Sample records for histocompatibility complex dqb
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Sonsthagen, Sarah A.; Fales, Krystal; Jay, Chadwick V.; Sage, George K.; Talbot, Sandra L.
2014-01-01
Increased global temperature and associated changes to Arctic habitats will likely result in the northward advance of species, including an influx of pathogens novel to the Arctic. How species respond to these immunological challenges will depend in part on the adaptive potential of their immune response system. We compared levels of genetic diversity at a gene associated with adaptive immune response [Class II major histocompatibility complex (MHC), DQB exon 2] between populations of walrus (Odobenus rosmarus), a sea ice-dependent Arctic species. Walrus was represented by only five MHC DQB alleles, with frequency differences observed between Pacific and Atlantic populations. MHC DQB alleles appear to be under balancing selection, and most (80 %; n = 4/5) of the alleles were observed in walruses from both oceans, suggesting broad scale differences in the frequency of exposure and diversity of pathogens may be influencing levels of heterozygosity at DQB in walruses. Limited genetic diversity at MHC, however, suggests that walrus may have a reduced capacity to respond to novel immunological challenges associated with shifts in ecological communities and environmental stressors predicted for changing climates. This is particularly pertinent for walrus, since reductions in summer sea ice may facilitate both northward expansion of marine species and associated pathogens from more temperate regions, and exchange of marine mammals and associated pathogens through the recently opened Northwest Passage between the Atlantic and Pacific Oceans in the Canadian high Arctic.
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Evolution of major histocompatibility complex class I and class II genes in the brown bear
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Kuduk Katarzyna
2012-10-01
Full Text Available Abstract Background Major histocompatibility complex (MHC proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. Results We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN exceeded the rate of synonymous substitutions (dS at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Conclusions Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South–north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia.
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Evolution of major histocompatibility complex class I and class II genes in the brown bear.
Kuduk, Katarzyna; Babik, Wiesław; Bojarska, Katarzyna; Sliwińska, Ewa B; Kindberg, Jonas; Taberlet, Pierre; Swenson, Jon E; Radwan, Jacek
2012-10-02
Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South-north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia.
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Evolution of major histocompatibility complex class I and class II genes in the brown bear
2012-01-01
Background Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. Results We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Conclusions Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South–north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia. PMID:23031405
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Positive selection on MHC class II DRB and DQB genes in the bank vole (Myodes glareolus).
Scherman, Kristin; Råberg, Lars; Westerdahl, Helena
2014-05-01
The major histocompatibility complex (MHC) class IIB genes show considerable sequence similarity between loci. The MHC class II DQB and DRB genes are known to exhibit a high level of polymorphism, most likely maintained by parasite-mediated selection. Studies of the MHC in wild rodents have focused on DRB, whilst DQB has been given much less attention. Here, we characterised DQB genes in Swedish bank voles Myodes glareolus, using full-length transcripts. We then designed primers that specifically amplify exon 2 from DRB (202 bp) and DQB (205 bp) and investigated molecular signatures of natural selection on DRB and DQB alleles. The presence of two separate gene clusters was confirmed using BLASTN and phylogenetic analysis, where our seven transcripts clustered according to either DQB or DRB homologues. These gene clusters were again confirmed on exon 2 data from 454-amplicon sequencing. Our DRB primers amplify a similar number of alleles per individual as previously published DRB primers, though our reads are longer. Traditional d N/d S analyses of DRB sequences in the bank vole have not found a conclusive signal of positive selection. Using a more advanced substitution model (the Kumar method) we found positive selection in the peptide binding region (PBR) of both DRB and DQB genes. Maximum likelihood models of codon substitutions detected positively selected sites located in the PBR of both DQB and DRB. Interestingly, these analyses detected at least twice as many positively selected sites in DQB than DRB, suggesting that DQB has been under stronger positive selection than DRB over evolutionary time.
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Directory of Open Access Journals (Sweden)
Wei-Cheng Yang
2008-03-01
Full Text Available The major histocompatibility complex (MHC is a large multigene coding for glycoproteins that play a key role in the initiation of immune responses in vertebrates. For a better understanding of the immunologic diversity in thriving marine mammal species, the sequence variation of the exon 2 region of MHC DQB locus was analyzed in 42 bottlenose dolphins (Tursiops truncatus collected from strandings and fishery bycatch in Taiwanese waters. The 172 bp sequences amplified showed no more than two alleles in each individual. The high proportion of non-synonymous nucleotide substitutions and the moderate amount of variation suggest positive selection pressure on this locus, arguing against a reduction in the marine environment selection pressure. The phylogenetic relationship among DQB exon 2 sequences of T. truncatus and other cetaceans did not coincide with taxonomic relationship, indicating a trans-species evolutionary pattern.
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MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus
2012-01-01
Background The major histocompatibility complex (MHC) genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus). Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus) from 12 local populations. Results Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes) and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. Conclusions The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other endangered mammalian
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MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus
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Yasukochi Yoshiki
2012-11-01
Full Text Available Abstract Background The major histocompatibility complex (MHC genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus. Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus from 12 local populations. Results Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. Conclusions The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other
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MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus.
Yasukochi, Yoshiki; Kurosaki, Toshifumi; Yoneda, Masaaki; Koike, Hiroko; Satta, Yoko
2012-11-29
The major histocompatibility complex (MHC) genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus). Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus) from 12 local populations. Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes) and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other endangered mammalian species. This result suggests that
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Zhang, Xiyang; Lin, Wenzhi; Zhou, Ruilian; Gui, Duan; Yu, Xinjian; Wu, Yuping
2016-03-01
It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis. © The American Genetic Association 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Restriction fragment length polymorphism of the major histocompatibility complex of the dog.
Sarmiento, U M; Storb, R F
1988-01-01
Human major histocompatibility complex (HLA) cDNA probes were used to analyze the restriction fragment length polymorphism (RFLP) of the DLA-D region in dogs. Genomic DNA from peripheral blood leucocytes of 23 unrelated DLA-D-homozygous dogs representing nine DLA-D types (defined by mixed leucocyte reaction) was digested with restriction enzymes (Bam HI, Eco RI, Hind III, Pvu II, Taq I, Rsa I, Msp I, Pst I, and Bgl II), separated by agarose gel electrophoresis, and transferred onto Biotrace membrane. The Southern blots were successively hybridized with radiolabeled HLA cDNA probes corresponding to DR, DQ, DP, and DO beta genes. The autoradiograms for all nine enzyme digests displayed multiple bands with the DRb, DQb, and DPb probes while the DOb probe hybridized with one to two bands. The RFLP patterns were highly polymorphic but consistent within each DLA-D type. Standard RFLP patterns were established for nine DLA-D types which could be discriminated from each other by using two enzymes (Rsa I and Pst I) and the HLA-DPb probe. Cluster analysis of the polymorphic restriction fragments detected by the DRb probe revealed four closely related supertypic groups or DLA-DR families: Dw3 + Dw4 + D1, Dw8 + D10, D7 + D16 + D9, and Dw1. This study provides the basis for DLA-D genotyping at a population level by RFLP analysis. These results also suggest that the genetic organization of the DLA-D region may closely resemble that of the HLA complex.
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Directory of Open Access Journals (Sweden)
Diana D Moreno-Santillán
Full Text Available The genes of the Major Histocompatibility Complex (MHC play an important role in the vertebrate immune response and are among the most polymorphic genes known in vertebrates. In some marine mammals, MHC genes have been shown to be characterized by low levels of polymorphism compared to terrestrial taxa; this reduction in variation is often explained as a result of lower pathogen pressures in marine habitats. To determine if this same reduction in variation applies to the migratory population of blue whales (Balaenoptera musculus that occurs in the Gulf of California, we genotyped a 172 bp fragment of exon 2 of the MHC Class II DQB locus for 80 members of this population. Twenty-two putatively functional DQB allotypes were identified, all of which were homologous with DQB sequences from other cetacean species. Up to 5 putative alleles per individual were identified, suggesting that gene duplication has occurred at this locus. Rates of non-synonymous to synonymous substitutions (ω and maximum likelihood analyses of models of nucleotide variation provided potential evidence of ongoing positive selection at this exon. Phylogenetic analyses of DQB alleles from B. musculus and 16 other species of cetaceans revealed trans-specific conservation of MHC variants, suggesting that selection has acted on this locus over prolonged periods of time. Collectively our findings reveal that immunogenic variation in blue whales is comparable to that in terrestrial mammals, thereby providing no evidence that marine taxa are subject to reduced pathogen-induced selective pressures.
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Dominguez, Cecilia A; Kalliomäki, Maija; Gunnarsson, Ulf; Moen, Aurora; Sandblom, Gabriel; Kockum, Ingrid; Lavant, Ewa; Olsson, Tomas; Nyberg, Fred; Rygh, Lars Jørgen; Røe, Cecilie; Gjerstad, Johannes; Gordh, Torsten; Piehl, Fredrik
2013-03-01
Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n=189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n=258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Mikk, M-L; Kiviniemi, M; Laine, A-P; Härkönen, T; Veijola, R; Simell, O; Knip, M; Ilonen, J
2014-01-01
To further characterise the effect of the HLA-B*39 allele on type 1 diabetes risk we assessed its role in different HLA-DR/DQ haplotypes and genotypes using 1764 nuclear families with a diabetic child collected in the framework of the Finnish Paediatric Diabetes Register. HLA assays were based on sequence specific hybridization using lanthanide labelled oligonucleotide probes. Transmissions of major HLA-DR/DQ haplotypes with and without the HLA-B*39 allele to diabetic index cases were analysed by direct haplotype and allele counting. The HLA-B*39 allele significantly increased the disease risk conferred by DRB1*04:04-DQA1*03-DQB1*03:02 and (DR8)-DQB1*04 haplotypes. The same effect was observed on genotype level as disease association for the HLA-B*39 allele was observed in multiple genotypes containing DRB1*04:04-DQA1*03-DQB1*03:02 or (DR8)-DQB1*04 haplotypes. Finally we considered the two common subtypes of the HLA-B*39 allele, B*39:01 and B*39:06 and observed their unequal distribution when stratified for specific DR-DQ haplotypes. The risk for type 1 diabetes conferred by certain DR/DQ haplotypes is modified by the presence of the HLA-B*39 and this confirms the independent disease predisposing effect of the HLA-B*39 allele. The results can be applied in enhancing the sensitivity and specificity of DR/DQ based screening programs for subjects at disease risk. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
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DEFF Research Database (Denmark)
Andersen, P S; Stryhn, A; Hansen, B E
1996-01-01
Specific recognition of peptide/major histocompatibility complex (MHC) molecule complexes by the T-cell receptor is a key reaction in the specific immune response. Antibodies against peptide/MHC complexes would therefore be valuable tools in studying MHC function and T-cell recognition and might ...
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The Major Histocompatibility Complex in Transplantation
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Marco Antonio Ayala García
2012-01-01
Full Text Available The transplant of organs is one of the greatest therapeutic achievements of the twentieth century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the principal target of the immune response is the MHC (major histocompatibility complex molecules expressed on the surface of donor cells. However, we should not forget that the innate and adaptive immunities are closely interrelated and should be viewed as complementary and cooperating. When a human transplant is performed, HLA (human leukocyte antigens molecules from a donor are recognized by the recipient's immune system triggering an alloimmune response Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. This paper will present MHC, the innate and adaptive immunities, and clinical HLA testing.
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Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Abbate, J. L.
2015-01-01
Roč. 6, 13 May (2015), s. 73-88 ISSN 1179-7274 Institutional support: RVO:68081766 Keywords : major histocompatibility complex * sexual selection * olfaction * facial attraction * parasite resistance * inbreeding avoidance Subject RIV: EB - Genetics ; Molecular Biology
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Association Study of HLA-DQB1*0602 Allele in Iranian Patients with Narcolepsy.
Geremew, Demeke; Rahimi-Golkhandan, Ania; Sadeghniiat-Haghighi, Khosro; Shakiba, Yadollah; Khajeh-Mehrizi, Ahmad; Ansaripour, Bita; Izad, Maryam
2017-10-01
Narcolepsy is a rare, disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Several studies demonstrated its association with HLA-DQB1*0602 in various ethnic groups. Our study aimed to determine the prevalence of HLA-DQB1*0602 allele in Iranian patients with narcolepsy and assess its predictive parameters for diagnosing narcolepsy. In addition, car accidents and job problems were assessed among narcoleptic patients. We studied 44 narcoleptic patients, 30 patients with other types of excessive daytime sleepiness (EDS) and 50 healthy age and sex matched individuals in this case-control study. Patients and controls filled out a questionnaire including items about car accidents due to sleepiness and job problems. International classification of sleep disorders-2 criteria was used as the gold standard for diagnosis of narcolepsy. The DNAs isolated from whole blood samples were collected from the patients and controls to assess the presence of HLA-DQB1*0602. The results showed that HLA DQB1*0602 was present in 4 (8%) individual of controls and 20 (45.5%) patients with higher prevalence in patients with cataplexy (78.9%) than patients without cataplexy (p<0.001). The sensitivities of the DQB1*0602 for diagnosing narcolepsy with cataplexy and narcolepsy without cataplexy were 78.9 and 20; specificities were 88 and 72.4, respectively. 18.2% of patients had car accidents due to sleepiness and 68.2% suffered from job problems. Our study shows that evaluation of DQB1*0602 in patients suspected to narcolepsy could be helpful especially in complex cases with atypical cataplexy and indistinguishable multiple sleep latency test MSLT results. Moreover, high rates of car accidents and job problems are found among narcoleptic patients.
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Sin, Yung Wa; Annavi, Geetha; Dugdale, Hannah L.; Newman, Chris; Burke, Terry; MacDonald, David W.
2014-01-01
Pathogen-mediated selection is thought to maintain the extreme diversity in the major histocompatibility complex (MHC) genes, operating through the heterozygote advantage, rare-allele advantage and fluctuating selection mechanisms. Heterozygote advantage (i.e. recognizing and binding a wider range
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DEFF Research Database (Denmark)
Chazara, Olympe; Juul-Madsen, Helle Risdahl; Chang, Chi-Seng
Background The LEI0258 marker is located within the B region of the chicken Major Histocompatibility Complex (MHC), and is surprisingly well associated with serology. Therefore, the correlation between the LEI0258 alleles and the MHC class I and the class II alleles at the level of sequences is w...
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DEFF Research Database (Denmark)
Viken, M.K.; Blomhoff, A.; Olsson, M.
2009-01-01
parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN......(*)03-DQA1(*)0501-DQB1(*)0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1(*)0401-DQA1(*)03-DQB1(*)0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one......)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note...
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The major histocompatibility complex and perfumers' descriptions of human body odors
Wedekind, C.; Escher, S.; Van de Waal, M.; Frei, E.
2007-01-01
The MHC (major histocompatibility complex) is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-sh...
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Andersen, Peter S.; Stryhn, Anette; Hansen, Bjarke E.; Fugger, Lars; Engberg, Jan; Buus, Soren
1996-03-01
Specific recognition of peptide/major histocompatibility complex (MHC) molecule complexes by the T-cell receptor is a key reaction in the specific immune response. Antibodies against peptide/MHC complexes would therefore be valuable tools in studying MHC function and T-cell recognition and might lead to novel approaches in immunotherapy. However, it has proven difficult to generate antibodies with the specificity of T cells by conventional hybridoma techniques. Here we report that the phage display technology is a feasible alternative to generate antibodies recognizing specific, predetermined peptide/MHC complexes.
