional study were to assess in a large cohort of patients affected by autoimmune gastritis the occurrence and the pattern of gastrointestinal symptoms and to evaluate whether symptomatic patients are characterized by specific clinical features. Gastrointestinal symptoms of 379 consecutive autoimmune gastritis patients were systematically assessed and classified following Rome III Criteria. Association between symptoms and anemia pattern, positivity to gastric autoantibodies, Helicobacter pylori infection, and concomitant autoimmune disease were evaluated. In total, 70.2% of patients were female, median age 55 years (range 17–83). Pernicious anemia (53.6%), iron deficiency anemia (34.8%), gastric autoantibodies (68.8%), and autoimmune disorders (41.7%) were present. However, 56.7% of patients complained of gastrointestinal symptoms, 69.8% of them had exclusively upper symptoms, 15.8% only lower and 14.4% concomitant upper and lower symptoms. Dyspepsia, subtype postprandial distress syndrome was the most represented, being present in 60.2% of symptomatic patients. Univariate and multivariate analyses showed that age gastritis is associated in almost 60% of cases with gastrointestinal symptoms, in particular dyspepsia. Dyspepsia is strictly related to younger age, no smoking, and absence of anemia. PMID:28072728

  6. Autoimmune gastritis: Pathologist’s viewpoint

    Science.gov (United States)

    Coati, Irene; Fassan, Matteo; Farinati, Fabio; Graham, David Y; Genta, Robert M; Rugge, Massimo

    2015-01-01

    Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling. PMID:26576102

  7. Autoimmune Abnormalities of Postpartum Thyroid Diseases.

    Science.gov (United States)

    Di Bari, Flavia; Granese, Roberta; Le Donne, Maria; Vita, Roberto; Benvenga, Salvatore

    2017-01-01

    The year following parturition is a critical time for the de novo appearance or exacerbation of autoimmune diseases, including autoimmune thyroid disease. The vast majority of postpartum thyroid disease consists of postpartum thyroiditis (PPT) and the minority by Graves' disease and non-autoimmune thyroiditis. PPT has a worldwide prevalence ranging from 1 to 22% and averaging 5% based on a review published in 2012. Several factors confer risk for the development of PPT. Typically, the clinical course of PPT is characterized by three phases: thyrotoxic, hypothyroid, and euthyroid phase. Approximately half of PPT women will have permanent hypothyroidism. The best humoral marker for predictivity, already during the first trimester of gestation, is considered positivity for thyroperoxidase autoantibodies (TPOAb), though only one-third to half of such TPOAb-positive pregnant women will develop PPT. Nutraceuticals (such as selenium) or omega-3-fatty acid supplements seem to have a role in prevention of PPT. In a recent study on pregnant women with stable dietary habits, we found that the fish consumers had lower rates of positivity (and lower serum levels) of both TPOAb and thyroglobulin Ab compared to meat eaters. Finally, we remind the reader of other diseases that can be observed in the postpartum period, either autoimmune or non-autoimmune, thyroid or non-thyroid.

  8. Different response to glucocorticoid therapy in autoimmune diseases of CNS

    Directory of Open Access Journals (Sweden)

    Stanojević Željka

    2016-01-01

    Full Text Available Th17 cells and interleukin (IL-17, their signature cytokine, have the main role in the pathogenesis of autoimmune diseases of the central nervous system such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE. The effect of glucocorticoids (GC on expression and production of IL-17 has not been thoroughly tested yet. Also, the site of action of GC is not precisely defined. This paper presents the main results of the Doctoral thesis devoted to studies of GC on the production of IL-17 in the model of EAE, induced in susceptible laboratory animals. Methylprednisolone (MP, a synthetic glucocorticoid, inhibit in vitro production of IL-17 in mitogen-stimulated lymph node cells (LNC as well as in myelin basic protein (MBP-stimulated draining LNC in dose- dependent manner. However, under the same conditions inhibitory effect of the MP on production and expression of the genes for IFN-γ, a cytokine that TH1 cells generate, is significantly more pronounced. Interestingly, when we analyzed effects of MP applied in vivo in EAE, the same phenomenon was observed: the proportion of IFN-γ producing, but not all of IL-17 cells were reduced in cells isolated from MP treated rats in comparison to control rats which indicates that MP achieves its effects not only in the peripheral lymphoid tissues, but also in target tissue. Different sensitivities of Th1 and Th17 cells that are major cellular sources of IFN-γ or IL-17 in the effect of the GC has been observed in other animal models and in human disease. Understanding the molecular mechanisms underlying the relative resistance of Th17 cells on the operation of GC is very important for the development of new strategies in the treatment of those forms of autoimmune and chronic diseases that are resistant to the effect of glucocorticoids.

  9. Is there a Common Genetic Basis for Autoimmune Diseases?

    Directory of Open Access Journals (Sweden)

    Juan-Manuel Anaya

    2006-01-01

    Full Text Available Autoimmune diseases (ADs represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. The commonality between them however, is the damage to tissues and organs that arises from the response to self-antigens. The presence of shared pathophysiological mechanisms within ADs has stimulated searches for common genetic roots to these diseases. Two approaches have been undertaken to sustain the “common genetic origin” theory of ADs. Firstly, a clinical genetic analysis showed that autoimmunity aggregates within families of probands diagnosed with primary Sjögren's (pSS syndrome or type 1 diabetes mellitus (T1D. A literature review supported the establishment of a familiar cluster of ADs depending upon the proband's disease phenotype. Secondly, in a same and well-defined population, a large genetic association study indicated that a number of polymorphic genes (i.e. HLA-DRB1, TNF and PTPN22 influence the susceptibility for acquiring different ADs. Likewise, association and linkage studies in different populations have revealed that several susceptibility loci overlap in ADs, and clinical studies have shown that frequent clustering of several ADs occurs. Thus, the genetic factors for ADs consist of two types: those which are common to many ADs (acting in epistatic pleitropy and those that are specific to a given disorder. Their identification and functional characterization will allow us to predict their effect as well as to indicate potential new therapeutic interventions. Both autoimmunity family history and the co-occurrence of ADs in affected probands should be considered when performing genetic association and linkage studies.

  10. Diagnosis and Management of Pediatric Autoimmune Liver Disease : ESPGHAN Hepatology Committee Position Statement

    NARCIS (Netherlands)

    Mieli-Vergani, Giorgina; Vergani, Diego; Baumann, Ulrich; Czubkowski, Piotr; Debray, Dominique; Dezsofi, Antal; Fischler, Björn; Gupte, Girish; Hierro, Loreto; Indolfi, Giuseppe; Jahnel, Jörg; Smets, Françoise; Verkade, Henkjan J; Hadžić, Nedim

    Paediatric autoimmune liver disease is characterised by inflammatory liver histology, circulating autoantibodies and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis

  11. [Type 1 polyglandular autoimmune syndrome associated with C322fsx372 mutation].

    Science.gov (United States)

    Roncalés-Samanes, P; de Arriba Muñoz, A; Lou Francés, G M; Ferrer Lozano, M; Justa Roldán, M L; Labarta Aizpun, J I

    2015-01-01

    Polyglandular autoimmune syndromes are rare diseases based on autoimmune mechanisms in which endocrine and non-endocrine disorders coexist. In type 1 the characteristic manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. A case is presented of a patient with typical clinical sequence, along with other changes, and in whom a mutation in homozygosis, C322fsX372, was detected after performing a molecular analysis of autoimmunity regulator gene (AIRE). Inheritance is autosomal recessive, associated with mutations in the AIRE gene, which encodes a protein involved in autoimmunity and immunodeficiency. For diagnosis, At least two of the three major clinical manifestations are required for a diagnosis. However, only one of them is necessary in the study of relatives of affected patients. These syndromes must be diagnosed early, given their high morbidity and mortality. Every manifestation needs to be treated, in order to maintain the quality of life. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  12. Antinuclear antibodies in autoimmune and allergic diseases.

    Science.gov (United States)

    Grygiel-Górniak, Bogna; Rogacka, Natalia; Rogacki, Michał; Puszczewicz, Mariusz

    2017-01-01

    Antinuclear antibodies (ANA) are primarily significant in the diagnosis of systemic connective tissue diseases. The relationship between their occurrence in allergic diseases is poorly documented. However, the mechanism of allergic and autoimmune diseases has a common thread. In both cases, an increased production of IgE antibodies and presence of ANA in selected disease entities is observed. Equally important is the activation of basophils secreting proinflammatory factors and affecting the differentiation of TH17 lymphocytes. Both autoimmune and allergic diseases have complex multi-pathogenesis and often occur in genetically predisposed individuals. The presence of antinuclear antibodies was confirmed in many systemic connective tissue diseases and some allergic diseases. Examples include atopic dermatitis, non-allergic asthma, and pollen allergy. Co-occurring allergic and autoimmune disorders induce further search for mechanisms involved in the aetiopathogenesis of both groups of diseases.

  13. Epidemiology of autoimmune diseases in Denmark

    DEFF Research Database (Denmark)

    Eaton, William W.; Rose, N.R.; Kalaydijan, A.

    2007-01-01

    An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. The National Patient Register of Denmark is used to estimate the population prevalence of 31 possible or probable autoimmune diseases. Record linkage is used to estimate 465 pairwise co...... diseases and weak across diseases. These data confirm the importance of the autoimmune diseases as a group and suggest that common etiopathologies exist among them......-morbidities in individuals among the 31 diseases, and familial aggregation among sibs, parents and offspring. The prevalence of any of the 31 diseases in the population is more than 5%. Within individuals, there is extensive comorbidity across the 31 diseases. Within families, aggregation is strongest for individual...

  14. Dendritic cells and aging: consequences for autoimmunity.

    Science.gov (United States)

    Agrawal, Anshu; Sridharan, Aishwarya; Prakash, Sangeetha; Agrawal, Harsh

    2012-01-01

    The immune system has evolved to mount immune responses against foreign pathogens and to remain silent against self-antigens. A balance between immunity and tolerance is required as any disturbance may result in chronic inflammation or autoimmunity. Dendritic cells (DCs) actively participate in maintaining this balance. Under steady-state conditions, DCs remain in an immature state and do not mount an immune response against circulating self-antigens in the periphery, which maintains a state of tolerance. By contrast, foreign antigens result in DC maturation and DC-induced T-cell activation. Inappropriate maturation of DCs due to infections or tissue injury may cause alterations in the balance between the tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases. This article provides an overview of the effects of advancing age on DC functions and their implications in autoimmunity.

  15. Pregnancy and autoimmune connective tissue diseases

    Science.gov (United States)

    Marder, Wendy; Littlejohn, Emily A

    2016-01-01

    The autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before and during pregnancy and the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy. PMID:27421217

  16. HTLV-1, Immune Response and Autoimmunity

    Directory of Open Access Journals (Sweden)

    Juarez A S Quaresma

    2015-12-01

    Full Text Available Human T-lymphotropic virus type-1 (HTLV-1 infection is associated with adult T-cell leukemia/lymphoma (ATL. Tropical spastic paraparesis/HTLV-1-associated myelopathy (PET/HAM is involved in the development of autoimmune diseases including Rheumatoid Arthritis (RA, Systemic Lupus Erythematosus (SLE, and Sjögren’s Syndrome (SS. The development of HTLV-1-driven autoimmunity is hypothesized to rely on molecular mimicry, because virus-like particles can trigger an inflammatory response. However, HTLV-1 modifies the behavior of CD4+ T cells on infection and alters their cytokine production. A previous study showed that in patients infected with HTLV-1, the activity of regulatory CD4+ T cells and their consequent expression of inflammatory and anti-inflammatory cytokines are altered. In this review, we discuss the mechanisms underlying changes in cytokine release leading to the loss of tolerance and development of autoimmunity.

  17. The clinical extremes of autoimmune cholangitis

    Directory of Open Access Journals (Sweden)

    Sara Campos

    Full Text Available Autoimmune cholangitis (AIC was first described in 1987 as immunocholangitis in three women who presented with signs and symptoms of primary biliary cholangitis (PBC, but who were antimitochondrial (AMA negative and antinuclear antibodies (ANA positive, and responded to immunosuppressive therapy with azathioprine and prednisolone (1. AIC is a rare chronic cholestatic inflammatory disease characterized by the presence of high ANA or smooth muscle antibodies (SMA but AMA seronegativity. Histologically, AIC exhibits bile duct injury (2. In terms of therapeutics, in addition to response to ursodeoxycholic acid, a prompt response to corticosteroids has also been reported in earlier stages, distinguishing it from PBC. Herein the authors describe two cases with mixed signs of PBC and autoimmune hepatitis (AIH. The diagnostic differentiation between these diseases (AIC, PBC and AIH is essential because of the different therapeutic strategies. Our cases highlight the importance of clinician awareness of the autoimmune spectrum of liver diseases.

  18. [Thymoma and autoimmune thyroiditis. A case report].

    Science.gov (United States)

    Brinkane, A; Bellamy, J; Leroy-Terquem, E; Levy, R

    2003-09-01

    We report an association between a thymus tumor and autoimmune thyroiditis. This association is probably related to loss of immune control secondary to loss of thymus integrity. A 48-year-old woman was hospitalized for thoracic pain. Her past history included thyroiditis treated by L-thyroxin for two years. The chest x-ray demonstrated a mediastinal opacity which was confirmed by computed tomography. Surgical resection was performed and histological analysis of the surgical specimen confirmed the diagnosis of lympho-epithelial thymoma. Thyroid immunity tests demonstrated the presence of anti-peroxidase antibodies confirming the diagnosis of Hashimoto's thyroiditis. Chest x-ray and CT-scan are indicated in patients with autoimmune thyroiditis to search for a thymic mass. Conversely, search for autoimmune thyroiditis is warranted in patients with an identified thymic mass.

  19. Human neutrophils in auto-immunity.

    Science.gov (United States)

    Thieblemont, Nathalie; Wright, Helen L; Edwards, Steven W; Witko-Sarsat, Véronique

    2016-04-01

    Human neutrophils have great capacity to cause tissue damage in inflammatory diseases via their inappropriate activation to release reactive oxygen species (ROS), proteases and other tissue-damaging molecules. Furthermore, activated neutrophils can release a wide variety of cytokines and chemokines that can regulate almost every element of the immune system. In addition to these important immuno-regulatory processes, activated neutrophils can also release, expose or generate neoepitopes that have the potential to break immune tolerance and result in the generation of autoantibodies, that characterise a number of human auto-immune diseases. For example, in vasculitis, anti-neutrophil cytoplasmic antibodies (ANCA) that are directed against proteinase 3 or myeloperoxidase are neutrophil-derived autoantigens and activated neutrophils are the main effector cells of vascular damage. In other auto-immune diseases, these neutrophil-derived neoepitopes may arise from a number of processes that include release of granule enzymes and ROS, changes in the properties of components of their plasma membrane as a result of activation or apoptosis, and via the release of Neutrophil Extracellular Traps (NETs). NETs are extracellular structures that contain chromatin that is decorated with granule enzymes (including citrullinated proteins) that can act as neo-epitopes to generate auto-immunity. This review therefore describes the processes that can result in neutrophil-mediated auto-immunity, and the role of neutrophils in the molecular pathologies of auto-immune diseases such as vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We discuss the potential role of NETs in these processes and some of the debate in the literature regarding the role of this phenomenon in microbial killing, cell death and auto-immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Safety of vaccine adjuvants: focus on autoimmunity.

    Science.gov (United States)

    van der Laan, Jan Willem; Gould, Sarah; Tanir, Jennifer Y

    2015-03-24

    Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists. The state of science around the use of animal models and biomarkers for the evaluation and prediction of AID were also discussed. Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID. The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals. Additionally, it is recommended that future research on the potential effects of vaccine adjuvants on AID should consider carefully the experimental design in animal models particularly if they are to be used in any risk assessment, as an improper design and model could result in misleading information. Finally, studies on the mechanistic aspects and potential biomarkers related to adjuvants and autoimmunity phenomena could be developed. Copyright © 2015. Published by Elsevier Ltd.. All rights reserved.

  1. Sexual dimorphism of miRNA expression: a new perspective in understanding the sex bias of autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Dai R

    2014-03-01

    Full Text Available Rujuan Dai, S Ansar Ahmed Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, USA Abstract: Autoimmune diseases encompass a diverse group of diseases which emanate from a dysregulated immune system that launches a damaging attack on its own tissues. Autoimmune attacks on self tissues can occur in any organ or body system. A notable feature of autoimmune disease is that a majority of these disorders occur predominantly in females. The precise basis of sex bias in autoimmune diseases is complex and potentially involves sex chromosomes, sex hormones, and sex-specific gene regulation in response to internal and external stimuli. Epigenetic regulation of genes, especially by microRNAs (miRNAs, is now attracting significant attention. miRNAs are small, non-protein-coding RNAs that are predicted to regulate a majority of human genes, including those involved in immune regulation. Therefore, it is not surprising that dysregulated miRNAs are evident in many diseases, including autoimmune diseases. Because there are marked sex differences in the incidence of autoimmune diseases, this review focuses on the role of sex factors on miRNA expression in the context of autoimmune diseases, an aspect not addressed thus far. Here, we initially review miRNA biogenesis and miRNA regulation of immunity and autoimmunity. We then summarize the recent findings of sexual dimorphism of miRNA expression in diverse tissues, which imply a critical role of miRNA in sex differentiation and in sex-specific regulation of tissue development and/or function. We also discuss the important contribution of the X chromosome and sex hormones to the sexual dimorphism of miRNA expression. Understanding sexually dimorphic miRNA expression in sex-biased autoimmune diseases not only offers us new insight into the mechanism of sex bias of the disease but will also aid us in developing new sex

  2. Genetics Home Reference: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

    Science.gov (United States)

    ... Facebook Twitter Home Health Conditions APECED Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy Printable PDF Open All Close All ... view the expand/collapse boxes. Description Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy ( APECED ) is an inherited condition that ...

  3. Shared genetic origins of allergy and autoimmune diseases

    DEFF Research Database (Denmark)

    Waage, J. E.; Kreiner-Møller, E.; Standl, M.

    2015-01-01

    Parallel increases in allergy and autoimmune disease prevalence in recent time suggest shared, but yet unknown, etiologies. Here, we investigated shared genetic loci and molecular pathways to identify possible shared disease mechanisms between allergy and autoimmune diseases....

  4. Generalized Vitiligo Associated Autoimmune Diseases in Japanese Patients Their Families

    Directory of Open Access Journals (Sweden)

    Tomohiko Narita

    2011-01-01

    Conclusions: Among Japanese vitiligo patients, there is a subgroup with strong evidence of genetically determined susceptibility to not only vitiligo, but also to autoimmune thyroid disease and other autoimmune disorders.

  5. Complement inhibitors to treat IgM-mediated autoimmune hemolysis

    NARCIS (Netherlands)

    Wouters, Diana; Zeerleder, Sacha

    2015-01-01

    Complement activation in autoimmune hemolytic anemia may exacerbate extravascular hemolysis and may occasionally result in intravascular hemolysis. IgM autoantibodies as characteristically found in cold autoantibody autoimmune hemolytic anemia, in cold agglutinin disease but also in a considerable

  6. The role of epigenetic mechanisms and processes in autoimmune disorders

    Directory of Open Access Journals (Sweden)

    Greer JM

    2012-09-01

    Full Text Available Judith M Greer, Pamela A McCombeThe University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, AustraliaAbstract: The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.Keywords: twins, concordance, autoimmune disease, nongenetic factors, immune system, epigenetic modifications

  7. [Ludwig van Beethoven: an autoimmune deafness?].

    Science.gov (United States)

    Davies, P J

    1995-01-01

    The author reminds us of the great moments of Beethoven's life and of the different stages of his deafness onset, until to last instants. The post-mortem examination, performed by doctor Wagner, and the scientific studies of the remains, during the exhumations, are reported. Beethoven's deafness was clearly a sensorineural impairment and the previously suggested prevalent hypotheses are discussed. A new theory is emphasized, based on modern studies about autoimmune sensorineural hearing losses in relation with chronic inflammatory bowel ailment. Conclusion is that Beethoven's deafness was probably owing to a primary autoimmune degeneration of the organ of Corti, giving rise to atrophy of the auditory nerve.

  8. Autoimmune Inner Ear Disease- A Clinical Viewpoint

    Directory of Open Access Journals (Sweden)

    Amirala Khalessi

    2010-10-01

    Full Text Available Recent developments in medicine have given us a better insight into a group of disorders known as autoimmune diseases. In particular, advances have occurred in our understanding of the Autoimmune Inner Ear Disease (AIED. In this article, the authors review the different postulated theories in the pathogenesis of this disease. The clinical presentation, the available para-clinical diagnostic tools, and the important differential diagnoses will be summarized. The management methods, including steroid therapy, immunosuppressive medications, other biological agents and intra-tympanic injections, will be addressed. Cochlear implantation as a final solution to the advanced stages of the disease, causing total deafness, will also be discussed.

  9. Diagnosis and classification of autoimmune hemolytic anemia.

    Science.gov (United States)

    Bass, Garrett F; Tuscano, Emily T; Tuscano, Joseph M

    2014-01-01

    Uncompensated autoantibody-mediated red blood cell (RBC) consumption is the hallmark of autoimmune hemolytic anemia (AIHA). Classification of AIHA is pathophysiologically based and divides AIHA into warm, mixed or cold-reactive subtypes. This thermal-based classification is based on the optimal autoantibody-RBC reactivity temperatures. AIHA is further subcategorized into idiopathic and secondary with the later being associated with a number of underlying infectious, neoplastic and autoimmune disorders. In most cases AIHA is confirmed by a positive direct antiglobulin test (DAT). The standard therapeutic approaches to treatment of AIHA include corticosteroids, splenectomy, immunosuppressive agents and monoclonal antibodies. Published by Elsevier B.V.

  10. Vitiligo: How do oxidative stress-induced autoantigens trigger autoimmunity?

    Science.gov (United States)

    Xie, Heng; Zhou, Fubo; Liu, Ling; Zhu, Guannan; Li, Qiang; Li, Chunying; Gao, Tianwen

    2016-01-01

    Vitiligo is a common depigmentation disorder characterized by a loss of functional melanocytes and melanin from epidermis, in which the autoantigens and subsequent autoimmunity caused by oxidative stress play significant roles according to hypotheses. Various factors lead to reactive oxygen species (ROS) overproduction in the melanocytes of vitiligo: the exogenous and endogenous stimuli that cause ROS production, low levels of enzymatic and non-enzymatic antioxidants, disturbed antioxidant pathways and polymorphisms of ROS-associated genes. These factors synergistically contribute to the accumulation of ROS in melanocytes, finally leading to melanocyte damage and the production of autoantigens through the following ways: apoptosis, accumulation of misfolded peptides and cytokines induced by endoplasmic reticulum stress as well as the sustained unfolded protein response, and an 'eat me' signal for phagocytic cells triggered by calreticulin. Subsequently, autoantigens presentation and dendritic cells maturation occurred mediated by the release of antigen-containing exosomes, adenosine triphosphate and melanosomal autophagy. With the involvement of inducible heat shock protein 70, cellular immunity targeting autoantigens takes the essential place in the destruction of melanocytes, which eventually results in vitiligo. Several treatments, such as narrow band ultraviolet, quercetin and α-melanophore-stimulating hormone, are reported to be able to lower ROS thereby achieving repigmentation in vitiligo. In therapies targeting autoimmunity, restore of regulatory T cells is absorbing attention, in which narrow band ultraviolet also plays a role. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Selective IgA deficiency in autoimmune diseases.

    Science.gov (United States)

    Wang, Ning; Shen, Nan; Vyse, Timothy J; Anand, Vidya; Gunnarson, Iva; Sturfelt, Gunnar; Rantapää-Dahlqvist, Solbritt; Elvin, Kerstin; Truedsson, Lennart; Andersson, Bengt A; Dahle, Charlotte; Ortqvist, Eva; Gregersen, Peter K; Behrens, Timothy W; Hammarström, Lennart

    2011-01-01

    Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) on the basis of both our own recent large-scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.

  12. Approaches to managing cytopenias in Autoimmune Lymphoproliferative Syndrome (ALPS.

    Directory of Open Access Journals (Sweden)

    V. Koneti eRao

    2015-07-01

    Full Text Available Autoimmune Lymphoproliferative Syndrome (ALPS is a rare disorder frequently due to mutations in FAS (TNFRSF6 gene. Unlike most of the self limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory as their inherited genetic defect is not going to go away. Historically more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to their disease and its treatments.

  13. Vitamin D Actions on CD4+ T Cells in Autoimmune Disease

    Science.gov (United States)

    Hayes, Colleen Elizabeth; Hubler, Shane L.; Moore, Jerott R.; Barta, Lauren E.; Praska, Corinne E.; Nashold, Faye E.

    2015-01-01

    This review summarizes and integrates research on vitamin D and CD4+ T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene–environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ T-regulatory cell and CD4+ T-regulatory cell type 1 (Tr1) cell functions, and a Th1–Tr1 switch. The proposed Th1–Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell–cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease. PMID:25852682

  14. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity.

    Science.gov (United States)

    Fischer, Henrike J; Witte, Ann-Kathrin; Walter, Lutz; Gröne, Hermann-Josef; van den Brandt, Jens; Reichardt, Holger M

    2016-05-01

    T-cell lymphopenia is a major risk factor for autoimmunity. Here we describe congenic Lewis (LEW) rats with a loss-of-function mutation in the Gimap5 gene, leading to a 92% reduction in peripheral T-cell numbers. Gimap5-deficient LEW rats developed eosinophilic autoimmune gastroenteritis accompanied by a 40-fold increase in IgE serum levels. This phenotype was ameliorated by antibiotic treatment, indicating a critical role of the microbial flora in the development of inflammatory bowel disease. Interestingly, Gimap5-deficient LEW rats showed strongly aggravated experimental autoimmune encephalomyelitis (EAE) after immunization with guinea pig myelin basic protein. This phenotype, however, persisted after antibiosis, confirming that the enhanced CNS autoimmune response in T-cell lymphopenic Gimap5-deficient LEW rats was unrelated to the composition of the microbial flora. Rather, it seems that it was caused by the 7-fold increase in the percentage of activated T cells producing IL-17 and IFN-γ, and the skewed T-cell receptor (TCR) repertoire, both of which were the result of T-cell lymphopenia and not affected by antibiosis. This notion was supported by the observation that adoptive T-cell transfer corrected the TCR repertoire and improved EAE. Collectively, our findings confirm a critical albeit differential role of T-cell lymphopenia in the susceptibility to organ-specific autoimmune responses.-Fischer, H. J., Witte, A.-K., Walter, L., Gröne, H.-J., van den Brandt, J., Reichardt, H. M. Distinct roles of T-cell lymphopenia and the microbial flora for gastrointestinal and CNS autoimmunity. © FASEB.

  15. Autoimmune Chronic Gastritis: New diagnostic and therapeutic approaches.

    OpenAIRE

    VALDES SOCIN, Hernan Gonzalo

    2016-01-01

    The challenge for the clinician is to detect early gastric autoimmunity markers to avoid some of its complications such as micronutriments and drug malabsorption. Indeed autoimmune gastritis may be associated with the development of neuroendocrine tumors (NET), gastric adenocarcinomas or even MALT lymphomas. In this lecture we summarize recent diagnostic tools and new therapies taylored for autoimmune gastritis.

  16. Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy in Calabria: clinical, immunological and genetic patterns.

    Science.gov (United States)

    Betterle, C; Ghizzoni, L; Cassio, A; Baronio, F; Cervato, S; Garelli, S; Barbi, E; Tonini, G

    2012-11-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal- dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1), is a very rare disease. Diagnosis requires the presence of at least two of three major clinical features: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. In this study, we analyzed Autoimmune Regulator (AIRE) gene mutations and genotype-phenotype correlation in APECED patients originating from Calabria, a region in the south of Italy. Four patients and their first-degree relatives were evaluated for clinical manifestations, autoantibody presence and AIRE gene mutations. Three patients carried a homozygous W78R mutation on exon 2, typical of patients with APECED from Apulia; the fourth patient had a homozygous R203X mutation on exon 5, typical of APECED patients from Sicily. Clinical disease expression showed wide variability. Analysis of relatives allowed the identification of 6 heterozygotes, none of whom showed major findings of APECED. No AIRE gene mutations specific to Calabria were found in patients with APS-1, but mutations similar to those in patients from Apulia and Sicily. Heterozygosity for AIRE gene mutation is not associated with major findings of APECED.

  17. [Influence of genetic polymorphisms (IL-10/CXCL8/CXCR2/NFκB) on the susceptibility of autoimmune rheumatic diseases].

    Science.gov (United States)

    Salim, Patricia Hartstein; Xavier, Ricardo Machado

    2014-01-01

    The autoimmune rheumatologic disorders mostly have a common genetic path to the autoimmunity. Several genes have been associated with rheumatologic disorders; therefore, we are analyzing just the ones in those containing several evidences of the existence of association with the risk or protection from autoimmune disorder. The nuclear factor kappa beta (NF-kappa B), which regulates the autoimmune and anti-inflammatory responses, is associated with systemic sclerosis (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), just as the CXCR2 e CXCL8 genes. On the other hand, the interleukin-10 (IL-10), which is an anti-inflammatory cytokine, is associated with almost all rheumatologic disorders. In this article, we are reviewing the potential roles of these genes in the immune system and in several rheumatologic disorders. In relation to IL-10, several studies have been carried out, but most of them are controversial - some detected the absence of association, and others found association in different genetic polymorphisms. Conversely, in relation to NF-kappa B, it was studied just in RA and SLE, and no relevant significant analyses were observed. The genetic polymorphisms of the CXCR2 gene were associated with SS, but not with RA e SLE. On the other side, the genetic polymorphisms of the CXCL8 gene are not associated with SS, but with RA. Copyright © 2014 Elsevier Editora Ltda. All rights reserved.

  18. Autoimmune Regulator Expression in DC2.4 Cells Regulates the NF-κB Signaling and Cytokine Expression of the Toll-Like Receptor 3 Pathway.

    Science.gov (United States)

    Sun, Jitong; Niu, Kunwei; Fu, Haiying; Li, Haijun; Li, Yi; Yang, Wei

    2016-12-01

    Autoimmune regulator (Aire) mutations result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), which manifests as multi-organ autoimmunity and chronic mucocutaneous candidiasis (CMC). Indendritic cells (DCs), pattern recognition receptors (PRR), such as Toll-like receptors (TLRs), are closely involved in the recognition of various pathogens, activating the intercellular signaling pathway, followed by the activation of transcription factors and the expression of downstream genes, which take part in mediating the immune response and maintaining immune tolerance. In this study, we found that Aire up-regulated TLR3 expression and modulated the downstream cytokine expression and nuclear factor-κB (NF-κB) of the TLR3 signaling pathway.

  19. Premature atherosclerosis in systemic autoimmune diseases

    NARCIS (Netherlands)

    Leeuw, Karina de

    2008-01-01

    Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and Wegener’s granulomatosis (WG) are associated with a significantly increased prevalence of cardiovascular disease (CVD) compared to age- and sex-matched controls. Many risk factors are involved in the pathogenesis of

  20. Checks and Balances in Autoimmune Vasculitis

    NARCIS (Netherlands)

    Cadena, Rebeca Hid; Abdulahad, Wayel H.; Hospers, G. A. P.; Wind, T. T.; Boots, Annemieke M. H.; Heeringa, Peter; Brouwer, Elisabeth

    2018-01-01

    Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune

  1. Immunosensors for Biomarker Detection in Autoimmune Diseases.

    Science.gov (United States)

    Zhang, Xuezhu; Zambrano, Amarayca; Lin, Zuan-Tao; Xing, Yikun; Rippy, Justin; Wu, Tianfu

    2017-04-01

    Autoimmune diseases occur when the immune system generates proinflammatory molecules and autoantibodies that mistakenly attack their own body. Traditional diagnosis of autoimmune disease is primarily based on physician assessment combined with core laboratory tests. However, these tests are not sensitive enough to detect early molecular events, and quite often, it is too late to control these autoimmune diseases and reverse tissue damage when conventional tests show positivity for disease. It is fortunate that during the past decade, research in nanotechnology has provided enormous opportunities for the development of ultrasensitive biosensors in detecting early biomarkers with high sensitivity. Biosensors consist of a biorecognition element and a transducer which are able to facilitate an accurate detection of proinflammatory molecules, autoantibodies and other disease-causing molecules. Apparently, novel biosensors could be superior to traditional metrics in assessing the drug efficacy in clinical trials, especially when specific biomarkers are indicative of the pathogenesis of disease. Furthermore, the portability of a biosensor enables the development of point-of-care devices. In this review, various types of biomolecule sensing systems, including electrochemical, optical and mechanical sensors, and their applications and future potentials in autoimmune disease treatment were discussed.