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van der Wel, Nicole N.; Sugita, Masahiko; Fluitsma, Donna M.; Cao, Xaiochun; Schreibelt, Gerty; Brenner, Michael B.; Peters, Peter J.
2003-01-01
The maturation of dendritic cells is accompanied by the redistribution of major histocompatibility complex (MHC) class II molecules from the lysosomal MHC class IT compartment to the plasma membrane to mediate presentation of peptide antigens. Besides MHC molecules, dendritic cells also express CD1
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NetMHCcons: a consensus method for the major histocompatibility complex class I predictions
DEFF Research Database (Denmark)
Karosiene, Edita; Lundegaard, Claus; Lund, Ole
2012-01-01
A key role in cell-mediated immunity is dedicated to the major histocompatibility complex (MHC) molecules that bind peptides for presentation on the cell surface. Several in silico methods capable of predicting peptide binding to MHC class I have been developed. The accuracy of these methods depe...... at www.cbs.dtu.dk/services/NetMHCcons, and allows the user in an automatic manner to obtain the most accurate predictions for any given MHC molecule....
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DNA polymorphism of HLA class II genes in pauciarticular juvenile rheumatoid arthritis
DEFF Research Database (Denmark)
Morling, N; Friis, J; Fugger, L
1991-01-01
We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II genes: HLA-DRB, -DQA, -DQB, DPA, and -DPB in 54 patients with pauciarticular juvenile rheumatoid arthritis (PJRA) and in healthy Danes. The frequencies of DNA fragments a...
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Restriction fragment polymorphisms in the major histocompatibility complex of diabetic BB rats
DEFF Research Database (Denmark)
Kastern, W.; Dyrberg, T.; Scholler, J.
1984-01-01
DNA isolated from diabetic BB (BB/Hagedorn) rats was examined for restriction fragment length differences within the major histocompatibility complex (MHC) as compared with nondiabetic (W-subline) BB rats. Polymorphisms were detected using a mouse class I MHC gene as probe. Specifically, a 2-kb Bam......HI fragment was present in all the nondiabetic rats examined, but absent in the diabetic rats. Similar polymorphisms were observed with various other restriction enzymes, particularly XbaI, HindII, and SacI. There were no polymorphisms detected using either a human DR-alpha (class II antigen heavy chain...
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1 RESEARCH ARTICLE Genetic diversity of Cahi DRB and DQB ...
Indian Academy of Sciences (India)
DADA
is a scarcity of research database for allelic association of DRB and DQB alleles .... typed for genotype of DRB or DQB1. μ = the intercept; Cj = cohort effect; ... amino acid occurs divided by the total number of protein examined. .... Alleles in low ranking genotypes and high ranking genotypes were exclusive to .... Health Prod.
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Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease
Gutierrez-Achury, Javier; Zhernakova, Alexandra; Pulit, Sara L.; Trynka, Gosia; Hunt, Karen A.; Romanos, Jihane; Raychaudhuri, Soumya; van Heel, David A.; Wijmenga, Cisca; de Balcker, Paul I. W.
Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and
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DNA polymorphism of HLA class II genes in systemic lupus erythematosus
DEFF Research Database (Denmark)
Cowland, J B; Andersen, V; Halberg, P
1994-01-01
We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) genes: HLA-DRB, -DQA, -DQB, -DPB in 24 Danish patients with systemic lupus erythematosus (SLE) and in 102 healthy Danes. A highly significant increase of the frequency of the DR3...
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HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency.
Han, Fang; Lin, Ling; Schormair, Barbara; Pizza, Fabio; Plazzi, Giuseppe; Ollila, Hanna M; Nevsimalova, Sona; Jennum, Poul; Knudsen, Stine; Winkelmann, Juliane; Coquillard, Cristin; Babrzadeh, Farbod; Strom, Tim M; Wang, Chunlin; Mindrinos, Michael; Fernandez Vina, Marcelo; Mignot, Emmanuel
2014-10-01
To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University). CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes. Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing. Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be
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Olfactory fingerprints for major histocompatibility complex-determined body odors.
Schaefer, M L; Young, D A; Restrepo, D
2001-04-01
Recognition of individual body odors is analogous to human face recognition in that it provides information about identity. Individual body odors determined by differences at the major histocompatibility complex (MHC or H-2) have been shown to influence mate choice, pregnancy block, and maternal behavior in mice. Unfortunately, the mechanism and extent of the main olfactory bulb (MOB) and accessory olfactory bulb (AOB) involvement in the discrimination of animals according to H-2-type has remained ambiguous. Here we study the neuronal activation patterns evoked in the MOB in different individuals on exposure to these complex, biologically meaningful sensory stimuli. We demonstrate that body odors from H-2 disparate mice evoke overlapping but distinct maps of neuronal activation in the MOB. The spatial patterns of odor-evoked activity are sufficient to be used like fingerprints to predict H-2 identity using a novel computer algorithm. These results provide functional evidence for discrimination of H-2-determined body odors in the MOB, but do not preclude a role for the AOB. These data further our understanding of the neural strategies used to decode socially relevant odors.
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Olfactory cues associated with the major histocompatibility complex.
Eggert, F; Müller-Ruchholtz, W; Ferstl, R
Besides its immunological function of self/non-self discrimination the major histocompatibility complex (MHC) has been recognized as a possible source of individual specific body odors. Dating back to speculations on the role of the extraordinary polymorphism of the MHC as background of an individual chemosensory identity and to early observations of MHC-dependent mate choice in inbred strains of mice, systematic experimental studies revealed a first evidence for H-2 related body odors in this species. Meanwhile a large number of animal studies with rodents and a series of field studies and experiments with humans have extended our knowledge of MHC-related odor signals and substantiated the hypothesis of immunogenetic associated odor types. These results suggest that the most prominent feature of the MHC, its extraordinary genetic diversity, seems in part to be selectively maintained by behavioral mechanisms which operate in contemporary natural populations. The high degree of heterozygosity found in natural populations of most species seems to be promoted by non-disease-based selection such as mating preferences and selective block of pregnancy.
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Bartl, S; Weissman, I L
1994-01-01
The major histocompatibility complex (MHC) contains a set of linked genes which encode cell surface proteins involved in the binding of small peptide antigens for their subsequent recognition by T lymphocytes. MHC proteins share structural features and the presence and location of polymorphic residues which play a role in the binding of antigens. In order to compare the structure of these molecules and gain insights into their evolution, we have isolated two MHC class IIB genes from the nurse...
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van Eijkeren, MA; Roovers, JP; Oorschot, [No Value; Geuze, HJ
2004-01-01
Downregulation of major histocompatibility complex (MHC) class I molecules in cervix cancer has been proposed as a mechanism for cancer cells to escape immunodetection. By means of light microscopic immunohistochemistry, it has been shown that in 20-70% of cervix cancers MHC class I is
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DEFF Research Database (Denmark)
Grey, H M; Buus, S; Colon, S
1989-01-01
Previous studies indicate that T cells recognize a complex between the major histocompatibility complex (MHC) restriction-element and peptide-antigen fragments. Two aspects of this complex formation are considered in this paper: (1) what is the nature of the specificity of the interactions that a...... of binding to Ia (i.e. determinant selection was operative), we found that about 40% of Ia-binding peptides were not immunogenic (i.e. there were also 'holes in the T-cell repertoire')....... responsiveness, we present data that suggest both mechanisms operate in concert with one another. Thus only about 30% of a collection of peptides that in sum represent the sequence of a protein molecule were found to bind to Ia. Although immunogenicity was restricted to those peptides that were capable...
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Association between HLA-DQA1, HLA-DQB1 and oral cancer
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Sheng-Chien Tsai
2011-10-01
Full Text Available Cancer is one of the most common causes of morbidity and mortality. Genes whose products play a critical role in regulation of the immune response include the HLA antigen and cytokine families of genes. Oral cancer is common in men in developing countries, and its frequency is increased by using betel-quid, tobacco, and alcohol. The association between certain HLA Class I and Class II haplotypes and cancer has been documented in a variety of tumors. There was no previous data concerning the association of specific HLA Class II DQA1, DQB1 alleles, or haplotypes with oral cancer patients. In this study, we enrolled 134 Taiwanese patients with histologically confirmed oral cancer and 268 age- and gender-matched healthy Taiwanese adults as control group to investigate the association between HLA-DQA1, HLA-DQB1 allele frequencies and oral cancer patients by using polymerase chain reaction with sequence-specific primers. We found that both HLA-DQA1* and HLA-DQB1* allele frequencies in oral cancer patients revealed no significant difference from those of control groups. Haplotype frequencies of HLA*DQA1-0103-DQB1*0601 in oral cancer patients were significantly lower than those of the control group (odds ratio: 0.18, 95% confidence interval: 0.054–0.583, pc=0.02. Our data suggest that HLA DQA1*0103-DQB1*0601 haplotype may be protective with regard to the development of oral cancer.
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Directory of Open Access Journals (Sweden)
Katherine Belov
2006-03-01
Full Text Available The first sequenced marsupial genome promises to reveal unparalleled insights into mammalian evolution. We have used the Monodelphis domestica (gray short-tailed opossum sequence to construct the first map of a marsupial major histocompatibility complex (MHC. The MHC is the most gene-dense region of the mammalian genome and is critical to immunity and reproductive success. The marsupial MHC bridges the phylogenetic gap between the complex MHC of eutherian mammals and the minimal essential MHC of birds. Here we show that the opossum MHC is gene dense and complex, as in humans, but shares more organizational features with non-mammals. The Class I genes have amplified within the Class II region, resulting in a unique Class I/II region. We present a model of the organization of the MHC in ancestral mammals and its elaboration during mammalian evolution. The opossum genome, together with other extant genomes, reveals the existence of an ancestral "immune supercomplex" that contained genes of both types of natural killer receptors together with antigen processing genes and MHC genes.
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Directory of Open Access Journals (Sweden)
Djidjik Réda
2012-08-01
Full Text Available Abstract Presenting processed antigens to CD4+ lymphocytes during the immune response involves major histocompatibility complex class II molecules. MHC class II genes transcription is regulated by four transcription factors: CIITA, RFXANK, RFX5 and RFXAP. Defects in these factors result in major histocompatibility complex class II expression deficiency, a primary combined immunodeficiency frequent in North Africa. Autosomal recessive mutations in the RFXANK gene have been reported as being the principal defect found in North African patients with this disorder. In this paper, we describe clinical, immunological and genetic features of 11 unrelated Algerian patients whose monocytes display a total absence of MHC class II molecules. They shared mainly the same clinical picture which included protracted diarrhoea and respiratory tract recurrent infections. Genetic analysis revealed that 9 of the 11 patients had the same RFXANK founder mutation, a 26 bp deletion (named I5E6-25_I5E6+1, also known as 752delG26. Immunological and genetic findings in our series may facilitate genetic counselling implementation for Algerian consanguineous families. Further studies need to be conducted to determine 752delG26 heterozygous mutation frequency in Algerian population.
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DEFF Research Database (Denmark)
Salomonsen, J; Dunon, D; Skjødt, K
1991-01-01
B-G antigens are a polymorphic multigene family of cell surface molecules encoded by the chicken major histocompatibility complex (MHC). They have previously been described only on cells of the erythroid lineage. By using flow cytometry, section staining, and immunoprecipitation with monoclonal a...
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Panter, Michaela S; Jain, Ankur; Leonhardt, Ralf M; Ha, Taekjip; Cresswell, Peter
2012-09-07
Although the human peptide-loading complex (PLC) is required for optimal major histocompatibility complex class I (MHC I) antigen presentation, its composition is still incompletely understood. The ratio of the transporter associated with antigen processing (TAP) and MHC I to tapasin, which is responsible for MHC I recruitment and peptide binding optimization, is particularly critical for modeling of the PLC. Here, we characterized the stoichiometry of the human PLC using both biophysical and biochemical approaches. By means of single-molecule pulldown (SiMPull), we determined a TAP/tapasin ratio of 1:2, consistent with previous studies of insect-cell microsomes, rat-human chimeric cells, and HeLa cells expressing truncated TAP subunits. We also report that the tapasin/MHC I ratio varies, with the PLC population comprising both 2:1 and 2:2 complexes, based on mutational and co-precipitation studies. The MHC I-saturated PLC may be particularly prevalent among peptide-selective alleles, such as HLA-C4. Additionally, MHC I association with the PLC increases when its peptide supply is reduced by inhibiting the proteasome or by blocking TAP-mediated peptide transport using viral inhibitors. Taken together, our results indicate that the composition of the human PLC varies under normal conditions and dynamically adapts to alterations in peptide supply that may arise during viral infection. These findings improve our understanding of the quality control of MHC I peptide loading and may aid the structural and functional modeling of the human PLC.
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The Major Histocompatibility Complex and Perfumers' Descriptions of Human Body Odors
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Claus Wedekind
2007-04-01
Full Text Available The MHC (major histocompatibility complex is a group of genes that play a crucial role in immune recognition and in tolerance of tissue grafting. The MHC has also been found to influence body odors, body odor preferences, and mate choice in mice and humans. Here we test whether verbal descriptions of human body odors can be linked to the MHC. We asked 45 male students to live as odor neutral as possible for two consecutive days and to wear a T-shirt during the nights. The odors of these T-shirts were then described by five evaluators: two professional perfumers and three laymen. One of the perfumers was able to describe the T-shirt odors in such a way that some of the allelic specificity of the MHC was significantly revealed (after Bonferroni correction for multiple testing. This shows that, although difficult, some people are able to describe MHC-correlated body odor components.
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Olfat Shaker
2013-01-01
Full Text Available Human leukocyte antigens class II play an important role in immune response against HCV. We investigated whether HLA class II alleles influence susceptibility to HCV infection and response to interferon therapy. HLA-DRB1 and -DQB1 loci were genotyped using PCR-SSO Luminex technology. According to our regimen, 41 (66% of patients achieved sustained virological response to combined treatment of IFN and ribavirin. Frequencies of DQB1*0313 allele and DRB1*04-DRB1*11, DQB1*0204-DQB1*0313, DQB1*0309-DQB1*0313, and DQB1*0313-DQB1*0319 haplotypes were significantly more frequent in nonresponders than in responders. In contrast, DQB1*02, DQB1*06, DRB1*13, and DRB1*15 alleles were significantly more frequent in responders than in nonresponders. Similarly, DRB1*1301, DRB1*1361, and DRB1*1369 alleles and DRB1*1301-DRB1*1328, DRB1*1301-DRB1*1361, DRB1*1301-DRB1*1369, DRB1*1328-DRB1*1361, and DRB1*1328-DRB1*1369 haplotypes were significantly found only in responders. Some alleles and linkages showed significantly different distributions between patient and healthy groups. These alleles may be used as predictors for response to treatment or to susceptibility to HCV infection in the Egyptian population.
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DEFF Research Database (Denmark)
Snabe, Torben; Røder, Gustav Andreas; Neves-Petersen, Maria Teresa
2005-01-01
Controlled and oriented immobilisation of proteins for biosensor purposes is of extreme interest since this provides more efficient sensors with a larger density of active binding sites per area compared to sensors produced by conventional immobilisation. In this paper oriented coupling of a major...... histocompatibility complex (MHC class I) to a sensor surface is presented. The coupling was performed using light assisted immobilisation--a novel immobilisation technology which allows specific opening of particular disulphide bridges in proteins which then is used for covalent bonding to thiol-derivatised surfaces...... via a new disulphide bond. Light assisted immobilisation specifically targets the disulphide bridge in the MHC-I molecule alpha(3)-domain which ensures oriented linking of the complex with the peptide binding site exposed away from the sensor surface. Structural analysis reveals that a similar...
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Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease.
Alshiekh, S; Zhao, L P; Lernmark, Å; Geraghty, D E; Naluai, Å T; Agardh, D
2017-08-01
Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4-DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non-HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02-DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Czech Academy of Sciences Publication Activity Database
Promerová, Marta; Babik, W.; Bryja, Josef; Albrecht, Tomáš; Stuglik, M.; Radwan, J.
2012-01-01
Roč. 12, č. 2 (2012), s. 285-292 ISSN 1755-098X R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/06/0851; GA ČR GAP505/10/1871 Institutional research plan: CEZ:AV0Z60930519 Keywords : avian * Carpodacus erythrinus * major histocompatibility complex * next-generation sequencing * scarlet rosefinch Subject RIV: EG - Zoology Impact factor: 7.432, year: 2012
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Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex
Daza-Vamenta, Riza; Glusman, Gustavo; Rowen, Lee; Guthrie, Brandon; Geraghty, Daniel E.
2004-01-01
The major histocompatibility complex (MHC) is comprised of the class I, class II, and class III regions, including the MHC class I and class II genes that play a primary role in the immune response and serve as an important model in studies of primate evolution. Although nonhuman primates contribute significantly to comparative human studies, relatively little is known about the genetic diversity and genomics underlying nonhuman primate immunity. To address this issue, we sequenced a complete rhesus macaque MHC spanning over 5.3 Mb, and obtained an additional 2.3 Mb from a second haplotype, including class II and portions of class I and class III. A major expansion of from six class I genes in humans to as many as 22 active MHC class I genes in rhesus and levels of sequence divergence some 10-fold higher than a similar human comparison were found, averaging from 2% to 6% throughout extended portions of class I and class II. These data pose new interpretations of the evolutionary constraints operating between MHC diversity and T-cell selection by contrasting with models predicting an optimal number of antigen presenting genes. For the clinical model, these data and derivative genetic tools can be implemented in ongoing genetic and disease studies that involve the rhesus macaque. PMID:15289473
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Molecular Genotype Identification of Different Chickens: Major Histocompatibility Complex
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Hongzhi Wang
2014-09-01
Full Text Available Chicken is a main poultry in China. Molecular breeding for disease resistance plays an important role in the control of diseases, especially infectious diseases. Choice of genes for disease resistance is the key technology of molecular breeding. The major histocompatibility complex (MHC is of great interest to poultry breeding scientists for its extraordinary polymorphism and close relation with traits of resistance against infectious diseases. The MHC-B haplotype plays an important role in the study of disease resistance in chicken. The traditional chicken MHC-B haplotype is commonly defined by serologic reactions of erythrocytes and the majority of studies have been conducted in Leghorn and broiler but study about other chicken breeds is little. In this study, firstly, the microsatellite marker LEI0258 which is located within the MHC was sequenced by using target sequence capture assay in different chicken breeds, and then according to the number of repeated structures and polymorphic sequences in microsatellite, sequence information for the region defined by LEI0258 was obtained for different haplotypes. Afterwards, we identified the relation between MHC-B haplotypes and disease resistance. Collectively, these observed results provided the reference data for disease-resistant breeding association with blood type and for further study of MHC gene function in poultry.
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Analysis of ELA-DQB exon 2 polymorphism in Argentine Creole horses by PCR-RFLP and PCR-SSCP.
Villegas-Castagnasso, E E; Díaz, S; Giovambattista, G; Dulout, F N; Peral-García, P
2003-08-01
The second exon of equine leucocyte antigen (ELA)-DQB genes was amplified from genomic DNA of 32 Argentine Creole horses by PCR. Amplified DNA was analysed by PCR-restriction fragment length polymorphism (RFLP) and PCR-single-strand conformation polymorphism (SSCP). The PCR-RFLP analysis revealed two HaeIII patterns, four RsaI patterns, five MspI patterns and two HinfI patterns. EcoRI showed no variation in the analysed sample. Additional patterns that did not account for known exon 2 DNA sequences were observed, suggesting the existence of novel ELA-DQB alleles. PCR-SSCP analysis exhibited seven different band patterns, and the number of bands per animal ranged from four to nine. Both methods indicated that at least two DQB genes are present. The presence of more than two alleles in each animal showed that the primers employed in this work are not specific for a unique DQB locus. The improvement of this PCR-RFLP method should provide a simple and rapid technique for an accurate definition of ELA-DQB typing in horses.
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Isolation and characterization of major histocompatibility complex class II B genes in cranes.
Kohyama, Tetsuo I; Akiyama, Takuya; Nishida, Chizuko; Takami, Kazutoshi; Onuma, Manabu; Momose, Kunikazu; Masuda, Ryuichi
2015-11-01
In this study, we isolated and characterized the major histocompatibility complex (MHC) class II B genes in cranes. Genomic sequences spanning exons 1 to 4 were amplified and determined in 13 crane species and three other species closely related to cranes. In all, 55 unique sequences were identified, and at least two polymorphic MHC class II B loci were found in most species. An analysis of sequence polymorphisms showed the signature of positive selection and recombination. A phylogenetic reconstruction based on exon 2 sequences indicated that trans-species polymorphism has persisted for at least 10 million years, whereas phylogenetic analyses of the sequences flanking exon 2 revealed a pattern of concerted evolution. These results suggest that both balancing selection and recombination play important roles in the crane MHC evolution.
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High-Resolution Patterns of Meiotic Recombination across the Human Major Histocompatibility Complex
Cullen, Michael; Perfetto, Stephen P.; Klitz, William; Nelson, George; Carrington, Mary
2002-01-01
Definitive characteristics of meiotic recombination events over large (i.e., >1 Mb) segments of the human genome remain obscure, yet they are essential for establishing the haplotypic structure of the genome and for efficient mapping of complex traits. We present a high-resolution map of recombination at the kilobase level across a 3.3-Mb interval encompassing the major histocompatibility complex (MHC). Genotyping of 20,031 single sperm from 12 individuals resulted in the identification and fine mapping of 325 recombinant chromosomes within genomic intervals as small as 7 kb. Several principal characteristics of recombination in this region were observed: (1) rates of recombination can differ significantly between individuals; (2) intense hot spots of recombination occur at least every 0.8 Mb but are not necessarily evenly spaced; (3) distribution in the location of recombination events can differ significantly among individuals; (4) between hot spots, low levels of recombination occur fairly evenly across 100-kb segments, suggesting the presence of warm spots of recombination; and (5) specific sequence motifs associate significantly with recombination distribution. These data provide a plausible model for recombination patterns of the human genome overall. PMID:12297984
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Qiu-Hong Wan
Full Text Available To gain an understanding of the genomic structure and evolutionary history of the giant panda major histocompatibility complex (MHC genes, we determined a 636,503-bp nucleotide sequence spanning the MHC class II region. Analysis revealed that the MHC class II region from this rare species contained 26 loci (17 predicted to be expressed, of which 10 are classical class II genes (1 DRA, 2 DRB, 2 DQA, 3 DQB, 1 DYB, 1 DPA, and 2 DPB and 4 are non-classical class II genes (1 DOA, 1 DOB, 1 DMA, and 1 DMB. The presence of DYB, a gene specific to ruminants, prompted a comparison of the giant panda class II sequence with those of humans, cats, dogs, cattle, pigs, and mice. The results indicated that birth and death events within the DQ and DRB-DY regions led to major lineage differences, with absence of these regions in the cat and in humans and mice respectively. The phylogenetic trees constructed using all expressed alpha and beta genes from marsupials and placental mammals showed that: (1 because marsupials carry loci corresponding to DR, DP, DO and DM genes, those subregions most likely developed before the divergence of marsupials and placental mammals, approximately 150 million years ago (MYA; (2 conversely, the DQ and DY regions must have evolved later, but before the radiation of placental mammals (100 MYA. As a result, the typical genomic structure of MHC class II genes for the giant panda is similar to that of the other placental mammals and corresponds to BTNL2 approximately DR1 approximately DQ approximately DR2 approximately DY approximately DO_box approximately DP approximately COL11A2. Over the past 100 million years, there has been birth and death of mammalian DR, DQ, DY, and DP genes, an evolutionary process that has brought about the current species-specific genomic structure of the MHC class II region. Furthermore, facing certain similar pathogens, mammals have adopted intra-subregion (DR and DQ and inter-subregion (between DQ and DP
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Wenqiao Hui
2012-12-01
Full Text Available Cystic echinococcosis (CE, one of the world’s most geographically widespread diseases, still represents a considerable economic and public health significance, although a variety of methods has been used to control the disease. It has been demonstrated that genetic factors, especially variations in MHC loci, can influence the outcome of CE infection in the human population. The study described here was designed to determine whether variation in MHC-DQB1 was associated with susceptibility or resistance to CE in sheep. If so, it would lay a theoretical foundation for breeding disease resistance sheep in future. This study was carried out on 204 Chinese Merino sheep, including 101 CE sheep and 103 healthy controls. The polymorphism of MHC-DQB1 exon 2 was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP method, and x2 test was used to compare genotype frequencies between CE sheep and healthy controls. A total of 22 alleles and 42 genotypes were identified in DQB1 exon 2 in Chinese Merino sheep. In addition, x2 test showed that frequencies of DQB1-TaqIaa and DQB1-HaeIIInn genotypes were significantly higher in the healthy group (82.5% and 57.3%, respectively than that in the CE group (57.4% and 28.9%, respectively (both p values = 0, OR = 0.286, 0.303, respectively, suggesting that these genotypes appeared to be associated with resistance to CE. Whereas, frequencies of DQB1-TaqIab and DQB1-HaeIIImn genotypes were significantly higher in the CE group (36.9% and 32.0%, respectively, as compared with the healthy group (16.5% and 11.15%, respectively (p = 0.001, 0.001 and OR = 2.963, 3.629, respectively, indicating that these genotypes might be associated with susceptibility to CE. It is concluded that the genetic polymorphism within MHC-DQB1 might influence immune responses to pathogens, thus leading to the development of CE or protection against CE in Chinese Merino sheep, which would pave the way for breeding
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Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in Inhabitants of Astana, the Capital City of Kazakhstan
Kuranov, Alexandr B.; Vavilov, Mikhail N.; Abildinova, Gulshara Zh.; Akilzhanova, Ainur R.; Iskakova, Aisha N.; Zholdybayeva, Elena V.; Boldyreva, Margarita N.; Müller, Claudia A.; Momynaliev, Kuvat T.
2014-01-01
Background Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA) genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations. Methodology/Principal Findings A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT-Method) for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS). Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%), HLA-DQA1*03:01 (13.1%) and HLA-DQB1*03:01 (17.6%). In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0%) was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians. Conclusions/Significance The HLA-DRB1, -DQA1and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations. PMID:25531278
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Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in inhabitants of Astana, the capital city of Kazakhstan.
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Alexandr B Kuranov
Full Text Available BACKGROUND: Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations. METHODOLOGY/PRINCIPAL FINDINGS: A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT-Method for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS. Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%, HLA-DQA1*03:01 (13.1% and HLA-DQB1*03:01 (17.6%. In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0% was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians. CONCLUSIONS/SIGNIFICANCE: The HLA-DRB1, -DQA1 and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations.
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Signal transduction by the major histocompatibility complex class I molecule
DEFF Research Database (Denmark)
Pedersen, A E; Skov, Svend; Bregenholt, S
1999-01-01
Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....
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Multiple major histocompatibility complex class I genes in Asian anurans: Ontogeny and phylogeny.
Didinger, Chelsea; Eimes, John A; Lillie, Mette; Waldman, Bruce
2017-05-01
Amphibians, as the first terrestrial vertebrates, offer a window into early major histocompatibility complex (MHC) evolution. We characterized the MHC class I of two Korean amphibians, the Asiatic toad (Bufo gargarizans) and the Japanese tree frog (Hyla japonica). We found at least four transcribed MHC class I (MHC I) loci, the highest number confirmed in any anuran to date. Furthermore, we identified MHC I transcripts in terrestrial adults, and possibly in aquatic larvae, of both species. We conducted a phylogenetic analysis based on MHC I sequence data and found that B. gargarizans and H. japonica cluster together in the superfamily Nobleobatrachia. We further identified three supertypes shared by the two species. Our results reveal substantial variation in the number of MHC I loci in anurans and suggest that certain supertypes have particular physiochemical properties that may confer pathogen resistance. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Hacking, Jessica; Bertozzi, Terry; Moussalli, Adnan; Bradford, Tessa; Gardner, Michael
2018-07-01
Characterisation of squamate major histocompatibility complex (MHC) genes has lagged behind other taxonomic groups. MHC genes encode cell-surface glycoproteins that present self- and pathogen-derived peptides to T cells and play a critical role in pathogen recognition. Here we characterise MHC class I transcripts for an agamid lizard (Ctenophorus decresii) and investigate the evolution of MHC class I in Iguanian lizards. An iterative assembly strategy was used to identify six full-length C. decresii MHC class I transcripts, which were validated as likely to encode classical class I MHC molecules. Evidence for exon shuffling recombination was uncovered for C. decresii transcripts and Bayesian phylogenetic analysis of Iguanian MHC class I sequences revealed a pattern expected under a birth-and-death mode of evolution. This work provides a stepping stone towards further research on the agamid MHC class I region. Copyright © 2018 Elsevier Ltd. All rights reserved.
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Directory of Open Access Journals (Sweden)
Gustafsson Lars
2010-12-01
Full Text Available Abstract Background Because of their functional significance, the Major Histocompatibility Complex (MHC class I and II genes have been the subject of continuous interest in the fields of ecology, evolution and conservation. In some vertebrate groups MHC consists of multiple loci with similar alleles; therefore, the multiple loci must be genotyped simultaneously. In such complex systems, understanding of the evolutionary patterns and their causes has been limited due to challenges posed by genotyping. Results Here we used 454 amplicon sequencing to characterize MHC class IIB exon 2 variation in the collared flycatcher, an important organism in evolutionary and immuno-ecological studies. On the basis of over 152,000 sequencing reads we identified 194 putative alleles in 237 individuals. We found an extreme complexity of the MHC class IIB in the collared flycatchers, with our estimates pointing to the presence of at least nine expressed loci and a large, though difficult to estimate precisely, number of pseudogene loci. Many similar alleles occurred in the pseudogenes indicating either a series of recent duplications or extensive concerted evolution. The expressed alleles showed unambiguous signals of historical selection and the occurrence of apparent interlocus exchange of alleles. Placing the collared flycatcher's MHC sequences in the context of passerine diversity revealed transspecific MHC class II evolution within the Muscicapidae family. Conclusions 454 amplicon sequencing is an effective tool for advancing our understanding of the MHC class II structure and evolutionary patterns in Passeriformes. We found a highly dynamic pattern of evolution of MHC class IIB genes with strong signals of selection and pronounced sequence divergence in expressed genes, in contrast to the apparent sequence homogenization in pseudogenes. We show that next generation sequencing offers a universal, affordable method for the characterization and, in perspective
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Mimbacas, Adriana; Pérez-Bravo, Francisco; Hidalgo, Pedro C; Javiel, Gerardo; Pisciottano, Carmen; Grignola, Rosario; Jorge, Ana María; Gallino, Juan Pablo; Gasagoite, Jackeline; Cardoso, Horacio
2003-03-31
We studied HLA DQB1 allele frequencies and the relative risk (RR) of various genotypes in 72 type 1 diabetic patients and 40 control individuals in Uruguay. This is a tri-racial (Caucasian, Black and Indo-American) mixed population. The products of the polymerase chain reaction amplifications were hybridized with oligonucleotides by allele-specific oligonucleotide reverse or dot blot methods. Significant differences between these two groups were observed only for allele DQB1*0302 (35%, RR = 7.34, P<0.001). The frequency of the alleles carrying a non-aspartic acid residue at position 57 was significantly higher in the diabetic patients (85 vs 53%, P<0.001). In contrast, the frequency of Asp alleles was negatively associated with type 1 diabetes (RR = 0.20, P<0.001). The genotype DQB1*0302/DQB1*0201 (33%, RR = 5.41, P<0.05) was positively associated with this disease. The genotype frequencies associated with type 1 diabetes in our population were significantly different from what is known for Caucasian and Black populations as well as compared with another admixed population, from Chile.