  2. Anti-cytokine autoantibodies in autoimmune diseases

    Science.gov (United States)

    Cappellano, Giuseppe; Orilieri, Elisabetta; Woldetsadik, Abiy D; Boggio, Elena; Soluri, Maria F; Comi, Cristoforo; Sblattero, Daniele; Chiocchetti, Annalisa; Dianzani, Umberto

    2012-01-01

    An overview of the current literature is showing that autoantibodies (AutoAbs) against cytokines are produced in several pathological conditions, including autoimmune diseases, but can also be detected in healthy individuals. In autoimmune diseases, these AutoAbs may also be prognostic markers, either negative (such as AutoAbs to IL-8 and IL-1α in rheumatoid arthritis) or positive (such as AutoAbs to IL-6 in systemic sclerosis and those to osteopontin in rheumatoid arthritis). They may have neutralizing activity and influence the course of the physiological and pathological immune responses. High levels of AutoAbs against cytokines may even lead to immunodeficiency, such as those to IL-17 in autoimmune polyendocrine syndrome type I or those to IFN-γ in mycobacterial infections. Their role in human therapy may be exploited not only through passive immunization but also through vaccination, which may improve the costs for long lasting treatments of autoimmune diseases. Detection and quantification of these AutoAbs can be profoundly influenced by the technique used and standardization of these methods is needed to increase the value of their analysis. PMID:23885320

  3. Autoimmune diseases: MIF as a therapeutic target

    NARCIS (Netherlands)

    Greven, Dorothee; Leng, Lin; Bucala, Richard

    2010-01-01

    Areas covered in this review: Our aim is to discuss MIF-directed therapies as a novel therapeutic approach. The review covers literature from the past 10 years. What the reader will gain: MIF inhibition has been shown to be efficacious in many experimental and pre-clinical studies of autoimmune

  4. S2k Leitlinie Autoimmune Lebererkrankungen

    NARCIS (Netherlands)

    Strassburg, Christian P.; Beckebaum, Susanne; Geier, Andreas; Gotthardt, Daniel; Klein, Reinhild; Melter, Michael; Schott, Eckart; Spengler, Ulrich; Tacke, Frank; Trauner, Michael; Weiler-Normann, Christina; Weismüller, Tobias J.; Tannapfel, Andrea; Tischendorf, Jens J.; Schramm, Christoph; Albert, Jörg; Allescher, Hans-Dieter; Antoni, Christoph; Berg, Christoph; Bufler, Philip; Dannel, Frank; Dietrich, Christoph; Engelmann, Guido; Feist, Eugen; Fickert, Peter; Fischer, Lutz; Flechtenmacher, Christa; Friedrich-Rust, Mireen; Giek, Angelika; Görtz, Rüdiger Stephan; Herzer, Kerstin; Hofer, Harald; Hohenester, Simon; Höhn, Mariele; Hüppe, Dietrich; In der Smitten, Susanne; Jahnel, Jörg; Keitel-Anselmino, Verena; Kirchner, Gabriele; Kremer, Andreas; Lauenstein, Andreas; Lenzen, Henrike; Mayerle, Julia; Müller, Tobias; Müllhaupt, Beat; Nashan, Björn; Rust, Christian; Schattenberg, Jörn M.; Schmidt, Hartmut; Schreyer, Andreas; Sebode, Marcial; Siegmund, Britta; Terjung, Birgit; Teufel, Andreas; van Thiel, Ingo; Wirth, Stefan; Witte, Torsten; Beuers, Ulrich; Gerken, Guido; Graziadei, Ivo; Lohse, Ansgar; Manns, Michael P.; Tilg, Herbert

    2017-01-01

    The guideline was created under the leadership of the DGVS and with participation of neighbouring scientific societies and is intended as a practical aid for the diagnosis and therapy of autoimmune liver diseases. The aim is to represent the current state of science, promote the recognition of the

  5. Increased prevalence of autoimmunity in Turner syndrome

    DEFF Research Database (Denmark)

    Mortensen, K H; Cleemann, L; Hjerrild, B E

    2009-01-01

    Individuals with Turner syndrome (TS) are prone to develop autoimmune conditions such as coeliac disease (CD), thyroiditis and type 1 diabetes (T1DM). The objective of the present study was to examine TS of various karyotypes for autoantibodies and corresponding diseases. This was investigated...

  6. Celiac disease in autoimmune cholestatic liver disorders.

    Science.gov (United States)

    Volta, Umberto; Rodrigo, Luis; Granito, Alessandro; Petrolini, Nunzio; Muratori, Paolo; Muratori, Luigi; Linares, Antonio; Veronesi, Lorenza; Fuentes, Dolores; Zauli, Daniela; Bianchi, Francesco B

    2002-10-01

    In this study, serological screening for celiac disease (CD) was performed in patients with autoimmune cholestasis to define the prevalence of such an association and to evaluate the impact of gluten withdrawal on liver disease associated with gluten sensitive enteropathy. Immunoglobulin A endomysial, human and guinea pig tissue transglutaminase antibodies, and immunoglobulin A and G gliadin antibodies were sought in 255 patients with primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis. Immunoglobulin A endomysial and human tissue transglutaminase antibodies were positive in nine patients (seven primary biliary cirrhosis, one autoimmune cholangitis, and one primary sclerosing cholangitis), whose duodenal biopsy results showed villous atrophy consistent with CD. Two of these patients had a malabsorption syndrome, and one had iron-deficiency anemia. Clinical and biochemical signs of cholestasis did not improve after gluten withdrawal in the three patients with severe liver disease. A longer follow-up of the six celiac patients with mild liver damage is needed to clarify whether gluten restriction can contribute to slow down the progression of liver disease. The high prevalence of CD (3.5%) in autoimmune cholestasis suggests that serological screening for CD should be routinely performed in such patients by immunoglobulin A endomysial or human tissue transglutaminase antibodies.

  7. Costimulation and autoimmune diabetes in BB rats

    NARCIS (Netherlands)

    Beaudette-Zlatanova, BC; Whalen, B; Zipris, D; Yagita, H; Rozing, J; Groen, H; Benjamin, CD; Hunig, T; Drexhage, HA; Ansari, MJ; Leif, J; Mordes, JP; Greiner, DL; Sayegh, MH; Rossini, AA

    Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28

  8. Autoimmun hepatitis. Fremtroedelsesformer, diagnostik og behandling

    DEFF Research Database (Denmark)

    Poulsen, L O; Tage-Jensen, U; Vyberg, M

    1992-01-01

    A retrospective study concerning ten patients with autoimmune hepatitis (AiH), diagnosed during a 2 1/2-year period is presented. The age of the patients ranged from 25 to 82 years and nine of the patients were women. Their symptoms included jaundice, pruritus, fever, anorexia and fatigue during...

  9. Autoimmune hepatitis : Pathogenesis, diagnosis and treatment

    NARCIS (Netherlands)

    van den Berg, AP

    Background: Autoimmune hepatitis (AIH) is a chronic necro-inflammatory disease of the liver. Early recognition is important in order to prevent the development of cirrosis. This review discusses recent developments in the fields of diagnosis, pathophysiology and management of AIH. Methods: Relevant

  10. Autoimmun hypophysitis--en differentialdiagnose til hypofyseadenomer

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    A 66-year-old man with a headache in the left temporal region which had persisted for eight months is presented. The patient developed polydipsia and polyuria and also suffered from tinnitus, impaired hearing and episodes of double vision. The patient was diagnosed with autoimmune hypophysitis (AH...

  11. Study of cytokines microenvironment during autoimmune diseases ...

    African Journals Online (AJOL)

    22, IL-23, TNF-α and TGF-β) were determined. We used the immunoenzymatic technology to assess the titer of cytokines. We found that there was no significant variation of TNF-α level in normal controls and autoimmune diseases ...

  12. Autoimmun synaptisk encefalitis er en underdiagnosticeret sygdomsgruppe

    DEFF Research Database (Denmark)

    Nielsen, Signe Modvig; Høi-Hansen, Christina Engel; Uldall, Peter

    2012-01-01

    The term autoimmune synaptic encephalitis (ASE) comprises encephalitides associated with autoantibodies against structures of the neuronal synapse. We review four types of ASE (anti-N-methyl-D-aspartate receptor encephalitis, anti-α-amine-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor...

  13. Is Tourette's syndrome an autoimmune disease?

    NARCIS (Netherlands)

    Hoekstra, PJ; Kallenberg, CGM; Korf, J; Minderaa, RB

    2002-01-01

    We provide a review of recent research findings which support the involvement of autoimmunity in childhood-onset tic disorders, in particular the presence of antineuronal autoantibodies, D8/17 B lymphocyte overexpression, a marker of chorea associated with streptococcal infection, and possible

  14. Is Tourette's syndrome an autoimmune disease?

    NARCIS (Netherlands)

    Hoekstra, P; Limburg, P; Kallenberg, C; Minderaa, R; Battistin, L

    2004-01-01

    Tourette's syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While its pathogenesis at a molecular and cellular level remains unknown, recent research findings point to the possible involvement of autoimmunity in at least a

  15. Autoimmune hepatitis in children in Eastern Denmark

    DEFF Research Database (Denmark)

    Vitfell-Pedersen, Joanna; Jørgensen, Marianne Hørby; Müller, Klaus

    2012-01-01

    Autoimmune hepatitis (AIH) in childhood is a progressive chronic inflammatory liver disease. The aim of this study was to compare the clinical and biochemical characteristics of 33 paediatric patients diagnosed as having AIH with earlier described cohorts, and to examine the effect of early...

  16. Auto-immune Haemolytic Anaemia and Paroxys

    African Journals Online (AJOL)

    who presented with an acute auto-immune haemolytic anaemia. In addition to a persistently positive Coombs test, with specific red cell auto-antibodies, the acidified serum test and the sucrose haemolysis test were repeatedly positive. CASE REPORT. A 24-year-old Indian woman was admitted to hospital in. July 1969.

  17. Systemic autoimmune disease and Raynaud's phenomonen.

    NARCIS (Netherlands)

    Kallenberg, Cornelis

    1982-01-01

    Systemic autoimmune diseases (AID) are clinically characterized by the involvement of multiple organ systems in the desease process, and immunologically by immune responsiveness against "self". The constitute a heterogenous group of disorders wich are presented to the clinician in a wide variety of

  18. Alopecia areata and autoimmunity: A clinical study

    Directory of Open Access Journals (Sweden)

    Thomas Emy

    2008-01-01

    Full Text Available Alopecia areata (AA frequently occur in association with other autoimmune diseases such as thyroid disorders, anemias and other skin disorders with autoimmune etiology. Despite numerous studies related to individual disease associations in alopecia areata, there is paucity of literature regarding comprehensive studies on concomitant cutaneous and systemic diseases. The present study has been designed to determine if there is a significant association between alopecia areata and other autoimmune diseases. This study covers 71 patients with the diagnosis of alopecia areata as the case group and 71 patients with no evidence of alopecia areata as the control group. Among the cutaneous diseases associated with AA, atopic dermatitis (AD showed maximum frequency with an O/E ratio of 2.5, which indicates that it is two to three times more common in patients with alopecia areata. In our study, thyroid disorders showed the highest frequency with on O/E ratio of 3.2 and a P value of 0.01, which is statistically highly significant. Among the thyroid disorders, hypothyroidism was the most frequent association (14.1% in our study. Since systemic involvement is not infrequent in patients with alopecia areata, it is imperative to screen these patients for associated disorders, particularly atopy, thyroid diseases, anemias and other autoimmune disorders, especially if alopecia areata is chronic, recurrent and extensive.

  19. Impact of Autoantibodies against Glycolytic Enzymes on Pathogenicity of Autoimmune Retinopathy and Other Autoimmune Disorders

    Directory of Open Access Journals (Sweden)

    Grazyna Adamus

    2017-04-01

    Full Text Available Autoantibodies (AAbs against glycolytic enzymes: aldolase, α-enolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase are prevalent in sera of patients with blinding retinal diseases, such as paraneoplastic [cancer-associated retinopathy (CAR] and non-paraneoplastic autoimmune retinopathies, as well as in many other autoimmune diseases. CAR is a degenerative disease of the retina characterized by sudden vision loss in patients with cancer and serum anti-retinal AAbs. In this review, we discuss the widespread serum presence of anti-glycolytic enzyme AAbs and their significance in autoimmune diseases. There are multiple mechanisms responsible for antibody generation, including the innate anti-microbial response, anti-tumor response, or autoimmune response against released self-antigens from damaged, inflamed tissue. AAbs against enolase, GADPH, and aldolase exist in a single patient in elevated titers, suggesting their participation in pathogenicity. The lack of restriction of AAbs to one disease may be related to an increased expression of glycolytic enzymes in various metabolically active tissues that triggers an autoimmune response and generation of AAbs with the same specificity in several chronic and autoimmune conditions. In CAR, the importance of serum anti-glycolytic enzyme AAbs had been previously dismissed, but the retina may be without pathological consequence until a failure of the blood–retinal barrier function, which would then allow pathogenic AAbs access to their retinal targets, ultimately leading to damaging effects.

  20. Role of passive T-cell death in chronic experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Abdallah, K; Chitnis, T

    2000-01-01

    The mechanisms of chronic disease and recovery from relapses in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, are unknown. Deletion of myelin-specific lymphocytes by apoptosis may play a role in termination of the inflammatory response. One pathway...... of apoptosis is the passive cell death or "cell death by neglect" pathway, which is under the control of the Bcl family of genes. To investigate the role of passive cell death pathway in EAE, we used mice with transgenic expression of the long form of the bcl-x gene (Bcl-x(L)) targeted to the T-cell lineage...... central nervous system (CNS) compared with controls. There was also a decreased number of apoptotic cells in the CNS of Bcl-x(L) transgenic mice when compared with littermates at all time points tested. This is the first report of an autoimmune disease model in Bcl-x(L) transgenic mice. Our data indicate...

  1. Rheumatic Disease Autoantibodies in Autoimmune Liver Diseases.

    Science.gov (United States)

    Utiyama, Shirley R R; Zenatti, Katiane B; Nóbrega, Heloisa A J; Soares, Juliana Z C; Skare, Thelma L; Matsubara, Caroline; Muzzilo, Dominique A; Nisihara, Renato M

    2016-08-01

    Autoimmune liver diseases (ALDs) are known to be associated with systemic autoimmune rheumatic diseases (SARDs) and their autoantibodies. We aimed to study the prevalence of SARDs and related autoantibodies, as well as their prognostic implications in a group of patients with ALDs. This was a cross-sectional study. Sixty patients with ALDs (38.3% with autoimmune hepatitis; 11.7% with primary biliary cirrhosis; 25% with primary sclerosing cholangitis and 25% with overlap syndrome) were studied for the presence of SARDs and their autoantibodies. There was autoimmune rheumatic disease in 20% of the studied sample. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were the commonest (11.6% and 5%, respectively). Antinuclear antibodies (ANAs) were present in 35% of the patients, followed by anti-Ro (20.0%); anti-nucleosome (18.3%); rheumatoid factor (10%) anti-CCP (8.3%); anti-RNP (8.3%); anti-ds-DNA (6.6%); anti-La (3.3%); anti-Sm (3.3%), anti-ribosomal P (3.3%). Anti-Ro (p = 0.0004), anti-La (p = 0.03), anti-RNP (p = 0.04) and anti-Sm (p = 0.03) were commonly found in patients with SARD, but not anti-DNA, anti-nucleosome and anti-ribosomal P. No differences were found in liver function tests regarding to the presence of autoantibodies. There was a high prevalence of SARD and their autoantibodies in ALD patients. Anti-Ro, anti-La, anti-RNP and anti-Sm positivity points to an association with systemic autoimmune rheumatic diseases. The presence of autoantibodies was not related to liver function tests.

  2. Eating Disorders, Autoimmune, and Autoinflammatory Disease.

    Science.gov (United States)

    Zerwas, Stephanie; Larsen, Janne Tidselbak; Petersen, Liselotte; Thornton, Laura M; Quaranta, Michela; Koch, Susanne Vinkel; Pisetsky, David; Mortensen, Preben Bo; Bulik, Cynthia M

    2017-12-01

    Identifying factors associated with risk for eating disorders is important for clarifying etiology and for enhancing early detection of eating disorders in primary care. We hypothesized that autoimmune and autoinflammatory diseases would be associated with eating disorders in children and adolescents and that family history of these illnesses would be associated with eating disorders in probands. In this large, nationwide, population-based cohort study of all children and adolescents born in Denmark between 1989 and 2006 and managed until 2012, Danish medical registers captured all inpatient and outpatient diagnoses of eating disorders and autoimmune and autoinflammatory diseases. The study population included 930 977 individuals (48.7% girls). Cox proportional hazards regression models and logistic regression were applied to evaluate associations. We found significantly higher hazards of eating disorders for children and adolescents with autoimmune or autoinflammatory diseases: 36% higher hazard for anorexia nervosa, 73% for bulimia nervosa, and 72% for an eating disorder not otherwise specified. The association was particularly strong in boys. Parental autoimmune or autoinflammatory disease history was associated with significantly increased odds for anorexia nervosa (odds ratio [OR] = 1.13, confidence interval [CI] = 1.01-1.25), bulimia nervosa (OR = 1.29; CI = 1.08-1.55) and for an eating disorder not otherwise specified (OR = 1.27; CI = 1.13-1.44). Autoimmune and autoinflammatory diseases are associated with increased risk for eating disorders. Ultimately, understanding the role of immune system disturbance for the etiology and pathogenesis of eating disorders could point toward novel treatment targets. Copyright © 2017 by the American Academy of Pediatrics.

  3. Antineutrophil Cytoplasmic Antibodies, Autoimmune Neutropenia, and Vasculitis

    Science.gov (United States)

    Grayson, Peter C.; Sloan, J. Mark; Niles, John L.; Monach, Paul A.; Merkel, Peter A.