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van Endert, P M; Lopez, M T; Patel, S D; Monaco, J J; McDevitt, H O
1992-01-01
Recently, two subunits of a large cytosolic protease and two putative peptide transporter proteins were found to be encoded by genes within the class II region of the major histocompatibility complex (MHC). These genes have been suggested to be involved in the processing of antigenic proteins for presentation by MHC class I molecules. Because of the high degree of polymorphism in MHC genes, and previous evidence for both functional and polypeptide sequence polymorphism in the proteins encoded by the antigen-processing genes, we tested DNA from 27 consanguineous human cell lines for genomic polymorphism by restriction fragment length polymorphism (RFLP) analysis. These studies demonstrate a strong linkage disequilibrium between TAP1 and LMP2 RFLPs. Moreover, RFLPs, as well as a polymorphic stop codon in the telomeric TAP2 gene, appear to be in linkage disequilibrium with HLA-DR alleles and RFLPs in the HLA-DO gene. A high rate of recombination, however, seems to occur in the center of the complex, between the TAP1 and TAP2 genes. Images PMID:1360671
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DEFF Research Database (Denmark)
Lamberth, K; Claesson, M H
2001-01-01
Early apoptosis in Jurkat T-lymphoma cells was induced by agonistic anti-Fas Ab or by anisomycin which activates the stress kinases SAPK/JNK. Apoptosis was inhibited by ligation of major histocompatibility complex class I antigens (MHC-I). MHC-I ligation induced upregulation of the anti-apoptotic......Early apoptosis in Jurkat T-lymphoma cells was induced by agonistic anti-Fas Ab or by anisomycin which activates the stress kinases SAPK/JNK. Apoptosis was inhibited by ligation of major histocompatibility complex class I antigens (MHC-I). MHC-I ligation induced upregulation of the anti......-apoptotic Bcl-2 protein and stabilized the mitochondrial membrane potential (Deltapsim). MHC-I ligation also prevented downregulation of Bcl-2 and destabilization of Deltapsim induced by anti-Fas Ab treatment or anisomycin exposure. Studies on three different Jurkat cell mutants deficient for src p56(lck), ZAP......-70 kinase, or TCR/CD3 gamma-chain showed that the cells undergo apoptosis after Fas ligation. Anisomycin exposure induced apoptosis in the src p56(lck)-deficient cell line but not in the two other mutant cell lines. Simultaneous cross-linking of MHC-I and Fas ligation inhibited apoptosis in the ZAP...
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HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency
DEFF Research Database (Denmark)
Han, Fang; Lin, Ling; Schormair, Barbara
2014-01-01
STUDY OBJECTIVES: To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02. SETTINGS: China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University o...
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Fox, B A; Drury, M; Hu, H M; Cao, Z; Huntzicker, E G; Qie, W; Urba, W J
1998-01-01
Direct intratumoral injection of a lipid/DNA complex encoding an allogeneic major histocompatibility complex (MHC) class I molecule leads to regression of both an immunogenic murine tumor and also melanoma lesions in some patients. We have sought to understand the mechanism(s) for this augmentation of antitumor activity. While optimizing parameters for in vitro gene transfer into the D5 subclone of B16BL6, it was noted that lipofected tumors not only expressed the new alloantigen but also exhibited increased expression of endogenous MHC class I, both H-2 Kb and H-2 Db. This increase in expression was not restricted to the small percentage of cells that expressed the transfected gene, but appeared to affect the majority of cells in culture. Class I expression was not increased by lipopolysaccharide, DNA alone, lipid, or lipid/lipopolysaccharide mixtures. Enhanced class I expression required a DNA/lipid complex and was greatest when parameters optimized for gene transfer of the alloantigen were used. All DNA plasmids tested had this effect, including one plasmid whose DNA was not transcribed because it lacked an expression cassette. Because of the critical role that MHC class I antigens play in immune recognition, we propose that lipid complex-mediated gene transfer may provide immunological advantages beyond those that are attributable to expression of the specific gene transferred.
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DEFF Research Database (Denmark)
Pedersen, Lasse Eggers; Harndahl, Mikkel; Rasmussen, Michael
2011-01-01
a HLA-I molecule (HLA-A*11:01), thereby generating recombinant human/swine chimeric MHC-I molecules as well as the intact SLA-1*0401 molecule. Biochemical peptide-binding assays and positional scanning combinatorial peptide libraries were used to analyze the peptide-binding motifs of these molecules....... A pan-specific predictor of peptide–MHC-I binding, NetMHCpan, which was originally developed to cover the binding specificities of all known HLA-I molecules, was successfully used to predict the specificities of the SLA-1*0401 molecule as well as the porcine/human chimeric MHC-I molecules. These data......In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules. These are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating CTLs. The polymorphism of the MHC...
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Lau, Quintin; Jobbins, Sarah E; Belov, Katherine; Higgins, Damien P
2013-01-01
Major histocompatibility complex (MHC) class II molecules have an integral role in the adaptive immune response, as they bind and present antigenic peptides to T helper lymphocytes. In this study of koalas, species-specific primers were designed to amplify exon 2 of the MHC class II DA and DB genes, which contain much of the peptide-binding regions of the α and β chains. A total of two DA α1 domain variants and eight DA β1 (DAB), three DB α1 and five DB β1 variants were amplified from 20 koalas from two free-living populations from South East Queensland and the Port Macquarie region in northern New South Wales. We detected greater variation in the β1 than in the α1 domains as well as evidence of positive selection in DAB. The present study provides a springboard to future investigation of the role of MHC in disease susceptibility in koalas.
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DEFF Research Database (Denmark)
Stryhn, A; Andersen, P S; Pedersen, L O
1996-01-01
Cytotoxic T cells recognize mosaic structures consisting of target peptides embedded within self-major histocompatibility complex (MHC) class I molecules. This structure has been described in great detail for several peptide-MHC complexes. In contrast, how T-cell receptors recognize peptide...... each other showing that peptide residues 1, 3, 4, 6, and 7 were exposed on the MHC surface and recognized by the T cells. Thus, the majority, and perhaps all, of the side chains of the non-primary anchor residues may be available for T-cell recognition, and contribute to the stringent specificity of T...... cells. A striking similarity between the specificity of the T cells and that of the pSAN antibody was found and most of the peptide residues, which could be recognized by the T cells, could also be recognized by the antibody....
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HLA-DQA1 and HLA-DQB1 allele diversity and its extended haplotypes in Madeira Island (Portugal).
Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A
2017-02-01
This study shows, for the first time, high-resolution allele frequencies of HLA-DQA1 loci in Madeira Island (Portugal) and allows us to better understand and refine present knowledge on DQB1 variation, with the identification of several alleles not previously reported in this population. Estimates on haplotype profile, involving HLA-A, HLA-B, HLA-DRB1, HLA-DQA1 and HLA-DQB1, are also reported. © 2016 John Wiley & Sons Ltd.
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International Nuclear Information System (INIS)
Spies, T.; Bresnahan, M.; Strominger, J.L.
1989-01-01
A 600-kilobase (kb) DNA segment from the human major histocompatibility complex (MHC) class III region was isolated by extension of a previous 435-kb chromosome walk. The contiguous series of cloned overlapping cosmids contains the entire 555-kb interval between C2 in the complement gene cluster and HLA-B. This region is known to encode the tumor necrosis factors (TNFs) α and β, B144, and the major heat shock protein HSP70. Moreover, a cluster of genes, BAT1-BAT5 (HLA-B-associated transcripts) have been localized in the vicinity of the genes for TNFα and TNFβ. An additional four genes were identified by isolation of corresponding cDNA clones with cosmid DNA probes. These genes for BAT6-BAT9 were mapped near the gene for C2 within a 120-kb region that includes a HSP70 gene pair. These results, together with complementary data from a similar recent study, indicated the presence of a minimum of 19 genes within the C2-HLA-B interval of the MHC class III region. Although the functional properties of most of these genes are yet unknown, they may be involved in some aspects of immunity. This idea is supported by the genetic mapping of the hematopoietic histocompatibility locus-1 (Hh-1) in recombinant mice between TNFα and H-2S, which is homologous to the complement gene cluster in humans
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Energy Technology Data Exchange (ETDEWEB)
Yuhki, Naoya; O' Brien, S.J. (National Cancer Institute, Frederick, MD (USA))
1990-01-01
The major histocompatibility complex (MHC) is a multigene complex of tightly linked homologous genes that encode cell surface antigens that play a key role in immune regulation and response to foreign antigens. In most species, MHC gene products display extreme antigenic polymorphism, and their variability has been interpreted to reflect an adaptive strategy for accommodating rapidly evolving infectious agents that periodically afflict natural populations. Determination of the extent of MHC variation has been limited to populations in which skin grafting is feasible or for which serological reagents have been developed. The authors present here a quantitative analysis of restriction fragment length polymorphism of MHC class I genes in several mammalian species (cats, rodents, humans) known to have very different levels of genetic diversity based on functional MHC assays and on allozyme surveys. When homologous class I probes were employed, a notable concordance was observed between the extent of MHC restriction fragment variation and functional MHC variation detected by skin grafts or genome-wide diversity estimated by allozyme screens. These results confirm the genetically depauperate character of the African cheetah, Acinonyx jubatus, and the Asiatic lion, Panthera leo persica; further, they support the use of class I MHC molecular reagents in estimating the extent and character of genetic diversity in natural populations.
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International Nuclear Information System (INIS)
Yuhki, Naoya; O'Brien, S.J.
1990-01-01
The major histocompatibility complex (MHC) is a multigene complex of tightly linked homologous genes that encode cell surface antigens that play a key role in immune regulation and response to foreign antigens. In most species, MHC gene products display extreme antigenic polymorphism, and their variability has been interpreted to reflect an adaptive strategy for accommodating rapidly evolving infectious agents that periodically afflict natural populations. Determination of the extent of MHC variation has been limited to populations in which skin grafting is feasible or for which serological reagents have been developed. The authors present here a quantitative analysis of restriction fragment length polymorphism of MHC class I genes in several mammalian species (cats, rodents, humans) known to have very different levels of genetic diversity based on functional MHC assays and on allozyme surveys. When homologous class I probes were employed, a notable concordance was observed between the extent of MHC restriction fragment variation and functional MHC variation detected by skin grafts or genome-wide diversity estimated by allozyme screens. These results confirm the genetically depauperate character of the African cheetah, Acinonyx jubatus, and the Asiatic lion, Panthera leo persica; further, they support the use of class I MHC molecular reagents in estimating the extent and character of genetic diversity in natural populations
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Gene duplication and fragmentation in the zebra finch major histocompatibility complex.
Balakrishnan, Christopher N; Ekblom, Robert; Völker, Martin; Westerdahl, Helena; Godinez, Ricardo; Kotkiewicz, Holly; Burt, David W; Graves, Tina; Griffin, Darren K; Warren, Wesley C; Edwards, Scott V
2010-04-01
Due to its high polymorphism and importance for disease resistance, the major histocompatibility complex (MHC) has been an important focus of many vertebrate genome projects. Avian MHC organization is of particular interest because the chicken Gallus gallus, the avian species with the best characterized MHC, possesses a highly streamlined minimal essential MHC, which is linked to resistance against specific pathogens. It remains unclear the extent to which this organization describes the situation in other birds and whether it represents a derived or ancestral condition. The sequencing of the zebra finch Taeniopygia guttata genome, in combination with targeted bacterial artificial chromosome (BAC) sequencing, has allowed us to characterize an MHC from a highly divergent and diverse avian lineage, the passerines. The zebra finch MHC exhibits a complex structure and history involving gene duplication and fragmentation. The zebra finch MHC includes multiple Class I and Class II genes, some of which appear to be pseudogenes, and spans a much more extensive genomic region than the chicken MHC, as evidenced by the presence of MHC genes on each of seven BACs spanning 739 kb. Cytogenetic (FISH) evidence and the genome assembly itself place core MHC genes on as many as four chromosomes with TAP and Class I genes mapping to different chromosomes. MHC Class II regions are further characterized by high endogenous retroviral content. Lastly, we find strong evidence of selection acting on sites within passerine MHC Class I and Class II genes. The zebra finch MHC differs markedly from that of the chicken, the only other bird species with a complete genome sequence. The apparent lack of synteny between TAP and the expressed MHC Class I locus is in fact reminiscent of a pattern seen in some mammalian lineages and may represent convergent evolution. Our analyses of the zebra finch MHC suggest a complex history involving chromosomal fission, gene duplication and translocation in the
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Gene duplication and fragmentation in the zebra finch major histocompatibility complex
Directory of Open Access Journals (Sweden)
Burt David W
2010-04-01
Full Text Available Abstract Background Due to its high polymorphism and importance for disease resistance, the major histocompatibility complex (MHC has been an important focus of many vertebrate genome projects. Avian MHC organization is of particular interest because the chicken Gallus gallus, the avian species with the best characterized MHC, possesses a highly streamlined minimal essential MHC, which is linked to resistance against specific pathogens. It remains unclear the extent to which this organization describes the situation in other birds and whether it represents a derived or ancestral condition. The sequencing of the zebra finch Taeniopygia guttata genome, in combination with targeted bacterial artificial chromosome (BAC sequencing, has allowed us to characterize an MHC from a highly divergent and diverse avian lineage, the passerines. Results The zebra finch MHC exhibits a complex structure and history involving gene duplication and fragmentation. The zebra finch MHC includes multiple Class I and Class II genes, some of which appear to be pseudogenes, and spans a much more extensive genomic region than the chicken MHC, as evidenced by the presence of MHC genes on each of seven BACs spanning 739 kb. Cytogenetic (FISH evidence and the genome assembly itself place core MHC genes on as many as four chromosomes with TAP and Class I genes mapping to different chromosomes. MHC Class II regions are further characterized by high endogenous retroviral content. Lastly, we find strong evidence of selection acting on sites within passerine MHC Class I and Class II genes. Conclusion The zebra finch MHC differs markedly from that of the chicken, the only other bird species with a complete genome sequence. The apparent lack of synteny between TAP and the expressed MHC Class I locus is in fact reminiscent of a pattern seen in some mammalian lineages and may represent convergent evolution. Our analyses of the zebra finch MHC suggest a complex history involving
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Villarroel-Dorrego, Mariana; Speight, Paul M; Barrett, A William
2005-01-01
Recognition in the 1980 s that keratinocytes can express class II molecules of the Major Histocompatibility Complex (MHC) first raised the possibility that these cells might have an immunological function, and may even act as antigen presenting cells (APC). For effective T lymphocyte activation, APC require, in addition to MHC II, appropriate costimulatory signals. The aim of this study was to determine the expression of MHC class II and the co-stimulatory molecules CD40, CD80 and CD86 in keratinocytes derived from healthy oral mucosa and oral carcinomas. Using flow cytometry, it was confirmed that oral keratinocytes, switch on, expression of MHC class II molecules after stimulation with IFNgamma in vitro. All keratinocyte lines expressed CD40 constitutively; by contrast, CD80 and CD86 were universally absent. Loss of CD80 and CD86 may be one means whereby tumours escape immunological surveillance.
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Detection of autoreactive CD4 T cells using major histocompatibility complex class II dextramers
Directory of Open Access Journals (Sweden)
Kuszynski Charles
2011-07-01
Full Text Available Abstract Background Tetramers are useful tools to enumerate the frequencies of antigen-specific T cells. However, unlike CD8 T cells, CD4 T cells - especially self-reactive cells - are challenging to detect with major histocompatibility complex (MHC class II tetramers because of low frequencies and low affinities of their T cell receptors to MHC-peptide complexes. Here, we report the use of fluorescent multimers, designated MHC dextramers that contain a large number of peptide-MHC complexes per reagent. Results The utility of MHC dextramers was evaluated in three autoimmune disease models: 1 proteolipid protein (PLP 139-151-induced experimental autoimmune encephalomyelitis in SJL/J (H-2s mice; 2 myelin oligodendrocyte glycoprotein (MOG 35-55-induced experimental autoimmune encephalomyelitis in C57Bl/6 (H-2b mice; and 3 cardiac myosin heavy chain (Myhc-α 334-352-induced experimental autoimmune myocarditis in A/J (H-2a mice. Flow cytometrically, we demonstrate that IAs/PLP 139-151, IAb/MOG 35-55 and IAk/Myhc-α 334-352 dextramers detect the antigen-sensitized cells with specificity, and with a detection sensitivity significantly higher than that achieved with conventional tetramers. Furthermore, we show that binding of dextramers, but not tetramers, is less dependent on the activation status of cells, permitting enumeration of antigen-specific cells ex vivo. Conclusions The data suggest that MHC dextramers are useful tools to track the generation and functionalities of self-reactive CD4 cells in various experimental systems.
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HLA –DRB1*, DQB1* Alleles In Hydatid Patients By Molecular Typing
Directory of Open Access Journals (Sweden)
mehdi Mosayebi
2007-10-01
Full Text Available Mosayebi M1, Dalimi Asl A2, Moazeni M3, Mosayebi Gh4 1. Ph.D Student, Department of Parasitology, Faculty of medicine, Tarbiat Modarres University 2. Professor, Department of Parasitology, Faculty of medicine, Tarbiat Modarres University 3. Professor, Department of Immunology, Faculty of medicine, Tarbiat Modarres University 4. Assistant professor, Department of Immunology, Faculty of medicine, Arak Medical Sciences University Abstract Background: Hydatidosis is a important disease that results from infection with larvae of the dog tape worm , Echinococcus granulosus in human and farm animals .Resistance or susceptibility to infectious diseases , for example , cystic and alveolar echinococcosis is restricted by individual host factors and immunologic responses,in many surveys has been shown.The target of this study that is the first survey dealing with the correlation between HLA-DRB1*& DQB1* alleles and cystic echinococcosis in Iranian patient,is investigation HLA-DRB1*and DQB1* allelic polymorphism in Iranian patient with hydatidosis . Materials and methods: The study was carried out on 56 patients with confirmed cystic echinococcosis and 30 apparently healthy individuals living on Arak area by HLA-DRB1*& DQB1* typing with PCR-SSP method.The first step was founding patients and blood sampling .DNA was prepared from whole blood and we used PCR-SSP with 31 primer mixes for per sample . PCR reaction mixtures were loaded in agarose gels and after electrophoresis , geles were examine under UV illumination and gel document . Analyse of results carried out with specific software and frequency& interpretation tables and homogeneity test for calculation of P-value in χ2 test with fisher΄s exact test . significant samples with logistic regression analysed and Odds-ratio calculate . Results: A statistically significant positive association was found between HLA-DQB1*02 and the occurrence of cystic echinococcosis(P<0.05,(Odds-ratio=2.87 Conclusion: The
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Directory of Open Access Journals (Sweden)
Megiorni Francesca
2012-10-01
Full Text Available Abstract Celiac disease (CD is a multifactorial disorder with an estimated prevalence in Europe and USA of 1:100 and a female:male ratio of approximately 2:1. The disorder has a multifactorial etiology in which the triggering environmental factor, the gluten, and the main genetic factors, Human Leukocyte Antigen (HLA-DQA1 and HLA-DQB1 loci, are well known. About 90-95% of CD patients carry DQ2.5 heterodimers, encoded by DQA1*05 and DQB1*02 alleles both in cis or in trans configuration, and DQ8 molecules, encoded by DQB1*03:02 generally in combination with DQA1*03 variant. Less frequently, CD occurs in individuals positive for the DQ2.x heterodimers (DQA1≠*05 and DQB1*02 and very rarely in patients negative for these DQ predisposing markers. HLA molecular typing for Celiac disease is, therefore, a genetic test with a negative predictive value. Nevertheless, it is an important tool able to discriminate individuals genetically susceptible to CD, especially in at-risk groups such as first-degree relatives (parents, siblings and offspring of patients and in presence of autoimmune conditions (type 1 diabetes, thyroiditis, multiple sclerosis or specific genetic disorders (Down, Turner or Williams syndromes.
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Genetic diversity of Cahi DRB and DQB genes of caprine MHC class ...
Indian Academy of Sciences (India)
G. R. Gowane
2018-05-31
May 31, 2018 ... of 16 of the 89 amino acid residue sites in DRB and 19 of 86 residue sites in DQB1 had more than three amino acid substitutions. Positive evolutionary ... substantially substitute the coding amino acid and ulti- ...... Health Prod.
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DEFF Research Database (Denmark)
Oleksiewicz, M.B.; Kristensen, B.; Ladekjaer-Mikkelsen, A.S.
2002-01-01
The extracellular domains of swine leukocyte antigen class I (SLA-I, major histocompatibility complex protein class 1) were cloned and sequenced for two haplotypes (114 and H7) which do not share any alleles based on serological typing, and which are the most important in Danish farmed pigs...
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Odour-based discrimination of similarity at the major histocompatibility complex in birds.
Leclaire, Sarah; Strandh, Maria; Mardon, Jérôme; Westerdahl, Helena; Bonadonna, Francesco
2017-01-11
Many animals are known to preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) in order to maximize the antigen binding repertoire (or disease resistance) in their offspring. Although several mammals, fish or lizards use odour cues to assess MHC similarity with potential partners, the ability of birds to assess MHC similarity using olfactory cues has not yet been explored. Here we used a behavioural binary choice test and high-throughput-sequencing of MHC class IIB to determine whether blue petrels can discriminate MHC similarity based on odour cues alone. Blue petrels are seabirds with particularly good sense of smell, they have a reciprocal mate choice and are known to preferentially mate with MHC-dissimilar partners. Incubating males preferentially approached the odour of the more MHC-dissimilar female, whereas incubating females showed opposite preferences. Given their mating pattern, females were, however, expected to show preference for the odour of the more MHC-dissimilar male. Further studies are needed to determine whether, as in women and female mice, the preference varies with the reproductive cycle in blue petrel females. Our results provide the first evidence that birds can use odour cues only to assess MHC dissimilarity. © 2017 The Author(s).
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Wei, Wen-Hua; Bowes, John; Plant, Darren; Viatte, Sebastien; Yarwood, Annie; Massey, Jonathan; Worthington, Jane; Eyre, Stephen
2016-04-25
Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P 5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals.
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DEFF Research Database (Denmark)
Iacovakis, Christos; Mamuris, Zissis; Moutou, Katerina A
2013-01-01
A study was conducted in order to determine the occurrence of European Brown Hare Syndrome virus (EBHSV) in Denmark and possible relation between disease pathogenesis and Major Histocompatibility Complex (MHC) host genotype. Liver samples were examined from 170 brown hares (hunted, found sick...... were found to be EBHSV-positive (RT-PCR, VP60 gene). In order to investigate associations between viral pathogenesis and host genotype, variation within the exon 2 DQA gene of MHC was assessed. DQA exon 2 analysis revealed the occurrence of seven different alleles in Denmark. Consistent with other...... populations examined so far in Europe, observed heterozygosity of DQA (H o = 0.1180) was lower than expected (H e = 0.5835). The overall variation for both nucleotide and amino acid differences (2.9% and 14.9%, respectively) were lower in Denmark than those assessed in other European countries (8.3% and 16...
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Directory of Open Access Journals (Sweden)
Shamilevna Avzaletdinova
2012-09-01
Full Text Available Aims. To estimate significance of HLA II DRB1 and DRB2 allele variants for development of type 1 diabetes mellitus (T1DM in Bashkortostanpopulation (ethnical Russians, Tatar, Bashkir. Materials and methods. We analyzed DNA of 323 patients with T1DM and 683 healthy controls. DNA was derived from venous bloodsamples by phenol-chloroform extraction. DRB1 and DQB1 gene typing was performed by PCR method. Amplification products wereidentified with electrophoresis on a 1% agarose gel. Statistica for Windows v6.0 and MS Excel 98 software were applied for statisticalprocessing of acquired data. Results. Common markers of high risk for T1DM were found to be DRB1*04, DRB1*17, genotype DRB1*04/*17. On the contrary,lower risk was associated with DRB1*15 allele. In ethnical Russians lower risk of T1DM is also determined by DRB1*11 allele andDRB1*01 in Tatars. Predisposition by DQB1-alleles in Russians and Bashkir realizes only within DRB1*04/*17 genotype. However,in Tatar subpopulation DQB1*0302 is an independent risk marker of T1DM development. Conclusion. Common low risk markers for all three ethnic groups are DQB1*0301, DQB1*0602-08 alleles. Their presence negates riskof disease in all studied subpopulations even within DRB1*04/*17-genotype.
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DEFF Research Database (Denmark)
Kaufman, J; Salomonsen, J; Skjødt, K
1990-01-01
B-G antigens are cell-surface molecules encoded by a highly polymorphic multigene family located in the chicken major histocompatibility complex (MHC). Rabbit antisera to B-G molecules immunoprecipitate 3-6 bands from iodinated erythrocytes by sodium dodecyl sulfate (SDS) gels under reducing......, which bear intrachain disulfide bonds. All 3-6 bands have different mobilities in SDS gels between different haplotypes, ranging from 30 to 55 kDa. This size polymorphism is not affected by glycosidase treatment or addition of protease inhibitors. Partial proteolysis of cell surface-iodinated B...
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Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L.
2010-01-01
Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of…
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Recombinational hotspot specific to female meiosis in the mouse major histocompatibility complex.
Shiroishi, T; Hanzawa, N; Sagai, T; Ishiura, M; Gojobori, T; Steinmetz, M; Moriwaki, K
1990-01-01
The wm7 haplotype of the major histocompatibility complex (MHC), derived from the Japanese wild mouse Mus musculus molossinus, enhances recombination specific to female meiosis in the K/A beta interval of the MHC. We have mapped crossover points of fifteen independent recombinants from genetic crosses of the wm7 and laboratory haplotypes. Most of them were confined to a short segment of approximately 1 kilobase (kb) of DNA between the A beta 3 and A beta 2 genes, indicating the presence of a female-specific recombinational hotspot. Its location overlaps with a sex-independent hotspot previously identified in the Mus musculus castaneus CAS3 haplotype. We have cloned and sequenced DNA fragments surrounding the hotspot from the wm7 haplotype and the corresponding regions from the hotspot-negative B10.A and C57BL/10 strains. There is no significant difference between the sequences of these three strains, or between these and the published sequences of the CAS3 and C57BL/6 strains. However, a comparison of this A beta 3/A beta 2 hotspot with a previously characterized hotspot in the E beta gene revealed that they have a very similar molecular organization. Each hotspot consists of two elements, the consensus sequence of the mouse middle repetitive MT family and the tetrameric repeated sequences, which are separated by 1 kb of DNA.
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Directory of Open Access Journals (Sweden)
Sergio E. Rivera-Pirela
2016-08-01
Full Text Available Background: The HLA complex is involved in the pathogenesis of leukemia. Objectives: The presence of class II HLA alleles DRB1 *, DQB1 *, DPA1 *, and DPB1 * was evaluated in 47 patients with acute lymphoblastic leukemia (ALL and 48 with chronic myeloid leukemia (CML for comparison with 48 healthy volunteers in Zulia, Venezuela, and to evaluate potential associations of HLA with leukemia. Methods: Low- and high-resolution PCR-SSP was used for class II HLA regions DRB1 *, DQB1 *, DPA1 *, and DPB1 * following the instructions of KIT Olerup SSP Genovision. Results: Alleles HLA-DRB1*14, especially DRB1*14:21, -DPA1*1:06, -DPA1*01:03,-DPA1*02:01, and the haplotypes HLA-DPA1*01:03-DPB1*04:01, DPA1*01:03-DPB1*02:01, DPA1*01:03-DPB1*99:01, -DRB1*14-DPA1*01:03, -DRB1*15-DPA1*01:03 were associated with CML (RR > 3; alleles HLA-DRB1*13, -DQB1*02, -DPA1*01:05, -DPA1*01:09 and the haplotypes HLA-DPA1*01:09-DPB1*02:01, DPA1*01:09-DPB1*04:01 were protective (RR < 1. Alleles HLA-DQB1*04, -DQB1*05, -DPA1*1:06, -DPA1*01:07, -DPA1*1:08 had a positive association with ALL. Alleles HLA-DPA1*01:09, -DPA1*02:01, -DPB1*02:01, -DPB1*03:01 and the haplotypes HLA-DPA1*01:03-DPB1*04:02, -DPA1*01:09-DPB1*02:01, -DPA1*01:09-DPB1*04:01, -DPA1*02:01-DPB1*04:02 were negatively associated. Conclusions: The absence of associations with HLA-DRB1 * region in ALL and other association patterns identified suggest marked differences in the pathogenesis of leukemia, which suggests possible deficiencies in antigen presentation for ALL or potential effects of molecular mimicry in CML.
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Shimomura-Kuroki, Junko; Yamashita, Kie; Shimooka, Shohachi
2009-01-01
Periodontal disease is a multiple factor disease caused by genetic factors, environmental factors, and periodontal bacteria (periodontal pathogens). The present study aimed to elucidate the risk factors for periodontal disease in Japanese adolescents. Subjects (11-16 years old) were classified into three groups: localized aggressive periodontitis (LAP), periodontal attachment loss (PAL), and periodontally healthy (PH) groups. Genomic DNA isolated from the buccal mucosa was used for single-nucleotide polymorphism analyses of the candidate genes (interleukin-1alpha-889; interleukin-1alpha +4845; interleukin-1beta +3954; an immunoglobulin G Fc gamma receptor, FcgammaRIIa-R/H131; and a human leukocyte antigen class II allele, HLA-DQB1) of aggressive periodontitis. Subgingival plaque samples obtained from the same subjects were used for 16S rRNAbased polymerase chain reaction analysis of five important periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Tannerella forsythia). Tannerella forsythia was detected in the deepest periodontal pockets in all subjects in the LAP and PAL groups. The prevalence of an atypical BamHI restriction site in HLA-DQB1 of the LAP group was significantly higher than that in the PH and PAL groups. Furthermore, all subjects who had the atypical BamHI restriction site in HLA-DQB1 had T. forsythia infection. These results suggested that T. forsythia is associated with periodontal disease in Japanese adolescents and also suggested that HLA-DQB1 is related to LAP and is associated with T. forsythia infection.