    2011-01-01

    Objectives Reports of an association between antineutrophil cytoplasmic antibodies (ANCA) and autoimmune neutropenia have rarely included cases of proven vasculitis. A case of ANCA-associated vasculitis (AAV) with recurrent neutropenia is described and relevant literature on the association between ANCA, neutropenia, and vasculitis is reviewed. Methods Longitudinal clinical assessments and laboratory findings are described in a patient with AAV and recurrent episodes of profound neutropenia from December 2008 – October 2010. A PubMed database search of the medical literature was performed for papers published from 1960 through October 2010 to identify all reported cases of ANCA and neutropenia. Results A 49 year-old man developed recurrent neutropenia, periodic fevers, arthritis, biopsy-proven cutaneous vasculitis, sensorineural hearing loss, epididymitis, and positive tests for ANCA with specificity for antibodies to both proteinase 3 and myeloperoxidase. Antineutrophil membrane antibodies were detected during an acute neutropenic phase and were not detectable in a post-recovery sample, whereas ANCA titers did not seem to correlate with neutropenia. An association between ANCA and neutropenia has been reported in 74 cases from 24 studies in the context of drug/toxin exposure, underlying autoimmune disease, or chronic neutropenia without underlying autoimmune disease. In these cases, the presence of atypical ANCA patterns and other antibodies were common; however, vasculitis was uncommon and when it occurred was usually limited to the skin and in cases of underlying toxin exposure. Conclusions ANCA is associated with autoimmune neutropenia, but systemic vasculitis rarely occurs in association with ANCA and neutropenia. The interaction between neutrophils and ANCA may provide insight into understanding both autoimmune neutropenia and AAV. PMID:21507463

  4. Genomics and proteomics: Applications in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Wolfgang Hueber

    2009-08-01

    Full Text Available Wolfgang Hueber1,2,3, William H Robinson1,21VA Palo Alto Health Care System, Palo Alto, CA, USA; 2Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; 3Novartis Institutes of Biomedical Research, Novartis, Basle, SwitzerlandAbstract: Tremendous progress has been made over the past decade in the development and refinement of genomic and proteomic technologies for the identification of novel drug targets and molecular signatures associated with clinically important disease states, disease subsets, or differential responses to therapies. The rapid progress in high-throughput technologies has been preceded and paralleled by the elucidation of cytokine networks, followed by the stepwise clinical development of pathway-specific biological therapies that revolutionized the treatment of autoimmune diseases. Together, these advances provide opportunities for a long-anticipated personalized medicine approach to the treatment of autoimmune disease. The ever-increasing numbers of novel, innovative therapies will need to be harnessed wisely to achieve optimal long-term outcomes in as many patients as possible while complying with the demands of health authorities and health care providers for evidence-based, economically sound prescription of these expensive drugs. Genomic and proteomic profiling of patients with autoimmune diseases holds great promise in two major clinical areas: (1 rapid identification of new targets for the development of innovative therapies and (2 identification of patients who will experience optimal benefit and minimal risk from a specific (targeted therapy. In this review, we attempt to capture important recent developments in the application of genomic and proteomic technologies to translational research by discussing informative examples covering a diversity of autoimmune diseases.Keywords: proteomics, genomics, autoimmune diseases, antigen microarrays, 2-Dih, rheumatoid arthritis

  5. Infections as risk factor for autoimmune diseases - A nationwide study

    DEFF Research Database (Denmark)

    Nielsen, Philip Rising; Kragstrup, Tue Wenzel; Deleuran, Bent Winding

    2016-01-01

    Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons...... to the etiology of autoimmune diseases together with genetic factors....... born between 1945 and 2000. Information on infections and autoimmune diseases was obtained from the Danish Hospital Register. The cohort was followed from 1977 to 2012. Incidence rate ratios for developing an autoimmune disease were estimated using poisson regression. We found an association between...

  6. Autoimmune pancreatitis associated with primary sclerosing cholangitis: MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Eerens, I.; Vanbeckevoort, D.; Van Hoe, L. [University Hospital, Leuven (Belgium). Dept. of Radiology; Vansteenbergen, W. [Dept. of Hepatology, University Hospitals KU, Leuven (Belgium)

    2001-08-01

    Autoimmune pancreatitis is a relatively rare type of chronic pancreatitis that may be associated with other autoimmune disorders. The imaging features of this entity may be misleading and suggest the presence of a malignant tumour. We present a case in which MR imaging allowed us to diagnose autoimmune pancreatitis associated with primary sclerosing cholangitis, which is another autoimmune-related disease. Typical MR characteristics of autoimmune pancreatitis include focal or diffuse enlargement of the pancreas, the absence of parenchymal atrophy and significant dilation proximal to the site of stenosis, the absence of peripancreatic spread, the clear demarcation of the lesion and the presence of a peripancreatic rim. (orig.)

  7. Strategies for the prevention of autoimmune type 1 diabetes.

    Science.gov (United States)

    Todd, J A; Knip, M; Mathieu, C

    2011-10-01

    European experts on autoimmune Type 1 diabetes met for 2 days in October 2010 in Cambridge, to review the state-of-the-art and to discuss strategies for prevention of Type 1 diabetes (http://www-gene.cimr.cam.ac.uk/todd/sub_pages/T1D_prevention_Cambridge_workshop_20_21Oct2010.pdf). Meeting sessions examined the epidemiology of Type 1 diabetes; possible underlying causes of the continuing and rapid increase in Type 1 diabetes incidence at younger ages; and lessons learned from previous prevention trials. Consensus recommendations from the meeting were: 1. Resources such as national diabetes registries and natural history studies play an essential role in developing and refining assays to be used in screening for risk factors for Type 1 diabetes. 2. It is crucial to dissect out the earliest physiological events after birth, which are controlled by the susceptibility genes now identified in Type 1 diabetes, and the environmental factors that might affect these phenotypes, in order to bring forward a mechanistic approach to designing future prevention trials. 3. Current interventions at later stages of disease, such as in newly diagnosed Type 1 diabetes, have relied mainly on non-antigen-specific mechanisms. For primary prevention-preventing the onset of autoimmunity-interventions must be based on knowledge of the actual disease process such that: participants in a trial would be stratified according the disease-associated molecular phenotypes; the autoantigen(s) and immune responses to them; and the manipulation of the environment, as early as possible in life. Combinations of interventions should be considered as they may allow targeting different components of disease, thus lowering side effects while increasing efficacy. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

  8. Autoimmunity in patients with selective IgA deficiency.

    Science.gov (United States)

    Abolhassani, H; Gharib, B; Shahinpour, S; Masoom, S N; Havaei, A; Mirminachi, B; Arandi, N; Torabi-Sagvand, B; Khazaei, H A; Mohammadi, J; Rezaei, N; Aghamohammadi, A

    2015-01-01

    Selective immunoglobulin A deficiency (SIgAD) is the most common primary antibody deticiency. Patients with SIgAD have a greater risk of concomitant autoimmune disorders than healthy individuals. The exact mechanism underlying the relationship between autoimmunity and SIgAD is not fully understood. The aim of this study was to evaluate potential associations between autoimmunity and specific clinical or immunological findings in patients with SIgAD. The study population comprised 57 symptomatic patients (65% males) with confirmed SIgAD who were referred to our center. Demographic data and history of autoimmunity were recorded both for patients and for their relatives. Comprehensive clinical and laboratory examinations were performed to investigate autoimmune complications in all the patients. Autoimmune disorders were documented in 17 cases (29.8%; 9 males and 8 females). The most common manifestations were thyroiditis, vitiligo, and hemolytic anemia (3 cases each). Ten patients (17.5%) had a family history of autoimmunity. Significant associations were detected between autoimmunity and increased duration of follow-up (P = .003), serum level of IgM (P = .01), regulatory T-cell count (P = .03), and class-switched memory B-cell count (P = .01). Four cases of autoimmune SIgAD (23.5%) progressed to common variable immunodeficiency during the follow-up period (P = .006). Autoimmune disorders, autoimmune cytopenia, and Ig subclass deficiency can lead to severe clinical manifestations in patients with SIgAD. Therefore, immunologists and pediatricians should be aware of these conditions.

  9. Helicobacter pylori and autoimmune disease: Cause or bystander

    Science.gov (United States)

    Smyk, Daniel S; Koutsoumpas, Andreas L; Mytilinaiou, Maria G; Rigopoulou, Eirini I; Sakkas, Lazaros I; Bogdanos, Dimitrios P

    2014-01-01

    Helicobacter pylori (H. pylori) is the main cause of chronic gastritis and a major risk factor for gastric cancer. This pathogen has also been considered a potential trigger of gastric autoimmunity, and in particular of autoimmune gastritis. However, a considerable number of reports have attempted to link H. pylori infection with the development of extra-gastrointestinal autoimmune disorders, affecting organs not immediately relevant to the stomach. This review discusses the current evidence in support or against the role of H. pylori as a potential trigger of autoimmune rheumatic and skin diseases, as well as organ specific autoimmune diseases. We discuss epidemiological, serological, immunological and experimental evidence associating this pathogen with autoimmune diseases. Although over one hundred autoimmune diseases have been investigated in relation to H. pylori, we discuss a select number of papers with a larger literature base, and include Sjögrens syndrome, rheumatoid arthritis, systemic lupus erythematosus, vasculitides, autoimmune skin conditions, idiopathic thrombocytopenic purpura, autoimmune thyroid disease, multiple sclerosis, neuromyelitis optica and autoimmune liver diseases. Specific mention is given to those studies reporting an association of anti-H. pylori antibodies with the presence of autoimmune disease-specific clinical parameters, as well as those failing to find such associations. We also provide helpful hints for future research. PMID:24574735

  10. Infections as risk factor for autoimmune diseases - A nationwide study.

    Science.gov (United States)

    Nielsen, Philip Rising; Kragstrup, Tue Wenzel; Deleuran, Bent Winding; Benros, Michael Eriksen

    2016-11-01

    Viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity. In the present nation-wide study we describe the association between infections and 29 autoimmune diseases. We used the Danish Civil Registration System to identify 4.5 million persons born between 1945 and 2000. Information on infections and autoimmune diseases was obtained from the Danish Hospital Register. The cohort was followed from 1977 to 2012. Incidence rate ratios for developing an autoimmune disease were estimated using poisson regression. We found an association between hospital admission for an infection and 29 autoimmune diseases. This study shows that infections are risk factors for a broad spectrum of autoimmune diseases in a dose-response and temporal manner, in agreement with the hypothesis that infections are an environmental risk factor contributing to the etiology of autoimmune diseases together with genetic factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. [Coexistence of autoimmune polyglandular syndrome type 3 with diabetes insipidus].

    Science.gov (United States)

    Krysiak, Robert; Okopień, Bogusław

    2015-01-01

    Autoimmune polyglandular syndromes are conditions characterized by the combination of two or more organ-specific disorders. The underestimation oftheir real frequency probable results from physicians' inadequate knowledge of these clinical entities and sometimes their atypical clinical presentation. Because they comprise a wide spectrum of autoimmune disorders, autoimmune polyglandular syndromes are divided into four types, among which type-3 is the most common one. In this article, we report the case of a young female, initially diagnosed with diabetes mellitus who several years later developed full-blown autoimmune polyglandular syndrome type 3 consisting of autoimmune thyroid disorder and latent autoimmune diabetes in adults.The discussed case suggests that in selected patients diabetes insipidus may coexist with autoimmune endocrinopathies and nonendocrine autoimmunopathies, as well as that in some patients idiopathic diabetes insipidus may be secondary to lymphocytic infiltration and destruction of the hypothalamic supraoptic and paraventricular nuclei and/or the supraoptic-hypophyseal tract

  12. Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

    Science.gov (United States)

    Mazza, Cinzia; Buzi, Fabio; Ortolani, Federica; Vitali, Alberto; Notarangelo, Lucia D; Weber, Giovanna; Bacchetta, Rosa; Soresina, Annarosa; Lougaris, Vassilios; Greggio, Nella A; Taddio, Andrea; Pasic, Srdjan; de Vroede, Monique; Pac, Malgorzata; Kilic, Sara Sebnem; Ozden, Sanal; Rusconi, Roberto; Martino, Silvana; Capalbo, Donatella; Salerno, Mariacarolina; Pignata, Claudio; Radetti, Giorgio; Maggiore, Giuseppe; Plebani, Alessandro; Notarangelo, Luigi D; Badolato, Raffaele

    2011-04-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED. Copyright © 2010 Elsevier Inc. All rights reserved.

  13. Whole-genome analysis in Korean patients with autoimmune myasthenia gravis.

    Science.gov (United States)

    Na, Sang-Jun; Lee, Ji Hyun; Kim, So Won; Kim, Dae-Seong; Shon, Eun Hee; Park, Hyung Jun; Shin, Ha Young; Kim, Seung Min; Choi, Young-Chul

    2014-05-01

    The underlying cause of myasthenia gravis (MG) is unknown, although it likely involves a genetic component. However, no common genetic variants have been unequivocally linked to autoimmune MG. We sought to identify the genetic variants associated with an increased or decreased risk of developing MG in samples from a Korean Multicenter MG Cohort. To determine new genetic targets related to autoimmune MG, a whole genome-based single nucleotide polymorphisms (SNP) analysis was conducted using an Axiom™ Genome-Wide ASI 1 Array, comprising 598375 SNPs and samples from 109 MG patients and 150 neurologically normal controls. In total, 641 SNPs from five case-control associations showed p-values of less than 10⁻⁵. From regional analysis, we selected seven candidate genes (RYR3, CACNA1S, SLAMF1, SOX5, FHOD3, GABRB1, and SACS) for further analysis. The present study suggests that a few genetic polymorphisms, such as in RYR3, CACNA1S, and SLAMF1, might be related to autoimmune MG. Our findings also encourage further studies, particularly confirmatory studies with larger samples, to validate and analyze the association between these SNPs and autoimmune MG.

  14. Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals.

    Science.gov (United States)

    Fournié, G J; Mas, M; Cautain, B; Savignac, M; Subra, J F; Pelletier, L; Saoudi, A; Lagrange, D; Calise, M; Druet, P

    2001-05-01

    Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines. Copyright 2001 Academic Press.

  15. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases

    Science.gov (United States)

    Dragin, Nadine; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Biferi, Maria Grazia; Berthault, Claire; Serraf, Alain; Nottin, Rémi; Klatzmann, David; Cumano, Ana; Barkats, Martine; Le Panse, Rozen

    2016-01-01

    Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α–deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases. PMID:26999605

  16. Genetic analysis of inflammation, cytokine mRNA expression and disease course of relapsing experimental autoimmune encephalomyelitis in DA rats

    DEFF Research Database (Denmark)

    Lorentzen, J C; Andersson, M; Issazadeh-Navikas, Shohreh

    1997-01-01

    Genetic analysis of experimental autoimmune encephalomyelitis (EAE) can provide clues to the etiology of multiple sclerosis (MS). Identifying the susceptibility genes of DA rats may be particularly rewarding since they are prone to develop a remarkably MS-like chronic and demyelinating disease...

  17. Future perspective for diagnosis in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Luis E. C. Andrade

    2009-09-01

    Full Text Available Human beings have taken successive approaches for the understanding and management of diseases. Initially brewed in supernatural concepts and mystical procedures, a vigorous scientific approach has emerged on the grounds of fundamental disciplines such as anatomy, microbiology, biochemistry, physiology, immunology, pathology, and pharmacology. The resulting integrated knowledge contributed to the current classification of diseases and the way Medicine is carried out today. Despite considerable progress, this approach is rather insufficient when it comes to systemic inflammatory conditions, such as systemic lupus erythematosus, that covers clinical conditions ranging from mild pauci-symptomatic diseases to rapidly fatal conditions. The treatment for such conditions is often insufficient and novel approaches are needed for further progress in these areas of Medicine. A recent breakthrough has been achieved with respect to chronic auto-inflammatory syndromes, in which molecular dissection of underlying gene defects has provided directions for target-oriented therapy. Such approach may be amenable to application in systemic auto-immune diseases with the comprehension that such conditions may be the consequence of interaction of specific environmental stimuli and an array of several and interconnected gene polymorphisms. On the bulk of this transformation, the application of principles of pharmacogenetics may lead the way towards a progressively stronger personalized Medicine.O homem tem buscado sucessivas abordagens para o entendimento e manejo das doenças. Partindo de conceitos sobrenaturais e procedimentos místicos, uma abordagem científica vigorosa vicejou com base em disciplinas fundamentais como a anatomia, microbiologia, bioquímica, fisiologia, imunologia, patologia e farmacologia. O conhecimento integrado resultante contribuiu para a atual classificação das doenças e a formacom que a Medicina atual é praticada. Apesar deste consider

  18. Neuroelectrophysiological studies on neurological autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Yin-hong LIU

    2014-09-01

    Full Text Available The neuroelectrophysiological manifestations of four clinical typical neurological autoimmune diseases including multiple sclerosis (MS, Guillain-Barré syndrome (GBS, myasthenia gravis (MG, and polymyositis and dermatomyositis were reviewed in this paper. The diagnostic value of evoked potentials for multiple sclerosis, nerve conduction studies (NCS for Guillain-Barré syndrome, repetitive nerve stimulation (RNS and single-fiber electromyography (SFEMG for myasthenia gravis, and needle electromyography for polymyositis and dermatomyositis were respectively discussed. This review will help to have comprehensive understanding on electrophysiological examinations and their clinical significance in the diagnosis of neurological autoimmune diseases. doi: 10.3969/j.issn.1672-6731.2014.09.004

  19. The mechanisms behind helminth's immunomodulation in autoimmunity.

    Science.gov (United States)

    Bashi, Tomer; Bizzaro, Giorgia; Ben-Ami Shor, Dana; Blank, Miri; Shoenfeld, Yehuda

    2015-02-01

    The incidence of autoimmune diseases has risen throughout the last half a century, mostly in the industrialized world. Helminths and their derivatives were found to have a protective role in autoimmunity and inflammatory conditions, as they manipulate the immune network, attenuating the host's cellular and humoral responses. Indeed, various helminth species used in several human and animal models were shown to limit inflammatory activity in a variety of diseases including inflammatory bowel disease, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. Our review will focus on the main mechanisms by which helminths and their secreted molecules modulate the host's immune system. The main pathways induce a shift from Th1 to Th2 phenotype, accelerate T regulatory and B regulatory phenotypes, and attenuate the levels of the inflammatory cytokines, leading to a tolerable scenario. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Hypertension as an autoimmune and inflammatory disease.