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Papadopoulou, A.; Lynch, K. F.; Shaat, N.; Håkansson, R.; Ivarsson, S. A.; Berntorp, K.; Agardh, C. D.; Lernmark, Å
2011-01-01
Aims To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. Methods We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. Results The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P gestational diabetes in mothers born in Sweden (P = 0.010). Conclusions The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden. PMID:21672010
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National Research Council Canada - National Science Library
Bowen, Lizabeth
2002-01-01
.... Five unique Zaca-DQA sequences and eight unique Zaca-DQB sequences, all encoding functional proteins, were identified in the two animals, indicating the presence of multiple DQ- loci in this species...
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Berglund, A K; Schnabel, L V
2017-07-01
Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Experimental controlled study. Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. This study examined MSC death in vitro only and utilized antisera from a small number of horses. The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death. © 2016 The
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Bartl, S; Weissman, I L
1994-01-04
The major histocompatibility complex (MHC) contains a set of linked genes which encode cell surface proteins involved in the binding of small peptide antigens for their subsequent recognition by T lymphocytes. MHC proteins share structural features and the presence and location of polymorphic residues which play a role in the binding of antigens. In order to compare the structure of these molecules and gain insights into their evolution, we have isolated two MHC class IIB genes from the nurse shark, Ginglymostoma cirratum. Two clones, most probably alleles, encode proteins which differ by 13 amino acids located in the putative antigen-binding cleft. The protein structure and the location of polymorphic residues are similar to their mammalian counterparts. Although these genes appear to encode a typical MHC protein, no T-cell-mediated responses have been demonstrated in cartilaginous fish. The nurse shark represents the most phylogenetically primitive organism in which both class IIA [Kasahara, M., Vazquez, M., Sato, K., McKinney, E.C. & Flajnik, M.F. (1992) Proc. Natl. Acad. Sci USA 89, 6688-6692] and class IIB genes, presumably encoding the alpha/beta heterodimer, have been isolated.
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Evolutionary Analysis of Minor Histocompatibility Genes In Hydra
Aalismail, Nojood
2016-01-01
In the present study we took initiative to study the self/nonself recognition in hydra and its relation to the immune response. Moreover, performing phylogenetic analysis to look for annotated immune genes in hydra gave us a potential to analyze the expression of minor histocompatibility genes that have been shown to play a major role in grafting and transplantation in mammals. Here we obtained the cDNA library that shows expression of minor histocompatibility genes and confirmed that the annotated sequences in databases are actually present. In addition, grafting experiments suggested, although still preliminary, that homograft showed less rejection response than in heterograft. Involvement of possible minor histocompatibility gene orthologous in immune response was examined by qPCR.
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DEFF Research Database (Denmark)
Sainudiin, Raazesh; Wong, Wendy Shuk Wan; Yogeeswaran, Krithika
2005-01-01
:transversion biases. Here, we apply this method to two positively selected receptors involved in ligand-recognition: the class I alleles of the human major histocompatibility complex (MHC) of known structure and the S-locus receptor kinase (SRK) of the sporophytic self-incompatibility system (SSI) in cruciferous...... Bayes approach is used to identify sites that may be important for ligand recognition in these proteins....
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Directory of Open Access Journals (Sweden)
Barbara Lukasch
2017-08-01
Full Text Available Background A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA or heterozygosity at the MHC are more important. Methods To do this we used captive house sparrows (Passer domesticus to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Results Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral were associated with several different alleles. Discussion We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.
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Lukasch, Barbara; Westerdahl, Helena; Strandh, Maria; Winkler, Hans; Moodley, Yoshan; Knauer, Felix; Hoi, Herbert
2017-01-01
A well-functioning immune defence is crucial for fitness, but our knowledge about the immune system and its complex interactions is still limited. Major histocompatibility complex (MHC) molecules are involved in T-cell mediated adaptive immune responses, but MHC is also highly upregulated during the initial innate immune response. The aim of our study was therefore to determine to what extent the highly polymorphic MHC is involved in interactions of the innate and adaptive immune defence and if specific functional MHC alleles (FA) or heterozygosity at the MHC are more important. To do this we used captive house sparrows ( Passer domesticus ) to survey MHC diversity and immune function controlling for several environmental factors. MHC class I alleles were identified using parallel amplicon sequencing and to mirror immune function, several immunological tests that correspond to the innate and adaptive immunity were conducted. Our results reveal that MHC was linked to all immune tests, highlighting its importance for the immune defence. While all innate responses were associated with one single FA, adaptive responses (cell-mediated and humoral) were associated with several different alleles. We found that repeated injections of an antibody in nestlings and adults were linked to different FA and hence might affect different areas of the immune system. Also, individuals with a higher number of different FA produced a smaller secondary response, indicating a disadvantage of having numerous MHC alleles. These results demonstrate the complexity of the immune system in relation to the MHC and lay the foundation for other studies to further investigate this topic.
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Energy Technology Data Exchange (ETDEWEB)
Burrows, Scott R.; Chen, Zhenjun; Archbold, Julia K.; Tynan, Fleur E.; Beddoe, Travis; Kjer-Nielsen, Lars; Miles, John J.; Khanna, Rajiv; Moss, Denis J.; Liu, Yu Chih; Gras, Stephanie; Kostenko, Lyudmila; Brennan, Rebekah M.; Clements, Craig S.; Brooks, Andrew G.; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie (Monash); (Queensland Inst. of Med. Rsrch.); (Melbourne)
2010-07-07
{alpha}{beta} T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementarity-determining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.
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Directory of Open Access Journals (Sweden)
Daiki Miki
Full Text Available Hepatitis C virus (HCV establishes a chronic infection in 70-80% of infected individuals. Many researchers have examined the effect of human leukocyte antigen (HLA on viral persistence because of its critical role in the immune response against exposure to HCV, but almost all studies have proven to be inconclusive. To identify genetic risk factors for chronic HCV infection, we analyzed 458,207 single nucleotide polymorphisms (SNPs in 481 chronic HCV patients and 2,963 controls in a Japanese cohort. Next, we performed a replication study with an independent panel of 4,358 cases and 1,114 controls. We further confirmed the association in 1,379 cases and 25,817 controls. In the GWAS phase, we found 17 SNPs that showed suggestive association (P < 1 × 10⁻⁵. After the first replication study, we found one intronic SNP in the HLA-DQ locus associated with chronic HCV infection, and when we combined the two studies, the association reached the level of genome-wide significance. In the second replication study, we again confirmed the association (P(combined = 3.59 × 10⁻¹⁶, odds ratio [OR] = 0.79. Subsequent analysis revealed another SNP, rs1130380, with a stronger association (OR=0.72. This nucleotide substitution causes an amino acid substitution (R55P in the HLA-DQB1 protein specific to the DQB1*03 allele, which is common worldwide. In addition, we confirmed an association with the previously reported IFNL3-IFNL4 locus and propose that the effect of DQB1*03 on HCV persistence might be affected by the IFNL4 polymorphism. Our findings suggest that a common amino acid substitution in HLA-DQB1 affects susceptibility to chronic infection with HCV in the Japanese population and may not be independent of the IFNL4 genotype.
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Westerdahl, Helena; Asghar, Muhammad; Hasselquist, Dennis; Bensch, Staffan
2012-02-07
We outline a descriptive framework of how candidate alleles of the immune system associate with infectious diseases in natural populations of animals. Three kinds of alleles can be separated when both prevalence of infection and infection intensity are measured--qualitative disease resistance, quantitative disease resistance and susceptibility alleles. Our descriptive framework demonstrates why alleles for quantitative resistance and susceptibility cannot be separated based on prevalence data alone, but are distinguishable on infection intensity. We then present a case study to evaluate a previous finding of a positive association between prevalence of a severe avian malaria infection (GRW2, Plasmodium ashfordi) and a major histocompatibility complex (MHC) class I allele (B4b) in great reed warblers Acrocephalus arundinaceus. Using the same dataset, we find that individuals with allele B4b have lower GRW2 infection intensities than individuals without this allele. Therefore, allele B4b provides quantitative resistance rather than increasing susceptibility to infection. This implies that birds carrying B4b can mount an immune response that suppresses the acute-phase GRW2 infection, while birds without this allele cannot and may die. We argue that it is important to determine whether MHC alleles related to infections are advantageous (quantitative and qualitative resistance) or disadvantageous (susceptibility) to obtain a more complete picture of pathogen-mediated balancing selection.
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1984-01-01
Human T cell clones and a cDNA probe specific for constant regions of the beta subunit of the antigen/major histocompatibility complex (MHC) receptor, TiC beta 1 and TiC beta 2, were employed to determine whether these genes were differentially used by functional classes of T lymphocytes. DNA from 10 interleukin-2-dependent T cell clones including class I and class II MHC-specific cytotoxic T lymphocytes (n = 6), T4+ inducer T lymphocytes (n = 2), and T8+ suppressor T lymphocytes (n = 2) show...
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DEFF Research Database (Denmark)
Eyler, Y L; Pfau, C J; Broomhall, K S
1989-01-01
with the recessive disease phenotype. In all cases, susceptibility was dominant. In backcross progeny obtained from matings of parental strains differing in both major histocompatibility complex (MHC) and non-MHC (SWR; C3H), 90% of the challenged mice died, indicating that at least three loci controlled...... susceptibility to the disease. When the parental strains carried similar MHC haplotypes but dissimilar background genes (B10.BR; CBA), 78% of the backcross mice succumbed, indicating that at least two non-MHC loci influenced disease susceptibility. It is unlikely, however, that the same two non-MHC loci...... are critical in all genetic combinations, since F1 produced from two H-2 identical, resistant strains (B10.BR; C3H) were found to be fully susceptible. When congenic mice, differing only in the D-end of the MHC region, were analysed, 50% of the backcross animals died, indicating that one gene in the MHC region...
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DNA polymorphism of HLA class II genes in primary biliary cirrhosis
DEFF Research Database (Denmark)
Morling, Niels; Dalhoff, K; Fugger, L
1992-01-01
We investigated the DNA restriction fragment length polymorphism of the major histocompatibility complex class II genes: HLA-DRB, -DQA, -DQB, DPA, -DPB, the serologically defined HLA-A, B, C, DR antigens, and the primed lymphocyte typing defined HLA-DP antigens in 23 Danish patients with primary...... than 0.05, 'corrected' P greater than 0.05). No DNA fragments specific for DRB1*0301 (DR3) could be identified. The frequencies in PBC of other genetic markers including DRw8, DRB1*08, HLA-DP antigens, DPA, and DPB genes did not differ significantly from those in controls. The associations between PBC...
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Eichhorn, M; Prospero, T D; Heussler, Volker; Dobbelaere, D A
1993-01-01
We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti- MHC class II Abs is not due to interference with the state of activation of the T cel...
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Simske, Steven J.; Bateman, Ted A.; Smith, Erin E.; Ferguson, Virginia L.; Chapes, Stephen K.
2002-01-01
We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls.
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DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status
DEFF Research Database (Denmark)
Weiner Lachmi, Karin; Lin, Ling; Kornum, Birgitte Rahbek
2012-01-01
The association of narcolepsy-cataplexy, a sleep disorder caused by the loss of hypocretin/orexin neurons in the hypothalamus, with DQA1*01:02-DQB1*06:02 is one of the tightest known single-allele human leukocyte antigen (HLA) associations. In this study, we explored genome-wide expression...
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Blood parasites shape extreme major histocompatibility complex diversity in a migratory passerine.
Biedrzycka, Aleksandra; Bielański, Wojciech; Ćmiel, Adam; Solarz, Wojciech; Zając, Tadeusz; Migalska, Magdalena; Sebastian, Alvaro; Westerdahl, Helena; Radwan, Jacek
2018-06-01
Pathogens are one of the main forces driving the evolution and maintenance of the highly polymorphic genes of the vertebrate major histocompatibility complex (MHC). Although MHC proteins are crucial in pathogen recognition, it is still poorly understood how pathogen-mediated selection promotes and maintains MHC diversity, and especially so in host species with highly duplicated MHC genes. Sedge warblers (Acrocephalus schoenobaenus) have highly duplicated MHC genes, and using data from high-throughput MHC genotyping, we were able to investigate to what extent avian malaria parasites explain temporal MHC class I supertype fluctuations in a long-term study population. We investigated infection status and infection intensities of two different strains of Haemoproteus, that is avian malaria parasites that are known to have significant fitness consequences in sedge warblers. We found that prevalence of avian malaria in carriers of specific MHC class I supertypes was a significant predictor of their frequency changes between years. This finding suggests that avian malaria infections partly drive the temporal fluctuations of the MHC class I supertypes. Furthermore, we found that individuals with a large number of different supertypes had higher resistance to avian malaria, but there was no evidence for an optimal MHC class I diversity. Thus, the two studied malaria parasite strains appear to select for a high MHC class I supertype diversity. Such selection may explain the maintenance of the extremely high number of MHC class I gene copies in sedge warblers and possibly also in other passerines where avian malaria is a common disease. © 2018 John Wiley & Sons Ltd.
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Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC Genes.
Directory of Open Access Journals (Sweden)
Maciej Jan Ejsmond
2015-11-01
Full Text Available Major Histocompatibility Complex (MHC genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS are positively selected. This is attributed to pathogen-driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process. Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation.
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DEFF Research Database (Denmark)
Röpke, M; Röpke, C; Claesson, Mogens Helweg
1993-01-01
Murine T splenocytes stimulated in primary allogeneic mixed lymphocyte culture (MLC) were incubated with soluble anti-major histocompatibility complex (MHC) class I monoclonal antibodies. These antibodies induced inhibition in the cytotoxicity of the responding population and this inhibition...... was not dependent on the domain on class I molecules recognized by the antibodies. Cross-reactivity of the antibodies between the responder and stimulating cell population caused a marked reduction in the inhibitory effect compared to systems where no such cross-reactivity was present. Saturating levels...... of the antibodies caused a reduction in generation of T-cell cytotoxicity, whereas low concentrations stimulated the same response. These results demonstrate that the MHC class I molecules of T cells are of significant importance in antigen-induced signal transduction....