    Science.gov (United States)

    Solak, Yalcin; Afsar, Baris; Vaziri, Nosratola D; Aslan, Gamze; Yalcin, Can Ege; Covic, Adrian; Kanbay, Mehmet

    2016-08-01

    Hypertension that is considered idiopathic is called essential hypertension and accordingly has no clear culprit for its cause. However, basic research and clinical studies in recent years have expanded our understanding of the mechanisms underlying the development of essential hypertension. Of these, increased oxidative stress, both in the kidney and arterial wall, closely coupled with inflammatory infiltration now appear to have a prominent role. Discovery of regulatory and interleukin-17-producing T cells has enabled us to better understand the mechanism by which inflammation and autoimmunity, or autoinflammation, lead to the development of hypertension. Despite achieving considerable progress, the intricate interactions between oxidative stress, the immune system and the development of hypertension remain to be fully elucidated. In this review, we summarize recent developments in the pathophysiology of hypertension with a focus on the oxidant stress-autoimmunity-inflammation interaction.

  1. Eating disorders, autoimmune, and autoinflammatory disease

    DEFF Research Database (Denmark)

    Zerwas, Stephanie; Larsen, Janne Tidselbak; Petersen, Liselotte

    2017-01-01

    OBJECTIVES: Identifying factors associated with risk for eating disorders is important for clarifying etiology and for enhancing early detection of eating disorders in primary care. We hypothesized that autoimmune and autoinflammatory diseases would be associated with eating disorders in children...... and adolescents and that family history of these illnesses would be associated with eating disorders in probands. METHODS: In this large, nationwide, population-based cohort study of all children and adolescents born in Denmark between 1989 and 2006 and managed until 2012, Danish medical registers captured all...... inpatient and outpatient diagnoses of eating disorders and autoimmune and autoinflammatory diseases. The study population included 930 977 individuals (48.7% girls). Cox proportional hazards regression models and logistic regression were applied to evaluate associations. RESULTS: We found significantly...

  2. [Glycosylation of autoantibodies in autoimmunes diseases].

    Science.gov (United States)

    Goulabchand, R; Batteux, F; Guilpain, P

    2013-12-01

    Protein glycosylation is one of the most common post-translational modifications, involved in the well described protein biosynthesis process. Protein glycosylation seems to play a major role in the pathogenesis of auto-immune diseases. Herein are described the main alterations of autoantibody glycosylation associated with autoimmunes diseases such as rheumatoid arthritis, IgA glomerulonephritis, Schoenlein-Henoch purpura, Sjögren's syndrome, systemic scleroderma, systemic lupus erythematosus, myasthenia gravis and granulomatosis with polyangiitis (Wegener). Molecular identification of altered immunoglobulin glycosylation could lead to a better understanding of the pathogenesis of those diseases, might allow an evaluation of their biological activity and could even be a new therapeutic target. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  3. Total lymphoid irradiation in alloimmunity and autoimmunity

    Energy Technology Data Exchange (ETDEWEB)

    Strober, S.

    1987-12-01

    Total lymphoid irradiation has been used as an immunosuppressive regimen in autoimmune disease and organ transplantation. The rationale for its use originated from studies of patients with Hodgkin disease, in whom this radiotherapy regimen was noted to induce profound and long-lasting immune suppression and yet was well tolerated, with few long-term side effects. Total lymphoid irradiation is a unique immunosuppressive regimen that produces a selective (and long-lasting) reduction in the number and function of helper T cells and certain subsets of B cells. Conventional immunosuppressive drugs show little selectivity, and their effects are short-lived. The most important aspect of total lymphoid irradiation is the potential for achieving transplantation tolerance and permanent remissions in autoimmune disease in laboratory animals. Attempts are being made to achieve similar goals in humans given total lymphoid irradiation, so that immunosuppressive drugs can be ultimately withdrawn from transplant recipients and patients with lupus nephritis. 28 references.

  4. Primary biliary cirrhosis--autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome.

    Science.gov (United States)

    Pamfil, Cristina; Candrea, Elisabeta; Berki, Emese; Popov, Horațiu I; Radu, Pompilia I; Rednic, Simona

    2015-03-01

    Autoimmune liver diseases may be associated with extrahepatic autoimmune pathology. We report the case of a 52-year old woman who initially presented to the gastroenterology department for extreme fatigue, pale stools, dark urine and pruritus. Laboratory tests showed significant cholestasis and elevation of aminotransferase levels. Immunological tests revealed positive antinuclear (ANA=1:320) and antimitochondrial antibodies (AMA=1:40) with negative anti-smooth muscle and liver kidney microsomal type 1 antibodies. The biopsy was compatible with overlap syndrome type 1. The patient was commenced on immunosuppressive therapy according to standard of care (azathioprine 50mg, ursodeoxycholic acid and prednisone 0.5mg/kg), with moderate biochemical improvement. She subsequently developed proximal symmetrical weakness and cutaneous involvement and was diagnosed with biopsy-proven dermatomyositis. The immunosuppressive regimen was intensified to 150 mg azathioprine. At the three-month follow-up, her symptoms subsided and aminotransferases and muscle enzymes normalized. Upon further investigation the patient was diagnosed with autoimmune thyroiditis and antiphospholipid syndrome. To our knowledge, this is the first case of primary biliary cirrhosis - autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome.

  5. Genetic variation associated with cardiovascular risk in autoimmune diseases.

    Science.gov (United States)

    Perrotti, Pedro P; Aterido, Adrià; Fernández-Nebro, Antonio; Cañete, Juan D; Ferrándiz, Carlos; Tornero, Jesús; Gisbert, Javier P; Domènech, Eugeni; Fernández-Gutiérrez, Benjamín; Gomollón, Fernando; García-Planella, Esther; Fernández, Emilia; Sanmartí, Raimon; Gratacós, Jordi; Martínez-Taboada, Víctor Manuel; Rodríguez-Rodríguez, Luís; Palau, Núria; Tortosa, Raül; Corbeto, Mireia L; Lasanta, María L; Marsal, Sara; Julià, Antonio

    2017-01-01

    Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

  6. Genetic variation associated with cardiovascular risk in autoimmune diseases.

    Directory of Open Access Journals (Sweden)

    Pedro P Perrotti

    Full Text Available Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways. The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

  7. Extracellular Vesicles: Evolving Contributors in Autoimmunity

    OpenAIRE

    Katsiougiannis, Stergios

    2015-01-01

    Extracellular vesicles, including microvesicles, exosomes and apoptotic bodies are recognized as carriers of pathogen-associated molecules with direct involvement in immune signaling and inflammation. Those observations have enforced the way these membranous vesicles are being considered as promising immunotherapeutic targets. In this review, we discuss the emerging roles of extracellular vesicles in autoimmunity and highlights their potential use as disease biomarkers as well as targets for ...

  8. Conversion of autoimmune hypothyroidism to hyperthyroidism

    OpenAIRE

    Furqan, Saira; Haque, Naeem-ul; Islam, Najmul

    2014-01-01

    Background Graves’ disease and Hashimoto’s thyroiditis are the two autoimmune spectrum of thyroid disease. Cases of conversion from hyperthyroidism to hypothyroidism have been reported but conversion from hypothyroidism to hyperthyroidism is very rare. Although such cases have been reported rarely in the past we are now seeing such conversions from hypothyroidism to hyperthyroidism more frequently in clinical practice. Case presentation We are reporting three cases of middle aged Asian female...

  9. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Ana M. C. Faria

    2006-01-01

    Full Text Available Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10 and Th3 (TGF-β regulatory T cells (Tregs plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB, Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE, uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral, formulation, mucosal adjuvants, combination therapy and early therapy.

  10. The autoimmune concept of multiple sclerosis.

    Science.gov (United States)

    Nicol, Bryan; Salou, Marion; Laplaud, David-Axel; Wekerle, Hartmut

    2015-04-01

    Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). With growing evidence for environmental and genetic factors, MS is now accepted as an autoimmune disease. This complex disease seems to implicate various cell types in both innate and adaptive compartments. Here, we discuss recent advances in the immunological field of MS research. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. IgA deficiency and autoimmunity.

    Science.gov (United States)

    Singh, Karmtej; Chang, Christopher; Gershwin, M Eric

    2014-02-01

    IgA is the most abundant immunoglobulin in the human body, and performs a very specialized role which involves mucosal immunity, development of tolerance and protection against infection. IgA is the key immunoglobulin in the respiratory and gastrointestinal tracts, which provide the most intimate interface between the environment and self. Normal levels of IgA are based on early studies consisting of only small numbers of patients. The international consensus definition of IgA deficiency is a level of 0.07g/l after the age of four years in the absence of IgG and IgM deficiencies. The epidemiology of IgA deficiency reveals interesting variances between geographical regions - the incidence in Caucasians being much higher than that in Asians. IgA deficiency has also been found to co-exist with autoimmune diseases, allergies and malignancies. The association with autoimmunity is particularly interesting because it suggests a common genetic linkage that could potentially also explain the diversity in geoepidemiology. Both MHC and non-MHC associations have been described and the 8.1 haplotype has been significantly associated with autoimmunity in IgA deficiency patients over controls. Non-MHC genetic associations include IFIH1 and CLEC16A. The mutations leading to IgA deficiency have not been defined, but in some cases of IgA deficiency it has been suggested that the pathogenesis involves a failure in switched memory B cells that can lead to this cohort experiencing an increased incidence of recurrent bacterial infections or autoimmune diseases. Attempts to investigate the role of cytokines that can induce IgA synthesis in cells of patients with IgA deficiency, such as IL21 or the combination of CD40L/anti-CD40, IL-4 and IL10, are underway. © 2013.

  12. The new era of autoimmune disease research

    OpenAIRE

    Koike, Takao

    2011-01-01

    Recent genome-wide association studies have advanced our understanding of genetic factors that underlie systemic lupus erythematosus (SLE), a multifactorial autoimmune disease characterized by various clinical manifestations. SLE also has an environmental component, which can trigger or exacerbate the disease. Despite extensive efforts aimed at elucidating the cellular and biological abnormalities that arise in the immune system of patients with SLE, its pathology remains unclear. Lee and col...

  13. Fragile privileges: autoimmunity in brain and eye.

    Science.gov (United States)

    Wekerle, Hartmut; Sun, De-ming

    2010-09-01

    Brain and eye tissues are subject to a reduced version of immune surveillance, which has evolved to protect the particularly sensitive tissues from accidental bystander damage created by regular inflammatory responses. Yet, there are autoimmune diseases in both organs. This review discusses the nature of immune reactivity in the healthy eye and brain tissues, and mechanisms that can overcome the protective barriers to create tissue specific disease.

  14. Alcoholic Cirrhosis Increases Risk for Autoimmune Diseases

    DEFF Research Database (Denmark)

    Grønbæk, Lisbet; Vilstrup, Hendrik; Deleuran, Bent

    2015-01-01

    IRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate......BACKGROUND & AIMS: Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients...... (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination). RESULTS: Of the 24,679 patients...

  15. Automation, consolidation, and integration in autoimmune diagnostics.

    Science.gov (United States)

    Tozzoli, Renato; D'Aurizio, Federica; Villalta, Danilo; Bizzaro, Nicola

    2015-08-01

    Over the past two decades, we have witnessed an extraordinary change in autoimmune diagnostics, characterized by the progressive evolution of analytical technologies, the availability of new tests, and the explosive growth of molecular biology and proteomics. Aside from these huge improvements, organizational changes have also occurred which brought about a more modern vision of the autoimmune laboratory. The introduction of automation (for harmonization of testing, reduction of human error, reduction of handling steps, increase of productivity, decrease of turnaround time, improvement of safety), consolidation (combining different analytical technologies or strategies on one instrument or on one group of connected instruments) and integration (linking analytical instruments or group of instruments with pre- and post-analytical devices) opened a new era in immunodiagnostics. In this article, we review the most important changes that have occurred in autoimmune diagnostics and present some models related to the introduction of automation in the autoimmunology laboratory, such as automated indirect immunofluorescence and changes in the two-step strategy for detection of autoantibodies; automated monoplex immunoassays and reduction of turnaround time; and automated multiplex immunoassays for autoantibody profiling.

  16. Resilience in women with autoimmune rheumatic diseases.

    Science.gov (United States)

    Rojas, Manuel; Rodriguez, Yhojan; Pacheco, Yovana; Zapata, Elizabeth; Monsalve, Diana M; Mantilla, Rubén D; Rodríguez-Jimenez, Monica; Ramírez-Santana, Carolina; Molano-González, Nicolás; Anaya, Juan-Manuel

    2017-12-28

    To evaluate the relationship between resilience and clinical outcomes in patients with autoimmune rheumatic diseases. Focus groups, individual interviews, and chart reviews were done to collect data on 188 women with autoimmune rheumatic diseases, namely rheumatoid arthritis (n=51), systemic lupus erythematosus (n=70), systemic sclerosis (n=35), and Sjögren's syndrome (n=32). Demographic, clinical, and laboratory variables were assessed including disease activity by patient reported outcomes. Resilience was evaluated by using the Brief Resilience Scale. Bivariate, multiple linear regression, and classification and regression trees were used to analyse data. Resilience was influenced by age, duration of disease, and socioeconomic status. Lower resilience scores were observed in younger patients (50years) had higher resilience scores regardless of socioeconomic status. There was no influence of disease activity on resilience. A particular behaviour was observed in systemic sclerosis in which patients with high socioeconomic status and regular physical activity had higher resilience scores. Resilience in patients with autoimmune rheumatic diseases is a continuum process influenced by age and socioeconomic status. The ways in which these variables along with exercise influence resilience deserve further investigation. Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

  17. Experimental models of autoimmune inflammatory ocular diseases

    Directory of Open Access Journals (Sweden)

    Fabio Gasparin

    2012-04-01

    Full Text Available Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin. Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.

  18. Immunotherapy Treatments of Warm Autoimmune Hemolytic Anemia

    Directory of Open Access Journals (Sweden)

    Bainan Liu

    2013-01-01

    Full Text Available Warm autoimmune hemolytic anemia (WAIHA is one of four clinical types of autoimmune hemolytic anemia (AIHA, with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia—sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies.

  19. Association of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Thyroglobulin (TG) Genetic Variants with Autoimmune Hypothyroidism

    Science.gov (United States)

    Patel, Hinal; Mansuri, Mohmmad Shoab; Singh, Mala; Begum, Rasheedunnisa; Shastri, Minal; Misra, Ambikanandan

    2016-01-01

    Autoimmune hypothyroidism is known to be caused by immune responses related to the thyroid gland and its immunological feature includes presence of autoimmune antibodies. Therefore the aim was to analyze presence of anti-TPO antibodies in hypothyroidism patients in Gujarat. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) is one of the susceptibility genes for various autoimmune diseases. Hence, exon1 +49A/G and 3’UTR CT60A/G single nucleotide polymorphisms (SNPs) in CTLA4 and its mRNA expression levels were investigated in autoimmune hypothyroidism patients. Thyroglobulin (TG) is known to be associated with autoimmune thyroid disorders and thus exon 33 (E33) SNP in TG was investigated. We analyzed the presence of anti-TPO antibodies in the plasma samples of 84 hypothyroidism patients and 62 controls by ELISA. PCR-RFLP technique was used for genotyping of polymorphisms. sCTLA4 and flCTLA4 mRNA expression levels were assessed by real time PCR. 59.52% of hypothyroid patients had anti-TPO antibodies in their circulation. The genotype and allele frequencies differed significantly for +49A/G (p = 0.0004 for +49AG, p = 0.0019 for +49GG & p = 0.0004 for allele), CT60 (p = 0.0110 for CT60AG, p = 0.0005 for CT60GG & phypothyroidism when adjusted for age and gender. Our results suggest +49A/G and CT60 polymorphism of CTLA4 and E33 polymorphism of TG may be genetic risk factors for autoimmune hypothyroidism susceptibility and down regulation of both forms of CTLA4 advocates the crucial role of CTLA4 in pathogenesis of autoimmune hypothyroidism. PMID:26963610

  20. Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells

    Science.gov (United States)

    Tanaka, H; Zhang, W; Yang, G-X; Ando, Y; Tomiyama, T; Tsuneyama, K; Leung, P; Coppel, R L; Ansari, A A; Lian, Z X; Ridgway, W M; Joh, T; Gershwin, M E

    2014-01-01

    Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+ T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice to recombination-activating gene (Rag)1–/– recipients. We then used this robust established adoptive transfer system and co-transferred CD8+ T cells from dnTGF-βRII mice with either C57BL/6 or dnTGF-βRII forkhead box protein 3 (FoxP3+) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-βRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versus dnTGF-βRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-βRII mice. Our data reflect the therapeutic potential of wild-type CD4+ FoxP3+ Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. PMID:25041369

  1. Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3(+) regulatory T cells.

    Science.gov (United States)

    Tanaka, H; Zhang, W; Yang, G-X; Ando, Y; Tomiyama, T; Tsuneyama, K; Leung, P; Coppel, R L; Ansari, A A; Lian, Z X; Ridgway, W M; Joh, T; Gershwin, M E

    2014-11-01

    Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg ) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8(+) T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice to recombination-activating gene (Rag)1(-/-) recipients. We then used this robust established adoptive transfer system and co-transferred CD8(+) T cells from dnTGF-βRII mice with either C57BL/6 or dnTGF-βRII forkhead box protein 3 (FoxP3(+) ) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-βRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Treg versus dnTGF-βRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-βRII mice. Our data reflect the therapeutic potential of wild-type CD4(+) FoxP3(+) Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC. © 2014 British Society for Immunology.

  2. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.

    Directory of Open Access Journals (Sweden)

    Arsen Arakelyan

    Full Text Available Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune

  3. No major genes in autoimmune thyroid diseases: complex ...

    Indian Academy of Sciences (India)

    Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP '1177' 3018, Universiteé de Sfax, Sfax, Tunisia; Unité d' Epidémiologie Génétique et Moléculaire, Faculté de Médecine de Tunis, La Rabta-1007 Bab Saâdoun Tunis, Tunisia; Unité de Bioinformatique, Centre de Biotechnologie Sfax, BP ...

  4. No major genes in autoimmune thyroid diseases: complex ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... factors that trigger or contribute to the development of dis- ease. The importance of genetic factors in determining sus- ceptibility to AITDs has been demonstrated by the increased ... ent of genotype AA will transmit allele A to his child, and the cumulative probability that an individual with particular genotype ...

  5. No major genes in autoimmune thyroid diseases: complex ...

    Indian Academy of Sciences (India)

    2011-08-19

    Aug 19, 2011 ... Segregation analysis. Evidence for AITDs inheritance, in our study, was assessed with the statistical package SAGE 5.0 (version 5.0. 2004 Department of Epidemiology and Biostatistics, Care. Western Reserve University, Cleveland, USA) using the. REGTL program for segregation analysis of binary traits.

  6. Vaccination with DNA encoding an immunodominant myelin basic protein peptide targeted to Fc of immunoglobulin G suppresses experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Lobell, A; Weissert, R; Storch, M K; Svanholm, C; de Graaf, K L; Lassmann, H; Andersson, R; Olsson, T; Wigzell, H

    1998-05-04

    We explore here if vaccination with DNA encoding an autoantigenic peptide can suppress autoimmune disease. For this purpose we used experimental autoimmune encephalomyelitis (EAE), which is an autoaggressive disease in the central nervous system and an animal model for multiple sclerosis. Lewis rats were vaccinated with DNA encoding an encephalitogenic T cell epitope, guinea pig myelin basic protein peptide 68-85 (MBP68-85), before induction of EAE with MBP68-85 in complete Freund's adjuvant. Compared to vaccination with a control DNA construct, the vaccination suppressed clinical and histopathological signs of EAE, and reduced the interferon gamma production after challenge with MBP68-85. Targeting of the gene product to Fc of IgG was essential for this effect. There were no signs of a Th2 cytokine bias. Our data suggest that DNA vaccines encoding autoantigenic peptides may be useful tools in controlling autoimmune disease.

  7. Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity.

    Science.gov (United States)

    Melis, Daniela; Della Casa, Roberto; Balivo, Francesca; Minopoli, Giorgia; Rossi, Alessandro; Salerno, Mariacarolina; Andria, Generoso; Parenti, Giancarlo

    2014-03-19

    Glycogen storage disease type 1b (GSD1b) is an inherited metabolic defect of glycogenolysis and gluconeogenesis due to mutations of the SLC37A4 gene and to defective transport of glucose-6-phosphate. The clinical presentation of GSD1b is characterized by hepatomegaly, failure to thrive, fasting hypoglycemia, and dyslipidemia. Patients affected by GSD1b also show neutropenia and/or neutrophil dysfunction that cause increased susceptibility to recurrent bacterial infections. GSD1b patients are also at risk for inflammatory bowel disease. Occasional reports suggesting an increased risk of autoimmune disorders in GSD1b patients, have been published. These complications affect the clinical outcome of the patients. Here we describe the occurrence of autoimmune endocrine disorders including thyroiditis and growth hormone deficiency, in a patient affected by GSD1b. This case further supports the association between GSD1b and autoimmune diseases.

  8. Genetic homogeneity of autoimmune polyglandular disease type I

    Energy Technology Data Exchange (ETDEWEB)

    Bjoerses, P.; Aaltonen, J.; Vikman, A. [Univ. of Helsinki (Finland)] [and others

    1996-10-01

    Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pair-wise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for {approximately}90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21. 21 refs., 3 figs., 3 tabs.

  9. Genetic homogeneity of autoimmune polyglandular disease type I.

    Science.gov (United States)

    Björses, P.; Aaltonen, J.; Vikman, A.; Perheentupa, J.; Ben-Zion, G.; Chiumello, G.; Dahl, N.; Heideman, P.; Hoorweg-Nijman, J. J.; Mathivon, L.; Mullis, P. E.; Pohl, M.; Ritzen, M.; Romeo, G.; Shapiro, M. S.; Smith, C. S.; Solyom, J.; Zlotogora, J.; Peltonen, L.

    1996-01-01

    Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21. PMID:8808604

  10. Celiac Disease Autoimmunity in Patients with Autoimmune Diabetes and Thyroid Disease among Chinese Population.

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    Zhiyuan Zhao

    Full Text Available The prevalence of celiac disease autoimmunity or tissue transglutaminase autoantibodies (TGA amongst patients with type 1 diabetes (T1D and autoimmune thyroid disease (AITD in the Chinese population remains unknown. This study examined the rate of celiac disease autoimmunity amongst patients with T1D and AITD in the Chinese population. The study included 178 patients with type 1 diabetes and 119 with AITD where 36 had both T1D and AITD, classified as autoimmune polyglandular syndrome type 3 variant (APS3v. The study also included 145 patients with type 2 diabetes (T2D, 97 patients with non-autoimmune thyroid disease (NAITD, and 102 healthy controls. Serum islet autoantibodies, thyroid autoantibodies and TGA were measured by radioimmunoassay. TGA positivity was found in 22% of patients with either type 1 diabetes or AITD, much higher than that in patients with T2D (3.4%; p< 0.0001 or NAITD (3.1%; P < 0.0001 or healthy controls (1%; p<0.0001. The patients with APS3v having both T1D and AITD were 36% positive for TGA, significantly higher than patients with T1D alone (p = 0.040 or with AITD alone (p = 0.017. T1D and AITD were found to have a 20% and 30% frequency of overlap respectively at diagnosis. In conclusion, TGA positivity was high in the Chinese population having existing T1D and/or AITD, and even higher when both diseases were present. Routine TGA screening in patients with T1D or AITD will be important to early identify celiac disease autoimmunity for better clinical care of patients.

  11. The MicroRNA-21 in Autoimmune Diseases.

    Science.gov (United States)

    Wang, Shaowen; Wan, Xiaochun; Ruan, Qingguo

    2016-06-03

    MicroRNA-21 (miR-21) is an oncomiR and significantly upregulated in a wide range of cancers. It is strongly involved in apoptosis and oncogenesis, since most of its reported targets are tumor suppressors. Recently, miR-21 was found to be correlated with the pathogenesis of autoimmune diseases and may play an essential role in regulating autoimmune responses. In particular, miR-21 promotes Th17 cell differentiation, which mediates the development of multiple autoimmune diseases. In this article, we review the current research on the mechanisms that regulate miR-21 expression, the potential of miR-21 as a diagnostic biomarker for autoimmune disease and the mechanisms by which miR-21 promotes the development of autoimmune disease. We also discussed the therapeutic potential of targeting miR-21 in treating patients with autoimmune disease.

  12. The Epidemiologic Evidence Linking Autoimmune Diseases and Psychosis

    DEFF Research Database (Denmark)

    Benros, Michael E; Eaton, William W; Mortensen, Preben B

    2014-01-01

    This review summarizes the epidemiologic evidence linking autoimmune diseases and psychosis. The associations between autoimmune diseases and psychosis have been studied for more than a half century, but research has intensified within the last decades, since psychosis has been associated...... with genetic markers of the immune system and with excess autoreactivity and other immune alterations. A range of psychiatric disorders, including psychosis, have been observed to occur more frequently in some autoimmune diseases, such as systemic lupus erythematosus and multiple sclerosis. Many autoimmune......, there is some evidence of associations of psychosis with a family history of autoimmune disorders and vice versa. Additionally, several autoimmune diseases, individually and in aggregate, have been identified as raising the risk for psychotic disorders in longitudinal studies. The associations have been...

  13. Deletion of the Mineralocorticoid Receptor in Myeloid Cells Attenuates Central Nervous System Autoimmunity

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    Elena Montes-Cobos

    2017-10-01

    Full Text Available Myeloid cells play an important role in the pathogenesis of multiple sclerosis (MS and its animal model experimental autoimmune encephalomyelitis (EAE. Monocytes, macrophages, and microglia can adopt two distinct phenotypes, with M1-polarized cells being more related to inflammation and autoimmunity while M2-polarized cells contribute to tissue repair and anti-inflammatory processes. Here, we show that deletion of the mineralocorticoid receptor (MR in bone marrow-derived macrophages and peritoneal macrophages caused their polarization toward the M2 phenotype with its distinct gene expression, altered phagocytic and migratory properties, and dampened NO production. After induction of EAE, mice that are selectively devoid of the MR in their myeloid cells (MRlysM mice showed diminished clinical symptoms and ameliorated histological hallmarks of neuroinflammation. T cells in peripheral lymphoid organs of these mice produced less pro-inflammatory cytokines while their proliferation and the abundance of regulatory T cells were unaltered. The numbers of inflammatory monocytes and reactive microglia in the central nervous system (CNS in MRlysM mice were significantly lower and they adopted an M2-polarized phenotype based on their gene expression profile, presumably explaining the ameliorated neuroinflammation. Our results indicate that the MR in myeloid cells plays a critical role for CNS autoimmunity, providing a rational to interfere with diseases such as MS by pharmacologically targeting this receptor.

  14. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy: Insights into Genotype-Phenotype Correlation

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    Donatella Capalbo

    2012-01-01

    Full Text Available Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED is a rare autosomal recessive disease, caused by mutations of a single gene named autoimmune regulator gene (AIRE which results in a failure of T cell tolerance within the thymus. Chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison’s disease are the hallmarks of the syndrome. APECED is also characterized by several autoimmune endocrine and nonendocrine manifestations, and the phenotype is often complex. Moreover, even though APECED is a monogenic disease, its clinical picture is generally dominated by a wide heterogeneity both in the severity and in the number of components even among siblings with the same AIRE genotype. The variability of its clinical expression implies that diagnosis can be challenging, and a considerable delay often occurs between the appearance of symptoms and the diagnosis. Since a prompt diagnosis is essential to prevent severe complications, clinicians should be aware of all symptoms and signs of suspicion. The aim of this paper is to give an overview on the clinical presentation and diagnostic criteria of APECED and to focus on current knowledge on genotype-phenotype correlation.

  15. Renal failure associated with APECED and terminal 4q deletion: evidence of autoimmune nephropathy.

    Science.gov (United States)

    Al-Owain, Mohammed; Kaya, Namik; Al-Zaidan, Hamad; Bin Hussain, Ibrahim; Al-Manea, Hadeel; Al-Hindi, Hindi; Kennedy, Shelley; Iqbal, M Anwar; Al-Mojalli, Hamad; Al-Bakheet, Albandary; Puel, Anne; Casanova, Jean-Laurent; Al-Muhsen, Saleh

    2010-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.

  16. Renal Failure Associated with APECED and Terminal 4q Deletion: Evidence of Autoimmune Nephropathy

    Directory of Open Access Journals (Sweden)

    Mohammed Al-Owain

    2010-01-01

    Full Text Available Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE. Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response to Candida albicans at 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4(q33. FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH. AIRE full gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.

  17. Genetic and immunologic aspects of autoimmune poliendocrine syndrome type I: review

    Directory of Open Access Journals (Sweden)

    Alice Rachel Bandeira de Araújo

    2016-10-01

    Full Text Available The autoimmune polyendocrinopathy syndrome type 1 (APS-1, also known as candidiasis ectodermal-autoimmune polyendocrinopathy-dystrophy (APECED, it is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE. Therefore, it is immunologically characterized by cell attack and / or antibodymediated generating the destruction of target organs. Furthermore, it is characterized by the pathognomonic triad chronic candidiasis, hypoparathyroidism and Addison's disease with many other endocrine and non-endocrine events. Soon, the diagnosis is made based on the presence of two of the three classic features and treatment aims to control the numerous deficiencies that patients may present. This literature review was aimed at understanding the involvement of AIRE gene in relation to immunological aspects present and, consequently, clinical manifestations of this disease. Thus, evidence of the need to broaden the discussion about this disease, in order to improve the quality of life of patients by early diagnosis and treatment and are in accordance with the clinical manifestations of each patient. Thereby, qualitative research involved scientific articles from electronic journals LILACS (Latin American and Caribbean, SCIELO (Scientific Electronic Library Online and NCBI (National Center for Biotechnology Information, between the years 2009 and 2016. Pursuant to, there is the relevance of this review, it is noted that, although the authors converge on views on this syndrome, there are still many unclear matters with regard to the mechanisms of the disease. This highlights the need to promote more discussion on this topic.

  18. Cancer immunotherapy in patients with preexisting autoimmune disorders

    DEFF Research Database (Denmark)

    Donia, Marco; Pedersen, Magnus; Svane, Inge Marie

    2017-01-01

    Patients with preexisting active autoimmune disorders were excluded from clinical trials of immune checkpoint inhibitors. However, patients with autoimmune disorders are diagnosed with cancer at least as frequently as the global population, and clinicians treating patients outside clinical trials...... have generally been reluctant to offer cancer immunotherapy to this patient group. In this brief article, we review the most recent literature on the efficacy and safety of CTLA-4- and PD-1-blocking antibodies in patients with preexisting autoimmune disorders....

  19. Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura

    Science.gov (United States)

    Roriz, Mélanie; Landais, Mickael; Desprez, Jonathan; Barbet, Christelle; Azoulay, Elie; Galicier, Lionel; Wynckel, Alain; Baudel, Jean-Luc; Provôt, François; Pène, Frédéric; Mira, Jean-Paul; Presne, Claire; Poullin, Pascale; Delmas, Yahsou; Kanouni, Tarik; Seguin, Amélie; Mousson, Christiane; Servais, Aude; Bordessoule, Dominique; Perez, Pierre; Chauveau, Dominique; Veyradier, Agnès; Halimi, Jean-Michel; Hamidou, Mohamed; Coppo, Paul

    2015-01-01

    Abstract Autoimmune thrombotic thrombocytopenic purpura (TTP) can be associated with other autoimmune disorders, but their prevalence following autoimmune TTP remains unknown. To assess the prevalence of autoimmune disorders associated with TTP and to determine risk factors for and the time course of the development of an autoimmune disorder after a TTP episode, we performed a cross sectional study. Two-hundred sixty-one cases of autoimmune TTP were included in the French Reference Center registry between October, 2000 and May, 2009. Clinical and laboratory data available at time of TTP diagnosis were recovered. Each center was contacted to collect the more recent data and diagnosis criteria for autoimmunity. Fifty-six patients presented an autoimmune disorder in association with TTP, 9 years before TTP (median; min: 2 yr, max: 32 yr) (26 cases), at the time of TTP diagnosis (17 cases) or during follow-up (17 cases), up to 12 years after TTP diagnosis (mean, 22 mo). The most frequent autoimmune disorder reported was systemic lupus erythematosus (SLE) (26 cases) and Sjögren syndrome (8 cases). The presence of additional autoimmune disorders had no impact on outcomes of an acute TTP or the occurrence of relapse. Two factors evaluated at TTP diagnosis were significantly associated with the development of an autoimmune disorder during follow-up: the presence of antidouble stranded (ds)DNA antibodies (hazard ratio (HR): 4.98; 95% confidence interval (CI) [1.64–15.14]) and anti-SSA antibodies (HR: 9.98; 95% CI [3.59–27.76]). A follow-up across many years is necessary after an acute TTP, especially when anti-SSA or anti-dsDNA antibodies are present on TTP diagnosis, to detect autoimmune disorders early before immunologic events spread to prevent disabling complications. PMID:26496263

  20. Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity.

    Science.gov (United States)

    Havarinasab, S; Pollard, K M; Hultman, P

    2009-03-01

    Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s)) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s)) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 microg Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 microg Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.

  1. Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young.

    Science.gov (United States)

    Norris, Jill M; Kroehl, Miranda; Fingerlin, Tasha E; Frederiksen, Brittni N; Seifert, Jennifer; Wong, Randall; Clare-Salzler, Michael; Rewers, Marian

    2014-02-01

    We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY). DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)65, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children. Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (pinteraction = 0.017), at FADS2 rs174570 (pinteraction = 0.016) and at FADS2 rs174583 (pinteraction = 0.045). The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.

  2. Autoimmune Disease in Children and Adolescents with Psoriasis

    DEFF Research Database (Denmark)

    Blegvad, Christoffer; Egeberg, Alexander; Tind Nielsen, Tilde E.

    2017-01-01

    Psoriasis is an immune-mediated inflammatory disease, which, in studies among adults, have been shown to cluster with autoimmune disease. The aim of this cross-sectional register study was to examine possible associations between 9 pre-selected autoimmune diseases and psoriasis in children...... arthritis (adjusted OR 6.61; 2.75-15.87) and vitiligo (adjusted OR 4.76; 1.71-13.20) showed strong associations with psoriasis. In addition to increased risk of selected autoimmune diseases, the presence of psoriasis was associated with increased risk of multiple concurrent autoimmune diseases compared...

  3. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.

    Science.gov (United States)

    Kleinewietfeld, Markus; Manzel, Arndt; Titze, Jens; Kvakan, Heda; Yosef, Nir; Linker, Ralf A; Muller, Dominik N; Hafler, David A

    2013-04-25

    There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

  4. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis.