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Knight, Jo; Spain, Sarah L; Capon, Francesca; Hayday, Adrian; Nestle, Frank O; Clop, Alex; Barker, Jonathan N; Weale, Michael E; Trembath, Richard C
2012-12-01
Psoriasis is a common, chronic, inflammatory skin disorder. A number of genetic loci have been shown to confer risk for psoriasis. Collectively, these offer an integrated model for the inherited basis for susceptibility to psoriasis that combines altered skin barrier function together with the dysregulation of innate immune pathogen sensing and adap-tive immunity. The major histocompatibility complex (MHC) harbours the psoriasis susceptibility region which exhibits the largest effect size, driven in part by variation contained on the HLA-Cw*0602 allele. However, the resolution of the number and genomic location of potential independent risk loci are hampered by extensive linkage disequilibrium across the region. We leveraged the power of large psoriasis case and control data sets and the statistical approach of conditional analysis to identify potential further association signals distributed across the MHC. In addition to the major loci at HLA-C (P = 2.20 × 10(-236)), we observed and replicated four additional independent signals for disease association, three of which are novel. We detected evidence for association at SNPs rs2507971 (P = 6.73 × 10(-14)), rs9260313 (P = 7.93 × 10(-09)), rs66609536 (P = 3.54 × 10(-07)) and rs380924 (P = 6.24 × 10(-06)), located within the class I region of the MHC, with each observation replicated in an independent sample (P ≤ 0.01). The previously identified locus is close to MICA, the other three lie near MICB, HLA-A and HCG9 (a non-coding RNA gene). The identification of disease associations with both MICA and MICB is particularly intriguing, since each encodes an MHC class I-related protein with potent immunological function.
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Directory of Open Access Journals (Sweden)
Fernando Morgadinho Santos Coelho
2009-03-01
Full Text Available OBJECTIVE: Narcolepsy (with and without cataplexy and idiopathic hypersomnia, are disorders with common features but with different HLA-DQB1*0602 allele prevalence. The present study describes the prevalence of HLA-DQB1*0602 allele in narcoleptics with and without cataplexy and in patients with idiopathic hypersomnia. METHOD: Subjects comprised 68 patients who were diagnosed for narcolepsy or idiopathic hypersomnia and 23 healthy controls according to the International Classification of Sleep Disorders-2. Subjects comprised 43 patients with narcolepsy and cataplexy, 11 patients with narcolepsy but without cataplexy, 14 patients with idiopathic hypersomnia and 23 healthy controls. Genotyping of HLA-DQB1*0602 allele was performed for all subjects. RESULTS: The prevalence of the HLA-DQB1*0602 allele was increased in idiopathic hypersomnia and in narcoleptic patients with and without cataplexy when compared to healthy subjects (p = 0.04; p = 0.03 and p OBJETIVO: Narcolepsia (com e sem cataplexia e hipersonolência idiopática são transtornos com características clínicas comuns, mas com prevalências do alelo HLA-DQB1*0602 diferentes. Este estudo descreve a prevalência do alelo HLA-DQB1*0602 em pacientes narcolépticos com e sem cataplexia e em pacientes com hipersonolência idiopática. MÉTODO: A amostra consistiu de 68 pacientes com diagnóstico de narcolepsia ou hipersonolência idiopática e 23 controles saudáveis segundo o International Classification of Sleep Disorders-2. A amostra foi composta de 43 pacientes com narcolepsia e cataplexia, 11 pacientes com narcolepsia e sem cataplexia, 14 pacientes com hipersonolência idiopática e 23 controles saudáveis. A análise da presença do alelo HLA-DQ*0602 foi realizada em todos os sujeitos. RESULTADOS: A prevalência do alelo HLA-DQB1*0602 foi maior nos grupos de pacientes com hipersonolência idiopática e em pacientes narcolépticos com e sem cataplexia quando comparada com a dos sujeitos
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The major histocompatibility complex genes impact pain response in DA and DA.1U rats.
Guo, Yuan; Yao, Fan-Rong; Cao, Dong-Yuan; Li, Li; Wang, Hui-Sheng; Xie, Wen; Zhao, Yan
2015-08-01
Our recent studies have shown that the difference in basal pain sensitivity to mechanical and thermal stimulation between Dark-Agouti (DA) rats and a novel congenic DA.1U rats is major histocompatibility complex (MHC) genes dependent. In the present study, we further used DA and DA.1U rats to investigate the role of MHC genes in formalin-induced pain model by behavioral, electrophysiological and immunohistochemical methods. Behavioral results showed biphasic nociceptive behaviors increased significantly following the intraplantar injection of formalin in the hindpaw of DA and DA.1U rats. The main nociceptive behaviors were lifting and licking, especially in DA rats (PDA rats were significantly higher than those in DA.1U rats in both phases of the formalin test (PDA rats was significantly higher than that of DA.1U rats (PDA was greater than that in DA.1U rats (PDA rats was significantly higher than that in DA.1U rats in the respective experimental group (PDA and DA.1U rats exhibited nociceptive responses in formalin-induced pain model and DA rats were more sensitive to noxious chemical stimulus than DA.1U rats, indicating that MHC genes might contribute to the difference in pain sensitivity. Copyright © 2015 Elsevier Inc. All rights reserved.
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Hattotuwagama, Channa K; Guan, Pingping; Doytchinova, Irini A; Flower, Darren R
2004-11-21
Quantitative structure-activity relationship (QSAR) analysis is a main cornerstone of modern informatic disciplines. Predictive computational models, based on QSAR technology, of peptide-major histocompatibility complex (MHC) binding affinity have now become a vital component of modern day computational immunovaccinology. Historically, such approaches have been built around semi-qualitative, classification methods, but these are now giving way to quantitative regression methods. The additive method, an established immunoinformatics technique for the quantitative prediction of peptide-protein affinity, was used here to identify the sequence dependence of peptide binding specificity for three mouse class I MHC alleles: H2-D(b), H2-K(b) and H2-K(k). As we show, in terms of reliability the resulting models represent a significant advance on existing methods. They can be used for the accurate prediction of T-cell epitopes and are freely available online ( http://www.jenner.ac.uk/MHCPred).
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Directory of Open Access Journals (Sweden)
Sepil Irem
2012-05-01
Full Text Available Abstract Background The critical role of Major Histocompatibility Complex (Mhc genes in disease resistance and their highly polymorphic nature make them exceptional candidates for studies investigating genetic effects on survival, mate choice and conservation. Species that harbor many Mhc loci and high allelic diversity are particularly intriguing as they are potentially under strong selection and studies of such species provide valuable information as to the mechanisms maintaining Mhc diversity. However comprehensive genotyping of complex multilocus systems has been a major challenge to date with the result that little is known about the consequences of this complexity in terms of fitness effects and disease resistance. Results In this study, we genotyped the Mhc class I exon 3 of the great tit (Parus major from two nest-box breeding populations near Oxford, UK that have been monitored for decades. Characterization of Mhc class I exon 3 was adopted and bidirectional sequencing was carried using the 454 sequencing platform. Full analysis of sequences through a stepwise variant validation procedure allowed reliable typing of more than 800 great tits based on 214,357 reads; from duplicates we estimated the repeatability of typing as 0.94. A total of 862 alleles were detected, and the presence of at least 16 functional loci was shown - the highest number characterized in a wild bird species. Finally, the functional alleles were grouped into 17 supertypes based on their antigen binding affinities. Conclusions We found extreme complexity at the Mhc class I of the great tit both in terms of allelic diversity and gene number. The presence of many functional loci was shown, together with a pseudogene family and putatively non-functional alleles; there was clear evidence that functional alleles were under strong balancing selection. This study is the first step towards an in-depth analysis of this gene complex in this species, which will help
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Esmaeilzadeh, Hossein; Nabavi, Mohammad; Aryan, Zahra; Amirzargar, Ali Akbar
2015-10-01
This study is aimed at investigating the association of HLA-DRB1, HLA-DQA1, and HLA-DQB1 variability with the response to aspirin desensitization (AD). A total of 16 patients with aspirin-exacerbated respiratory diseases (AERD, 81.3% were female) with median age of 29 ± 4.3 years were included in this study. Following 6 months, Sino-Nasal Outcome Test-22 (SNOT-22), medication, symptom scores, and forced expiratory volume in 1 s (FEV1) (all p < 0.001) improved significantly. However, only seven patients (43.7%) had clinically significant improvement in all of the medication and symptom scores and FEV1, who were considered responders to AD. Responders to AD had significantly higher symptom scores compared with non-responders at baseline (20 ± 1.18 vs 10 ± 1.27; p = 0.003). HLADQB1*0302 was significantly lower in non-responders than in responders to AD (0.12 [0.02-0.76]; p = 0.022). Sensitivity and specificity of HLA-DQB1*0302 to predict response to AD was 71.4% (95% CI: 35.8-91.7) and 81.8% (95% CI: 52.3-94.8). This study introduces HLA-DQB1*0302 as a genetic marker for favorable response to AD.
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Evolutionary Analysis of Minor Histocompatibility Genes In Hydra
Aalismail, Nojood
2016-05-01
Hydra is a simple freshwater solitary polyp used as a model system to study evolutionary aspects. The immune response of this organism has not been studied extensively and the immune response genes have not been identified and characterized. On the other hand, immune response has been investigated and genetic analysis has been initiated in other lower invertebrates. In the present study we took initiative to study the self/nonself recognition in hydra and its relation to the immune response. Moreover, performing phylogenetic analysis to look for annotated immune genes in hydra gave us a potential to analyze the expression of minor histocompatibility genes that have been shown to play a major role in grafting and transplantation in mammals. Here we obtained the cDNA library that shows expression of minor histocompatibility genes and confirmed that the annotated sequences in databases are actually present. In addition, grafting experiments suggested, although still preliminary, that homograft showed less rejection response than in heterograft. Involvement of possible minor histocompatibility gene orthologous in immune response was examined by qPCR.
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Benedek, G; Paperna, T; Avidan, N; Lejbkowicz, I; Oksenberg, J R; Wang, J; Brautbar, C; Israel, S; Miller, A
2010-07-01
Different multiple sclerosis (MS) prevalence rates were reported for Muslim and Christian Arabs in Israel. In this study, we evaluated whether associations of human leukocyte antigen (HLA) genes with MS may contribute to this prevalence difference. DNA samples from Israeli Arab MS patients (n=109) and controls (n=132) were typed for HLA class I (HLA-A, -B and -C) and II (HLA-DRB1 and -DQB1) genes. Global comparisons of HLA allele frequencies revealed significant differences between Christians and Muslims; therefore, case-control analyses were stratified by religious affiliation. Disease characteristics of Muslim and Christian Arab MS patients were similar to those reported for European populations. Opposing association signals with MS were observed for alleles composing the DRB1*0301-DQB1*0201 haplotype: positive association of the HLA-DRB1*0301 allele in Muslims (P(Bonferroni)=0.004, odds ratio (OR)=3.07), and negative association in Christian Arabs (P(Bonferroni)=0.01, OR=0.12), with similar results obtained for HLA-DQB1*0201. HLA-B*52 was negatively associated with MS only in Muslims (P(Bonferroni)=0.01, OR=0.03). The study presents for the first time a high-resolution HLA gene analysis in clinically well-characterized Arab populations with MS, and shows the population-specific contribution of the DRB1*0301-DQB1*0201 haplotype to disease susceptibility.
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Directory of Open Access Journals (Sweden)
Benno Wölk
Full Text Available Fine mapping of human cytotoxic T lymphocyte (CTL responses against hepatitis C virus (HCV is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS 3 and 5B (NS3₁₄₀₆₋₁₄₁₅ and NS5B₂₅₉₄₋₂₆₀₂. In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.
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Directory of Open Access Journals (Sweden)
Mqondisi Tshabalala
2018-01-01
Full Text Available Human leukocyte antigen- (HLA- A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR. Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A∗02:02g (0.096, B∗07:02g (0.082, C∗07:02g (0.180, DQB1∗06:02 (0.157, and DRB1∗15:01 (0.072. The most common haplotype was A∗03:01g~B∗07:02g~C∗07:02g~DQB1∗06:02~DRB1∗15:01 (0.067, which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies.
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DEFF Research Database (Denmark)
Pedersen, Natasja Wulff; Chandran, P. Anoop; Qian, Yu
2017-01-01
Manual analysis of flow cytometry data and subjective gate-border decisions taken by individuals continue to be a source of variation in the assessment of antigen-specific T cells when comparing data across laboratories, and also over time in individual labs. Therefore, strategies to provide...... automated analysis of major histocompatibility complex (MHC) multimer-binding T cells represent an attractive solution to decrease subjectivity and technical variation. The challenge of using an automated analysis approach is that MHC multimer-binding T cell populations are often rare and therefore...... laboratories. We used three different methods, FLOw Clustering without K (FLOCK), Scalable Weighted Iterative Flow-clustering Technique (SWIFT), and ReFlow to analyze flow cytometry data files from 28 laboratories. Each laboratory screened for antigen-responsive T cell populations with frequency ranging from 0...
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Talmadge, J E; Talmadge, C B; Zbar, B; McEwen, R; Meeker, A K; Tribble, H
1987-06-01
The mechanism by which tumor allografts escape host immunologic attack was investigated. B16-BL6 cells (the bladder 6 subline of the B16 melanoma) (H-2b) were transfected with a gene (Dd) encoding an allogeneic class I major histocompatibility complex antigen. Clones that expressed Dd antigen were injected into the footpads of nonimmune syngeneic mice, syngeneic immune mice, and nude mice. Under conditions of immunologic selection a clone that contained multiple copies of the transfected gene formed variants that lacked the transfected gene. Primary tumors and pulmonary metastases of immunized mice and pulmonary metastases of nonimmunized mice had lost the Dd gene and, in most cases, all of the associated plasmid. In contrast, in immunodeficient nude mice, primary tumors and pulmonary metastases retained the Dd gene and the associated plasmid. Deletion of genes encoding cell surface antigens may be one of the mechanisms by which allogeneic tumors escape immunologic attack.
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Patente, Thiago A; Monteiro, Maria B; Vieira, Suzana M; Rossi da Silva, Maria E; Nery, Márcia; Queiroz, Márcia; Azevedo, Mirela J; Canani, Luis H; Parisi, Maria C; Pavin, Elizabeth J; Mainardi, Débora; Javor, Juraj; Velho, Gilberto; Coimbra, Cássio N; Corrêa-Giannella, Maria Lúcia
2015-08-15
A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D. Copyright © 2015 Elsevier B.V. All rights reserved.
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Expression of the major histocompatibility antigens HLA-A2 and HLA-B7 by DNA-mediated gene transfer
Bernabeu, C.; Finlay, D.; van de Rijn, M.; Maziarz, R. T.; Biro, P. A.; Spits, H.; de Vries, J.; Terhorst, C. P.
1983-01-01
Genes coding for the heavy chain of the class I antigens HLA-A2 or HLA-B7 of the human major histocompatibility complex have been introduced into mouse LtK- cells by cotransfection with the herpes simplex virus thymidine kinase gene. HAT-resistant colonies were isolated expressing either HLA-A2 or
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Runstadler, J A; Angles, J M; Pedersen, N C
2006-11-01
The genetic polymorphism at the dog leucocyte antigen (DLA) class II loci DQA1, DQB1 and DRB1 was studied in a large genetically diverse population of feral and wild-type dogs from the large island nations of Indonesia (Bali), Australia and New Guinea (Bali street dog, dingo and New Guinea singing dog, respectively). Sequence-based typing (SBT) of the hypervariable region of DLA-DRB1, -DQA1 and -DQB1 alleles was used to determine genetic diversity. No new DQA1 alleles were recognized among the three dog populations, but five novel DLA-DRB1 and 2 novel DLA-DQB1 allele sequences were detected. Additional unknown alleles were postulated to exist in Bali street dogs, as indicated by the large percentage of individuals (15%-33%) that had indeterminate DRB1, DQA1 and DQB1 alleles by SBT. All three groups of dogs possessed alleles that were relatively uncommon in conventional purebreds. The New Guinea singing dog and dingo shared alleles that were not present in the Bali street dogs. These findings suggested that the dingo was more closely related to indigenous dogs from New Guinea. Feral dog populations, in particular large ones such as that of Bali, show genetic diversity that existed prior to phenotypic selection for breeds originating from their respective regions. This diversity needs to be identified and maintained in the face of progressive Westernization. These populations deserve further study as potential model populations for the evolution of major histocompatibility complex alleles, for the study of canine genetic diversity, for the development of dog breeds and for studies on the comigration of ancestral human and dog populations.