    Science.gov (United States)

    Wegner, Natalia; Lundberg, Karin; Kinloch, Andrew; Fisher, Benjamin; Malmström, Vivianne; Feldmann, Marc; Venables, Patrick J

    2010-01-01

    Rheumatoid arthritis (RA) is now clearly a true autoimmune disease with accumulating evidence of pathogenic disease-specific autoimmunity to citrullinated proteins. Citrullination, also termed deimination, is a modification of arginine side chains catalyzed by peptidylarginine deiminase (PAD) enzymes. This post-translational modification has the potential to alter the structure, antigenicity, and function of proteins. In RA, antibodies to cyclic citrullinated peptides are now well established for clinical diagnosis, though we argue that the identification of specific citrullinated antigens, as whole proteins, is necessary for exploring pathogenic mechanisms. Four citrullinated antigens, fibrinogen, vimentin, collagen type II, and alpha-enolase, are now well established, with others awaiting further characterization. All four proteins are expressed in the joint, and there is evidence that antibodies to citrullinated fibrinogen and collagen type II mediate inflammation by the formation of immune complexes, both in humans and animal models. Antibodies to citrullinated proteins are associated with HLA 'shared epitope' alleles, and autoimmunity to at least one antigenic sequence, the CEP-1 peptide from citrullinated alpha-enolase (KIHAcitEIFDScitGNPTVE), shows a specific association with HLA-DRB1*0401, *0404, 620W PTPN22, and smoking. Periodontitis, in which Porphyromonas gingivalis is a major pathogenic bacterium, has been linked to RA in epidemiological studies and also shares similar gene/environment associations. This is also the only bacterium identified that expresses endogenous citrullinated proteins and its own bacterial PAD enzyme, though the precise molecular mechanisms of bacterial citrullination have yet to be explored. Thus, both smoking and Porphyromonas gingivalis are attractive etiological agents for further investigation into the gene/environment/autoimmunity triad of RA.

  5. Autoimmune polyendocrine syndrome type 1 in an Indian cohort: a longitudinal study

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    Ghazala Zaidi

    2017-07-01

    Full Text Available Objective: Autoimmune polyendocrine syndrome type 1 (APS1 is a rare autosomal recessive disorder characterized by progressive organ-specific autoimmunity. There is scant information on APS1 in ethnic groups other than European Caucasians. We studied clinical aspects and autoimmune regulator (AIRE gene mutations in a cohort of Indian APS1 patients. Design: Twenty-three patients (19 families from six referral centres in India, diagnosed between 1996 and 2016, were followed for [median (range] 4 (0.2–19 years. Methods: Clinical features, mortality, organ-specific autoantibodies and AIRE gene mutations were studied. Results: Patients varied widely in their age of presentation [3.5 (0.1–17 years] and number of clinical manifestations [5 (2–11]. Despite genetic heterogeneity, the frequencies of the major APS1 components (mucocutaneous candidiasis: 96%; hypoparathyroidism: 91%; primary adrenal insufficiency: 55% were similar to reports in European series. In contrast, primary hypothyroidism (23% occurred more frequently and at an early age, while kerato-conjunctivitis, urticarial rash and autoimmune hepatitis were uncommon (9% each. Six (26% patients died at a young age [5.8 (3–23 years] due to septicaemia, hepatic failure and adrenal/hypocalcaemic crisis from non-compliance/unexplained cause. Interferon-α and/or interleukin-22 antibodies were elevated in all 19 patients tested, including an asymptomatic infant. Eleven AIRE mutations were detected, the most common being p.C322fsX372 (haplotype frequency 37%. Four mutations were novel, while six others were previously described in European Caucasians. Conclusions: Indian APS1 patients exhibited considerable genetic heterogeneity and had highly variable clinical features. While the frequency of major manifestations was similar to that of European Caucasians, other features showed significant differences. A high mortality at a young age was observed.

  6. Autoimmune dysregulation and purine metabolism in adenosine deaminase (ADA-deficiency

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    Aisha Vanessa Sauer

    2012-08-01

    Full Text Available Genetic defects in the adenosine deaminase (ADA gene are among the most common causes for severe combined immunodeficiency (SCID. ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT, enzyme replacement therapy with bovine ADA (PEG-ADA or hematopoietic stem cell gene therapy (HSC-GT. Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment.A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T and B cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.

  7. Are individuals with an autoimmune disease at higher risk of a second autoimmune disorder?

    Science.gov (United States)

    Somers, Emily C; Thomas, Sara L; Smeeth, Liam; Hall, Andrew J

    2009-03-15

    Limited evidence suggests that autoimmune diseases tend to co-occur, although data are needed to determine whether individuals with an existing autoimmune disorder are at increased risk of a second disorder. The authors conducted a series of population-based cohort studies, utilizing the United Kingdom General Practice Research Database, to assess intraindividual risks of coexistence of rheumatoid arthritis (RA), autoimmune thyroiditis (AIT), multiple sclerosis (MS), and insulin-dependent diabetes mellitus (IDDM) during 1990-1999. Sex-specific age- and calendar-period standardized incidence ratios (SIRs) were calculated for development of a second autoimmune disease among index populations including 22,888 RA, 26,198 AIT, 4,332 MS, and 6,170 IDDM patients compared with the general population. Among those with IDDM, adjusted AIT rates were higher than expected for both males (SIR = 646.0, 95% confidence interval (CI): 466, 873) and females (SIR = 409.6, 95% CI: 343, 485), as were RA rates for females (SIR = 181.6, 95% CI: 136, 238). Coexistence of AIT and RA was also shown for either disease sequence (sex-specific SIRs = 130.4-162.0). However, point estimates suggested an inverse relation between RA and MS, irrespective of diagnostic sequence. This study demonstrates coexistence of RA, AIT, and IDDM at higher than expected rates but reduced comorbidity between RA and MS.

  8. Airway Autoimmune Inflammatory Response (AAIR) Syndrome: An Asthma-Autoimmune Overlap Disorder?

    Science.gov (United States)

    Spencer, Chantal Y; Millman, Jennifer; Veiga, Keila; Vicencio, Alfin G

    2018-02-15

    Asthma encompasses numerous phenotypes that may require alternate approaches to diagnosis and therapy, particularly for patients whose symptoms remain poorly controlled despite escalating treatment. We describe 3 patients with apparent asthma who demonstrated unusual findings on cryobiopsy by flexible bronchoscopy and responded to therapy directed against autoimmune disease. Copyright © 2018 by the American Academy of Pediatrics.

  9. Autoimmune Neurology of the Central Nervous System.

    Science.gov (United States)

    Tobin, W Oliver; Pittock, Sean J

    2017-06-01

    This article reviews the rapidly evolving spectrum of autoimmune neurologic disorders with a focus on those that involve the central nervous system, providing an understanding of how to approach the diagnostic workup of patients presenting with central nervous system symptoms or signs that could be immune mediated, either paraneoplastic or idiopathic, to guide therapeutic decision making. The past decade has seen a dramatic increase in the discovery of novel neural antibodies and their targets. Many commercial laboratories can now test for these antibodies, which serve as diagnostic markers of diverse neurologic disorders that occur on an autoimmune basis. Some are highly specific for certain cancer types, and the neural antibody profiles may help direct the physician's cancer search. The diagnosis of an autoimmune neurologic disorder is aided by the detection of an objective neurologic deficit (usually subacute in onset with a fluctuating course), the presence of a neural autoantibody, and improvement in the neurologic status after a course of immunotherapy. Neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, N-methyl-D-aspartate [NMDA] receptor antibodies are associated with teratoma, antineuronal nuclear antibody type 1 [ANNA-1, or anti-Hu] are associated with small cell lung cancer). MRI, EEG, functional imaging, videotaped evaluations, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention may allow reversal of deficits in many patients and prevention of future disability.

  10. Dental amalgam implantation and thyroid autoimmunity.

    Science.gov (United States)

    Kisakol, G

    2014-01-01

    Mercury was heavily studied as a factor in the autoimmune processes. We aimed to observe whether mercury of amalgam is associated with Hashimoto disease. 363 patients with Hashimoto's thyroiditis and 365 control subjects were included in to the study. Amalgam fillings were checked by the physician. 363 (49.9 %) patients and 365 (50.1 %) healthy controls were included into the study. Hashimoto's thyroiditis was diagnosed with thyroid hormones, antithyroid antibody levels, and ultrasonographic findings. Control subjects were selected from patients with no known autoimmune diseases. They were controlled with ultrasonography, as well as antibody titers. None of them had Hashimoto's thyroiditis. Sex distribution of the study population was following: 319 (87.9 %) female, 44 (12.1 %) male in the patient group and 277 (75.9 %) male and 88 (24.1 %) female in healthy control subjects, respectively. Mean free T4 values for Hashimoto's thyroiditis and healthy control group were 15.30±0.76, 17.30±0.96 pmol/L and mean TSH values for Hashimoto's thyroiditis and healthy control group were 9.29±20.79, 1.20±0.32 uIU/ml. Frequency of dental amalgam implantation in patients with Hashimoto's thyroiditis was not statistically significantly different from healthy controls (p=186) (t=-1.324) CONCLUSIONS: Some studies identified mercury of amalgam as responsible for autoimmune thyroiditis. We studied whether amalgam fillings are more frequent in Hashimoto's thyroiditis patients and whether it is a causative factor for Hashimoto's thyroiditis. Statistical analysis revealed that there is no relation of amalgam with Hashimoto's thyroiditis (Tab. 1, Ref. 34).

  11. Autoimmune pancreatitis in Japan. Overview and perspective

    International Nuclear Information System (INIS)

    Shimosegawa, Tooru; Kanno, Atsushi

    2009-01-01

    Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, id est (i.e.), association of extrapancreatic organ involvements. Initially misunderstood because it can be accompanied by other autoimmune disorders, such as Sjogren's syndrome or primary sclerosing cholangitis (PSC), AIP is now known to be associated with unique types of sialadenitis and cholangitis distinct from Sjogren's syndrome or PSC. Now the concept of 'IgG4-related sclerosing disease' has become widely accepted and the list of organs involved continues to increase. With worldwide recognition, an emerging issue is the clinical definition of other possible types of autoimmune-related pancreatitis called 'idiopathic duct-centric chronic pancreatitis (IDCP)' and AIP with granulocyte epithelial lesion (GEL)' and their relation to AIP with lymphoplasmacytic sclerosing pancreatitis (LPSP). The time has arrived to establish clinical diagnostic criteria of AIP based on international consensus and to discuss regional and racial differences in the clinicopathological features of AIP. Consensus guidelines are also required for the ideal use of steroids in the treatment of AIP to suppress recurrence efficiently with minimal side effects. There are many issues to be settled in AIP; international collaboration of experts in the pancreas field is necessary to clarify the entire picture of this unique and important disease. (author)

  12. Autoimmune pancreatitis in Japan: overview and perspective.

    Science.gov (United States)

    Shimosegawa, Tooru; Kanno, Atsushi

    2009-01-01

    Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, i.e., association of extrapancreatic organ involvements. Initially misunderstood because it can be accompanied by other autoimmune disorders, such as Sjögren's syndrome or primary sclerosing cholangitis (PSC), AIP is now known to be associated with unique types of sialadenitis and cholangitis distinct from Sjögren's syndrome or PSC. Now the concept of "IgG4-related sclerosing disease" has become widely accepted and the list of organs involved continues to increase. With worldwide recognition, an emerging issue is the clinical definition of other possible types of autoimmune-related pancreatitis called "idiopathic duct-centric chronic pancreatitis (IDCP)" and "AIP with granulocyte epithelial lesion (GEL)" and their relation to AIP with lymphoplasmacytic sclerosing pancreatitis (LPSP). The time has arrived to establish clinical diagnostic criteria of AIP based on international consensus and to discuss regional and racial differences in the clinicopathological features of AIP. Consensus guidelines are also required for the ideal use of steroids in the treatment of AIP to suppress recurrence efficiently with minimal side effects. There are many issues to be settled in AIP; international collaboration of experts in the pancreas field is necessary to clarify the entire picture of this unique and important disease.

  13. Post-Babesiosis Warm Autoimmune Hemolytic Anemia.

    Science.gov (United States)

    Woolley, Ann E; Montgomery, Mary W; Savage, William J; Achebe, Maureen O; Dunford, Kathleen; Villeda, Sarah; Maguire, James H; Marty, Francisco M

    2017-03-09

    Background Babesiosis, a tickborne zoonotic disease caused by intraerythrocytic protozoa of the genus babesia, is characterized by nonimmune hemolytic anemia that resolves with antimicrobial treatment and clearance of parasitemia. The development of warm-antibody autoimmune hemolytic anemia (also known as warm autoimmune hemolytic anemia [WAHA]) in patients with babesiosis has not previously been well described. Methods After the observation of sporadic cases of WAHA that occurred after treatment of patients for babesiosis, we conducted a retrospective cohort study of all the patients with babesiosis who were cared for at our center from January 2009 through June 2016. Data on covariates of interest were extracted from the medical records, including any hematologic complications that occurred within 3 months after the diagnosis and treatment of babesiosis. Results A total of 86 patients received a diagnosis of babesiosis during the 7.5-year study period; 18 of these patients were asplenic. WAHA developed in 6 patients 2 to 4 weeks after the diagnosis of babesiosis, by which time all the patients had had clinical and laboratory responses to antimicrobial treatment of babesiosis, including clearance of Babesia microti parasitemia. All 6 patients were asplenic (P<0.001) and had positive direct antiglobulin tests for IgG and complement component 3; warm autoantibodies were identified in all these patients. No alternative explanation for clinical hemolysis was found. WAHA required immunosuppressive treatment in 4 of the 6 patients. Conclusions We documented post-babesiosis WAHA in patients who did not have a history of autoimmunity; asplenic patients appeared to be particularly at risk.

  14. Dendritic cells in autoimmune thyroid disease.

    Science.gov (United States)

    Kabel, P J; Voorbij, H A; van der Gaag, R D; Wiersinga, W M; de Haan, M; Drexhage, H A

    1987-01-01

    Dendritic cells form a morphologically distinct class of cells characterized by shape, reniform nucleus, absent to weak acid-phosphatase activity and strong Class II MHC determinant positivity. Functionally they are the most efficient cells in antigen presentation to T-lymphocytes which indicates their role in the initiation of an immune response. Using immunehistochemical techniques we studied the presence of dendritic cells in normal Wistar rat and human thyroids, in thyroids of BBW rats developing thyroid autoimmunity and in Graves' goitres. Dendritic cells could be identified in all thyroids studied and were positioned underneath the thyrocytes in between the follicles. Skin dendritic cells travel via lymphatics to draining lymph nodes, thus forming an antigen presenting cell system. It is likely that a similar cell system exists on the level of the thyroid for dendritic cells have also been detected in thyroid draining lymph nodes. In normal thyroid tissue of both human and rat dendritic cells were relatively scarce. During the initial phases of the thyroid autoimmune response in the BBW rat (before the appearance of Tg-antibodies in the circulation) numbers of thyroid dendritic cells increased. Intrathyroidal T-helper cells, B-cells or plasma cells could not be found. The thyroid draining lymph node contained large numbers of plasma cells. During the later stages of the thyroid autoimmune response in the BB/W rat (after the appearance of Tg-antibodies in the circulation) and in Graves' goitres dendritic cells were not only present in high number, but 20-30% were seen in contact with now-present intrathyroidal T-helper lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

    NARCIS (Netherlands)

    Zimmerman, O.; Rosen, L.B.; Swamydas, M.; Ferre, E.M.N.; Natarajan, M.; Veerdonk, F.L. van de; Holland, S.M.; Lionakis, M.S.

    2017-01-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function

  16. Role of extracellular vesicles in autoimmune diseases.

    Science.gov (United States)

    Turpin, Delphine; Truchetet, Marie-Elise; Faustin, Benjamin; Augusto, Jean-François; Contin-Bordes, Cécile; Brisson, Alain; Blanco, Patrick; Duffau, Pierre

    2016-02-01

    Extracellular vesicles (EVs) consist of exosomes released upon fusion of multivesicular bodies with the cell plasma membrane and microparticles shed directly from the cell membrane of many cell types. EVs can mediate cell-cell communication and are involved in many processes including inflammation, immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. Accumulating evidence reveals that EVs act in the establishment, maintenance and modulation of autoimmune processes among several others involved in cancer and cardiovascular complications. EVs could also present biomedical applications, as disease biomarkers and therapeutic targets or agents for drug delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. The Clinical Pictures of Autoimmune Hemolytic Anemia

    Science.gov (United States)

    Packman, Charles H.

    2015-01-01

    Summary Autoimmune hemolytic anemia is characterized by shortened red blood cell survival and a positive Coombs test. The responsible autoantibodies may be either warm reactive or cold reactive. The rate of hemolysis and the severity of the anemia may vary from mild to severe and life-threatening. Diagnosis is made in the laboratory by the findings of anemia, reticulocytosis, a positive Coombs test, and specific serologic tests. The prognosis is generally good but renal failure and death sometimes occur, especially in cases mediated by drugs. PMID:26696800

  18. Autoimmun hypophysitis--en differentialdiagnose til hypofyseadenomer

    DEFF Research Database (Denmark)

    Krarup, Therese; Hagen, Claus

    2010-01-01

    A 66-year-old man with a headache in the left temporal region which had persisted for eight months is presented. The patient developed polydipsia and polyuria and also suffered from tinnitus, impaired hearing and episodes of double vision. The patient was diagnosed with autoimmune hypophysitis (A......) in 2007. This case story displays the importance of knowing AH, as it is an important differential diagnosis to pituitary gland adenomas and to diseases in the hypothalamus because it can be treated medically as opposed to surgically....

  19. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator–dependent autoimmunity

    Science.gov (United States)

    Mathieu, Anne-Laure; Verronese, Estelle; Rice, Gillian I.; Fouyssac, Fanny; Bertrand, Yves; Picard, Capucine; Chansel, Marie; Walter, Jolan E.; Notarangelo, Luigi D.; Butte, Manish J.; Nadeau, Kari Christine; Csomos, Krisztian; Chen, David J.; Chen, Karin; Delgado, Ana; Rigal, Chantal; Bardin, Christine; Schuetz, Catharina; Moshous, Despina; Reumaux, Héloïse; Plenat, François; Phan, Alice; Zabot, Marie-Thérèse; Balme, Brigitte; Viel, Sébastien; Bienvenu, Jacques; Cochat, Pierre; van der Burg, Mirjam; Caux, Christophe; Kemp, E. Helen; Rouvet, Isabelle; Malcus, Christophe; Méritet, Jean-Francois; Lim, Annick; Crow, Yanick J.; Fabien, Nicole; Ménétrier-Caux, Christine; De Villartay, Jean-Pierre; Walzer, Thierry; Belot, Alexandre

    2015-01-01

    Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects. PMID:25842288

  20. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.

    Science.gov (United States)

    Mathieu, Anne-Laure; Verronese, Estelle; Rice, Gillian I; Fouyssac, Fanny; Bertrand, Yves; Picard, Capucine; Chansel, Marie; Walter, Jolan E; Notarangelo, Luigi D; Butte, Manish J; Nadeau, Kari Christine; Csomos, Krisztian; Chen, David J; Chen, Karin; Delgado, Ana; Rigal, Chantal; Bardin, Christine; Schuetz, Catharina; Moshous, Despina; Reumaux, Héloïse; Plenat, François; Phan, Alice; Zabot, Marie-Thérèse; Balme, Brigitte; Viel, Sébastien; Bienvenu, Jacques; Cochat, Pierre; van der Burg, Mirjam; Caux, Christophe; Kemp, E Helen; Rouvet, Isabelle; Malcus, Christophe; Méritet, Jean-Francois; Lim, Annick; Crow, Yanick J; Fabien, Nicole; Ménétrier-Caux, Christine; De Villartay, Jean-Pierre; Walzer, Thierry; Belot, Alexandre

    2015-06-01

    PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  1. Prevalence of Celiac Disease in Children with Autoimmune Hepatitis and vice versa

    OpenAIRE

    Najafi, Mehri; Sadjadei, Nooshin; Eftekhari, Kambiz; Khodadad, Ahmad; Motamed, Farzaneh; Fallahi, Gholam-Hossain; Farahmand, Fatemeh

    2014-01-01

    Objective: Celiac disease is an autoimmune disorder in which the risk of autoimmune liver disease is high. Autoimmune hepatitis is a chronic and progressive entity and the risk of its being associated with other autoimmune disorders such as celiac disease is high also. The aim of this study was to determine the prevalence of celiac disease in patients with autoimmune hepatitis and vice versa. Methods: In a cross-sectional study children with autoimmune hepatitis underwent serological screenin...

  2. Efferocytosis promotes suppressive effects on dendritic cells through prostaglandin E2 production in the context of autoimmunity.

    Directory of Open Access Journals (Sweden)

    Irma Pujol-Autonell

    Full Text Available INTRODUCTION: Efferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, may be restored by the administration of autologous dendritic cells loaded with islet apoptotic cells in experimental type 1 diabetes. OBJECTIVE: To evaluate tolerogenic properties in dendritic cells induced by the clearance of apoptotic islet cells, thus explaining the re-establishment of tolerance in a context of autoimmunity. METHODS: Bone marrow derived dendritic cells from non-obese diabetic mice, a model of autoimmune diabetes, were generated and pulsed with islet apoptotic cells. The ability of these cells to induce autologous T cell proliferation and to suppress mature dendritic cell function was assessed, together with cytokine production. Microarray experiments were performed using dendritic cells to identify differentially expressed genes after efferocytosis. RESULTS: Molecular and functional changes in dendritic cells after the capture of apoptotic cells were observed. 1 Impaired ability of dendritic cells to stimulate autologous T cell proliferation after the capture of apoptotic cells even after proinflammatory stimuli, with a cytokine profile typical for immature dendritic cells. 2 Suppressive ability of mature dendritic cell function. 3 Microarray-based gene expression profiling of dendritic cells showed differential expression of genes involved in antigen processing and presentation after efferocytosis. 4 Prostaglandin E2 increased production was responsible for immunosuppressive mechanism of dendritic cells after the capture of apoptotic cells. CONCLUSIONS: The tolerogenic behaviour of dendritic cells after islet cells efferocytosis points to a mechanism of silencing potential autoreactive T cells in the microenvironment of autoimmunity. Our results suggest that dendritic cells may be programmed to induce

  3. Introducing Polyautoimmunity: Secondary Autoimmune Diseases No Longer Exist

    Science.gov (United States)

    Rojas-Villarraga, Adriana; Amaya-Amaya, Jenny; Rodriguez-Rodriguez, Alberto; Mantilla, Rubén D.; Anaya, Juan-Manuel

    2012-01-01

    Similar pathophysiological mechanisms within autoimmune diseases have stimulated searches for common genetic roots. Polyautoimmunity is defined as the presence of more than one autoimmune disease in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). We analyzed the presence of polyautoimmunity in 1,083 patients belonging to four autoimmune disease cohorts. Polyautoimmunity was observed in 373 patients (34.4%). Autoimmune thyroid disease (AITD) and Sjögren's syndrome (SS) were the most frequent diseases encountered. Factors significantly associated with polyautoimmunity were female gender and familial autoimmunity. Through a systematic literature review, an updated search was done for all MAS cases (January 2006–September 2011). There were 142 articles retrieved corresponding to 226 cases. Next, we performed a clustering analysis in which AITD followed by systemic lupus erythematosus and SS were the most hierarchical diseases encountered. Our results indicate that coexistence of autoimmune diseases is not uncommon and follows a grouping pattern. Polyautoimmunity is the term proposed for this association of disorders, which encompasses the concept of a common origin for these diseases. PMID:22454759

  4. Impaired hapten sensitization in patients with autoimmune disease

    DEFF Research Database (Denmark)

    Bangsgaard, N; Engkilde, K; Menné, T

    2011-01-01

    An inverse relation between contact allergy and autoimmune diseases is suggested from epidemiological studies. The aim of this study was to investigate susceptibility and reactivity in patients with psoriasis, patients with diabetes and healthy controls in an experimental sensitization study. We...... in individuals with autoimmune diseases such as psoriasis....

  5. Clinical implications of shared genetics and pathogenesis in autoimmune diseases

    NARCIS (Netherlands)

    Zhernakova, Alexandra; Withoff, Sebo; Wijmenga, Cisca

    2013-01-01

    Many endocrine diseases, including type 1 diabetes mellitus, Graves disease, Addison disease and Hashimoto disease, originate as an autoimmune reaction that affects disease-specific target organs. These autoimmune diseases are characterized by the development of specific autoantibodies and by the

  6. Autoimmune progesterone dermatitis: Case report with history of ...

    African Journals Online (AJOL)

    Autoimmune progesterone dermatitis (APD) is a rare autoimmune response to raised endogenous progesterone levels that occur during the luteal phase of the menstrual cycle. Cutaneous, mucosal lesions and other systemic manifestations develop cyclically during the luteal phase of the menstrual cycle when ...

  7. [AUTOIMMUNE REACTIONS IN PATIENTS WITH DISEASES OF A THYROID GLAND].

    Science.gov (United States)

    Saidova, F Kh; Shakhsuvarov, O M; Guseynov, R G; Akhmedova, L M; Aslanova, Zh B

    2015-11-01

    A state of autoimmunity was studied in 25 patients, suffering diffuse toxic goiter (DTG), and in 20--in nodular euthyroid goiter (NEG) before and after the operation. The level of circulating immune complexes, quantity of cytotoxic lymphocytes, the subpopulation index, the apoptosis marker were determined. There was established, that in NEG autoimmune disorders have occurred rarer and were less severe, than in DTG.

  8. Coeliac disease and autoimmune disease-genetic overlap and screening

    NARCIS (Netherlands)

    Lundin, Knut E. A.; Wijmenga, Cisca

    Coeliac disease is a treatable, gluten-induced disease that often occurs concurrently with other autoimmune diseases. In genetic studies since 2007, a partial genetic overlap between these diseases has been revealed and further insights into the pathophysiology of coeliac disease and autoimmunity

  9. Rhesus anti-D immunoglobulin in chronic autoimmune neuropathy

    NARCIS (Netherlands)

    de Jager, AEJ; van der Hoeven, JH

    Objective - To investigate the effect of Rhesus anti-D immunoglobulin (anti-D) in patients with an autoimmune demyelinating neuropathy. Material and methods - Three patients with an autoimmune mediated neuropathy received 1000 IU anti-D weekly for 2 months. Results - Two patients worsened gradually

  10. Autologous hematopoietic stem cell transplantation for autoimmune diseases.

    NARCIS (Netherlands)

    Gratwohl, A.; Passweg, J.R.; Bocelli-Tyndall, C.; Fassas, A.; Laar, J.M. van; Farge, D.; Andolina, M.; Arnold, R.; Carreras, E.; Finke, J.; Kotter, I.; Kozak, T.; Lisukov, I.; Lowenberg, B.; Marmont, A.; Moore, J.; Saccardi, R.; Snowden, J.A.; Hoogen, F.H.J. van den; Wulffraat, N.M.; Zhao, X.; Tyndall, A.

    2005-01-01

    Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune

  11. Dapsone in the management of autoimmune bullous diseases.

    Science.gov (United States)

    Piette, Evan W; Werth, Victoria P

    2012-05-01

    Dapsone is used in the treatment of autoimmune bullous diseases (AIBD), a group of disorders resulting from autoimmunity directed against basement membrane and/or intercellular adhesion molecules on cutaneous and mucosal surfaces. This review summarizes the limited published data evaluating dapsone as a therapy for AIBD. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Dapsone in the management of the autoimmune bullous diseases

    Science.gov (United States)

    Piette, Evan W.

    2013-01-01

    Synopsis Dapsone is occasionally used in the treatment of the autoimmune bullous diseases, a group of disorders resulting from autoimmunity directed against basement membrane and/or intercellular adhesion molecules on cutaneous and mucosal surfaces. This review will summarize the limited published data evaluating dapsone as a therapy for the AIBD. PMID:22560144

  13. ELISA for the Diagnosis of Autoimmune Bullous Disorders

    Directory of Open Access Journals (Sweden)

    Ayşe Akman Karakaş

    2011-06-01

    Full Text Available ELISA has been phrased as Enzyme Linked Immunosorbent Assay. The ELISA provide to detect autoantigens in autoimmune bullous disorders. Therefore, it is assited understanding of the immunopathogenesis of these diseases. Recently, commercial test systems has been developed for the diagnosis and course. The aim of this paper is to review applying investigation of the ELISA for autoimmune bullous disorders.

  14. Auto-immune encefalitis in de psychiatrische praktijk

    NARCIS (Netherlands)

    de Witte, L; Kromkamp, M|info:eu-repo/dai/nl/241613876; Schoenmaker, N; van Mierlo, H C|info:eu-repo/dai/nl/413967263; Martinez-Martínez, P; Palmen, S J M; Sommer, I E C|info:eu-repo/dai/nl/258791519

    BACKGROUND: Our knowledge about auto-immune limbic encephalitis is increasing rapidly and it is now evident that patients with this disease can present with psychiatric symptoms. AIM: To propose practical guidelines for the recognition and diagnosis of an underlying auto-immune limbic encephalitis

  15. Selected Aspects in the Pathogenesis of Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    György Nagy

    2015-01-01

    Full Text Available Autoimmune processes can be found in physiological circumstances. However, they are quenched with properly functioning regulatory mechanisms and do not evolve into full-blown autoimmune diseases. Once developed, autoimmune diseases are characterized by signature clinical features, accompanied by sustained cellular and/or humoral immunological abnormalities. Genetic, environmental, and hormonal defects, as well as a quantitative and qualitative impairment of immunoregulatory functions, have been shown in parallel to the relative dominance of proinflammatory Th17 cells in many of these diseases. In this review we focus on the derailed balance between regulatory and Th17 cells in the pathogenesis of autoimmune diseases. Additionally, we depict a cytokine imbalance, which gives rise to a biased T-cell homeostasis. The assessment of Th17/Treg-cell ratio and the simultaneous quantitation of cytokines, may give a useful diagnostic tool in autoimmune diseases. We also depict the multifaceted role of dendritic cells, serving as antigen presenting cells, contributing to the development of the pathognomonic cytokine signature and promote cellular and humoral autoimmune responses. Finally we describe the function and role of extracellular vesicles in particular autoimmune diseases. Targeting these key players of disease progression in patients with autoimmune diseases by immunomodulating therapy may be beneficial in future therapeutic strategies.

  16. Autoimmune haemolytic anaemia and fever of undetermined origin ...

    African Journals Online (AJOL)

    Autoimmune haemolytic anaemia and fever of undetermined origin as presenting manifestations of Hodgkin disease: A case report. ... Subjects and Methods: We report a 14 year-old male adolescent who presented with protracted recurrent fever, as well as clinical and laboratory findings suggestive of autoimmune ...

  17. Childhood Autoimmune Hepatitis in Bahrain: a Tertiary Center Experience.

    Science.gov (United States)

    Farid, Eman; Isa, Hasan M; Al Nasef, Mohamed; Mohamed, Rawia; Jamsheer, Huda

    2015-06-01

    Autoimmune hepatitis (AIH) in childhood has variable modes of presentation, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. In AIH, the liver biopsy histopathology shows inflammation in addition to presence of serum autoimmune antibodies and increased levels of immunoglobulin G (IgG). To investigate the situation of childhood autoimmune hepatitis in Bahrain and to compare it with other studies worldwide. A retrospective study describing the AIH pediatric cases diagnosed during the period of Jan 2005 to Dec 2009. We report the clinical, biochemical, histopathological, and immunological findings, mainly autoimmune profile, in addition to response to treatment, of Bahraini children with autoimmune hepatitis. Five Bahraini children, three females and two males were diagnosed as autoimmune hepatitis during the study period. Their ages at presentation ranged from 9 to 15 (median 10.6) years. One of our patients had a fulminating type. Two had other autoimmune related conditions, namely autoimmune sclerosing cholangitis and ulcerative colitis. All were AIH type 1. Variable response to conventional immunosuppressive therapy was found, from an excellent response with good prognosis, to cirrhosis, hepatic failure and liver transplantation. Childhood AIH is a rare medical problem in Bahrain, with both sexes affected and a variable response to immunosuppressive therapy.

  18. Continuing the quest for autoimmunity due to oral metal exposure

    NARCIS (Netherlands)

    Rachmawati, D.; Muris, J.; Scheper, R.J.; Rustemeyer, T.; Kleverlaan, C.J.; Feilzer, A.J.; von Blomberg, B.M.E.; van Hoogstraten, I.M.W.

    2015-01-01

    Aim: The role of metal exposure in the development of autoimmune disease (AID) is still controversial. Here, we studied the relationship between oral metal exposure, metal allergy and autoimmunity. Methods: A mixed population (n = 78) of non-allergic volunteers, metal-allergic patients and patients

  19. Skin Manifestations Associated with Autoimmune Liver Diseases: a Systematic Review.

    Science.gov (United States)

    Terziroli Beretta-Piccoli, Benedetta; Invernizzi, Pietro; Gershwin, M Eric; Mainetti, Carlo

    2017-12-01

    Autoimmune liver diseases, which include mainly autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and the variant syndromes, are often associated with extrahepatic autoimmune diseases. However, the association with cutaneous diseases is less well described. In the present article, we provide a systematic literature review on skin manifestations linked to each of these four autoimmune liver diseases, excluding skin manifestations of systemic diseases. The association of autoimmune hepatitis with vitiligo is well known, with a particular striking association with type 2 autoimmune hepatitis, a condition occurring almost entirely in children and adolescents, much rarer and more aggressive than type 1 autoimmune hepatitis; probable associations are also identified with alopecia areata, psoriasis, and pyoderma gangrenosum. Primary biliary cholangitis is not linked to lichen planus as previously assumed, but to vitiligo, psoriasis and the very rare amicrobial pustulosis of the folds. The proposed diagnostic criteria for this latter condition include the presence of anti-mitochondrial autoantibodies, the serological hallmark of primary biliary cholangitis. The very strong association of primary sclerosing cholangitis with inflammatory bowel diseases hampers the search for an association with skin diseases, since inflammatory bowel diseases have a strong association with various dermatological condition, including neutrophilic dermatoses and erythema nodosum. Nevertheless, a probable association of primary sclerosing cholangitis with psoriasis is identified in this review. Variant syndromes, also called overlap syndromes, are likely associated with vitiligo as well, which is not surprising, since autoimmune hepatitis is a feature of these conditions and they may share regions of the MHC.

  20. Autoimmune polyglandular syndrome in a 13-year old girl

    DEFF Research Database (Denmark)

    Borgwardt, L.; Pedersen, P.; Peitersen, B.

    2008-01-01

    Autoimmune polyglandular syndrome (APS) is an entity, defined by autoimmunity towards two or more endocrine organs. APS is classified in 3 subgroups (type-1, type-2a, type-2b), according to the organs involved. A case is presented of a 13-year old girl referred to the Department of Paediatrics...