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Directory of Open Access Journals (Sweden)
Anna Rapacz-Leonard
2014-01-01
Full Text Available During pregnancy in larger mammals, the maternal immune system must tolerate the fetus for months while resisting external infection. This tolerance is facilitated by immunological communication between the fetus and the mother, which is mediated by Major Histocompatibility Complex I (MHC I proteins, by leukocytes, and by the cytokines secreted by the leukocytes. Fetal-maternal immunological communication also supports pregnancy by inducing physiological changes in the mother. If the mother “misunderstands” the signal sent by the fetus during pregnancy, the fetus will be miscarried or delivered preterm. Unlike any other maternal organ, the placenta can express paternal antigens. At parturition, paternal antigens are known to be expressed in cows and may be expressed in horses, possibly so that the maternal immune system will reject the placenta and help to expel it. This review compares fetal-maternal crosstalk that is mediated by the immune system in three species with pregnancies that last for nine months or longer: humans, cattle, and horses. It raises the possibility that immunological communication early in pregnancy may prepare the mother for successful expulsion of fetal membranes at parturition.
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Directory of Open Access Journals (Sweden)
Jahnavi Aluri
2018-02-01
Full Text Available Major histocompatibility complex (MHC class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory and gastrointestinal tract infections. Hematopoietic stem cell transplantation (HSCT is the only curative therapy available for treating these patients. This is the first report from India wherein we describe the clinical, immunological, and molecular findings in five patients with MHC class II deficiency. Our patients presented with recurrent lower respiratory tract infection as the most common clinical presentation within their first year of life and had a complete absence of human leukocyte antigen-antigen D-related (HLA-DR expression on B cells and monocytes. Molecular characterization revealed novel mutations in RFAXP, RFX5, and CIITA genes. Despite genetic heterogeneity, these patients were clinically indistinguishable. Two patients underwent HSCT but had a poor survival outcome. Detectable level of T cell receptor excision circles (TRECs were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency.
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HLA-DRB and HLA-DQ genetic variability in patients with aspirin-exacerbated respiratory disease.
Esmaeilzadeh, Hossein; Nabavi, Mohammad; Amirzargar, Ali Akbar; Aryan, Zahra; Arshi, Saba; Bemanian, Mohammad Hassan; Fallahpour, Morteza; Mortazavi, Negar; Rezaei, Nima
2015-01-01
Major histocompatibility complex (MHC) class II is involved in T-cell activation, cytokine secretion, and induction of immune responses. Cytokines, staphylococcus super antigens, and eosinophil activation are proposed to play important roles in aspirin-exacerbated respiratory disease (AERD). This study is aimed at investigating the association of HLA-DRB and DQ genetic variabilities in patients with AERD. A genetic association analysis in three different groups, including 33 patients with AERD, 17 patients with aspirin-tolerant asthma (ATA), and 100 healthy controls was performed. Oral aspirin challenge (OAC) test was performed to identify aspirin hypersensitivity. Pulmonary function test (PFT) was performed for all patients. Eosinophil percentage in nasal smear and peripheral blood and serum immunoglobin (Ig)E were investigated. HLA-DRB, HLA-DQA1, and HLA-DQB1 were genotyped using polymerase chain reaction. HLA-DQB1*0302 (OR, 5.49, 95% confidence interval [CI],(2.40-12.59)), HLA-DQA1*0301 (OR, 2.90, 95% CI, (1.49-5.67)), HLA-DRB4 (OR, 2.94, 95% CI, (1.61-5.36)), and HLA-DRB1*04 (OR, 3.19, 95% CI, (1.57-6.47)) were higher in patients with AERD compared with controls. In patients with AERD, HLA-DQB1*0301 (OR,0.22, 95% CI, (0.09-0.54)), HLA-DQA1*0501 (OR, 0.42, 95% CI, (0.21-0.81)), HLA-DRB1*11 (OR, 0.30, 95% CI, (0.12-0.73)), and HLA-DRB3 (OR, 0.38, 95% CI, (0.21-0.70)) were significantly lower compared with healthy controls. Patients with AERD had lower frequencies of HLA-DQB1*0301 (OR, 0.27, 95% CI, (0.08-0.86)), and HLA-DRB1*011 (OR, 0.27, 95% CI, (0.08-0.86)) compared with ATA. Haplotypes of HLA-DRB1*04/ DQA1*0301/ DQB1*0302 (OR, 4.25, 95% CI, (1.94-9.29)) and HLA-DRB1*07 /DQA1*0201/ DQB1*0201 (OR, 3.52, 95% CI, (1.54-8.06)) were higher in patients with AERD compared with controls (all p < 0.05). Results of this study suggest that HLA-DQB1*0302 and HLA-DRB1*04 and their related haplotypes are genes involved in predisposing patients to AERD, whereas HLA-DQB1
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Environmental toxins and risk of narcolepsy among people with HLA DQB1*0602
Ton, Thanh G.N.; Longstreth, WT; Koepsell, Thomas D.
2010-01-01
One etiologic model for narcolepsy suggests that some environmental toxin selectively and irreversibly destroys hypocretin-producing cells in individuals with human leukocyte antigen (HLA) DQB1*0602. Between 2001-2005, the authors conducted a population-based case-control study in King County, Washington to examine narcolepsy risk in relation to toxins found in jobs, hobbies and other non-vocational activities. Sixty-seven cases and 95 controls were enrolled; all were between ages 18-50 and positive for HLA DQB1*0602. All were administered in-person interviews about jobs, hobbies or other non-vocational activities before age 21. All analyses were adjusted for African American race and income. Risk increased significantly for jobs involving heavy metals (odds ratio [OR]=4.7; 95% confidence interval [CI]: 1.5, 14.5) and for highest levels of exposure to woodwork (OR: 3.0; 95% CI: 1.0, 8.9), fertilizer (OR=3.1; 95% CI: 1.1, 9.1), and bug or weed killer (OR=4.5; 95% CI: 1.5, 13.4). Associations were of borderline significance for activities involving ceramics, pesticides, and painting projects. Significant dose-response relationships were evident for jobs involving metals (p<0.03), paints (p<0.03), and bug or weed killer (p<0.02). Additional studies are needed to replicate these findings and continue the search for specific toxins that could damage hypocretin neurons in genetically susceptible people. PMID:20519130
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Kornum, Birgitte Rahbek; Burgdorf, Kristoffer Sølvsten; Holm, Anja; Ullum, Henrik; Jennum, Poul; Knudsen, Stine
2017-08-15
Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4 + T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy patients with low CSF hcrt levels, and 23 DQB1*06:02 positive healthy controls. Our ELISpot assay had a detection limit of 1:10,000 cells. We present data showing that autoreactive CD4 + T-cells targeting epitopes from the hcrt precursor in the context of MHC-DQA1*01:02/DQB1*06:02 are either not present or present in a frequency is <1:10,000 among peripheral CD4 + T-cells from narcolepsy type 1 patients. Copyright © 2017 Elsevier B.V. All rights reserved.
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Directory of Open Access Journals (Sweden)
Ruan Xiang-Dong
2007-06-01
Full Text Available Abstract Background The giant panda (Ailuropoda melanoleuca is one of the most endangered animals due to habitat fragmentation and loss. Although the captive breeding program for this species is now nearly two decades old, researches on the genetic background of such captive populations, especially on adaptive molecular polymorphism of major histocompatibility complex (MHC, are still limited. In this study, we characterized adaptive variation of the giant panda's MHC DQA gene by PCR amplification of its antigen-recognizing region (i.e. the exon 2 and subsequent single-strand conformational polymorphism (SSCP and sequence analyses. Results The results revealed a low level of DQA exon 2 diversity in this rare animal, presenting 6 alleles from 61 giant panda individuals. The observed polymorphism was restricted to 9 amino acid substitutions, all of which occurred at and adjacent to positions forming the functionally important antigen-binding sites. All the samples were in Hardy-Weinberg proportions. A significantly higher rate of non-synonymous than synonymous substitutions at the antigen-binding sites indicated positive selection for diversity in the locus. Conclusion The DQA allelic diversity of giant pandas was low relative to other vertebrates. Nonetheless, the pandas exhibited more alleles in DQA than those in DRB, suggesting the alpha chain genes would play a leading role when coping with certain pathogens and thus should be included in conservation genetic investigation. The microsatellite and MHC loci might predict long-term persistence potential and short-term survival ability, respectively. Consequently, it is recommended to utilize multiple suites of microsatellite markers and multiple MHC loci to detect overall genetic variation in order to design unbiased conservation strategies.
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DEFF Research Database (Denmark)
Ostergaard Pedersen, L; Nissen, Mogens Holst; Hansen, N J
2001-01-01
The expression of major histocompatibility class I (MHC-I) crucially depends upon the binding of appropriate peptides. MHC-I from natural sources are therefore always preoccupied with peptides complicating their purification and analysis. Here, we present an efficient solution to this problem....... Recombinant MHC-I heavy chains were produced in Escherichia coli and subsequently purified under denaturing conditions. In contrast to common practice, the molecules were not reduced during the purification. The oxidized MHC-I heavy chain isoforms were highly active with respect to peptide binding....... This suggests that de novo folding of denatured MHC-I molecules proceed efficiently if directed by preformed disulfide bond(s). Importantly, these molecules express serological epitopes and stain specific T cells; and they bind peptides specifically. Several denatured MHC-I heavy chains were analyzed and shown...
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Directory of Open Access Journals (Sweden)
Kuo-Liang Yang
2017-01-01
Full Text Available Objective: We report here the human leukocyte antigen (HLA allelic variety and haplotype composition in a cohort of the Taiwanese Chinese population and their patterns of linkage disequilibria on HLA-B: HLA-C alleles and HLA-DRB1: HLA-DQB1 alleles at a high-resolution level. Materials and Methods: Peripheral whole blood from 11,423 Taiwanese Chinese unrelated individuals was collected in acid citrate dextrose. Genomic DNA was extracted using the QIAamp DNA Blood Mini Kit. The DNA material was subjected to HLA genotyping for HLA-A,-B,-C,-DRB1, and-DQB1 loci using a commercial polymerase chain reaction-sequence-based typing (PCR-SBT kit, the SeCore® A/B/C/DRB1/DQB1 Locus Sequencing kit. High-resolution allelic sequencing was performed as previously described. Results: The number of individual HLA-B alleles detected was greater than the number of alleles recognized in the both the HLA-A and-DRB1 loci. Several novel alleles were discovered as a result of employing the SBT method and the high number of donors tested. In addition, we observed a genetic polymorphic feature of association between HLA-A and-B, HLA-B and-C, and HLA-DRB1 and-DQB1 alleles. Further, the homozygous haplotype frequencies of HLA-A and-B; HLA-A,-C, and-B; HLA-A,-C,-B, and-DRB1; and HLA-A,-C,-B,-DRB1, and-DQB1 in Taiwanese Chinese population are presented. Conclusion: As increasing number of HLA alleles are being discovered, periodic HLA profile investigation in a given population is essential to recognize the HLA complexity in that population. Population study can also provide an up-to-date strategic plan for future needs in terms of compatibility measurement for HLA matching between transplant donors and patients.
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Directory of Open Access Journals (Sweden)
Mohammadreza Bazrafshani
2014-12-01
Conclusion: The HLA cluster might affect on susceptibility to vesicoureteral reflux es-pecially by locus which located close to HLA-DRB1 and HLA-DQB1 genes. This study demonstrates for the first time in Iran. However, further extensive researches with a large number of samples from different populations and ethnicities are required to val-idate the results obtained in this study.
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Chapman, Daniel C; Stocki, Pawel; Williams, David B
2015-01-01
Human cytomegalovirus uses a variety of mechanisms to evade immune recognition through major histocompatibility complex class I molecules. One mechanism mediated by the immunoevasin protein US2 causes rapid disposal of newly synthesized class I molecules by the endoplasmic reticulum-associated degradation pathway. Although several components of this degradation pathway have been identified, there are still questions concerning how US2 targets class I molecules for degradation. In this study we identify cyclophilin C, a peptidyl prolyl isomerase of the endoplasmic reticulum, as a component of US2-mediated immune evasion. Cyclophilin C could be co-isolated with US2 and with the class I molecule HLA-A2. Furthermore, it was required at a particular expression level since depletion or overexpression of cyclophilin C impaired the degradation of class I molecules. To better characterize the involvement of cyclophilin C in class I degradation, we used LC-MS/MS to detect US2-interacting proteins that were influenced by cyclophilin C expression levels. We identified malectin, PDIA6, and TMEM33 as proteins that increased in association with US2 upon cyclophilin C knockdown. In subsequent validation all were shown to play a functional role in US2 degradation of class I molecules. This was specific to US2 rather than general ER-associated degradation since depletion of these proteins did not impede the degradation of a misfolded substrate, the null Hong Kong variant of α1-antitrypsin.
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Evans, Melissa L.; Dionne, Mélanie; Miller, Kristina M.; Bernatchez, Louis
2012-01-01
Major histocompatibility complex (MHC)-dependent mating preferences have been observed across vertebrate taxa and these preferences are expected to promote offspring disease resistance and ultimately, viability. However, little empirical evidence linking MHC-dependent mate choice and fitness is available, particularly in wild populations. Here, we explore the adaptive potential of previously observed patterns of MHC-dependent mate choice in a wild population of Atlantic salmon (Salmo salar) in Québec, Canada, by examining the relationship between MHC genetic variation and adult reproductive success and offspring survival over 3 years of study. While Atlantic salmon choose their mates in order to increase MHC diversity in offspring, adult reproductive success was in fact maximized between pairs exhibiting an intermediate level of MHC dissimilarity. Moreover, patterns of offspring survival between years 0+ and 1+, and 1+ and 2+ and population genetic structure at the MHC locus relative to microsatellite loci indicate that strong temporal variation in selection is likely to be operating on the MHC. We interpret MHC-dependent mate choice for diversity as a likely bet-hedging strategy that maximizes parental fitness in the face of temporally variable and unpredictable natural selection pressures. PMID:21697172
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Directory of Open Access Journals (Sweden)
Daniela Maria Cardozo
2014-01-01
Full Text Available Dengue infection (DI transmitted by arthropod vectors is the viral disease with the highest incidence throughout the world, an estimated 300 million cases per year. In addition to environmental factors, genetic factors may also influence the manifestation of the disease; as even in endemic areas, only a small proportion of people develop the most serious form. Immune-response gene polymorphisms may be associated with the development of cases of DI. The aim of this study was to determine allele frequencies in the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in a Southern Brazil population with dengue virus serotype 3, confirmed by the ELISA serological method, and a control group. The identification of the HLA alleles was carried out using the SSO genotyping PCR program (One Lambda, based on Luminex technology. In conclusion, this study suggests that DQB1*06:11 allele could act as susceptible factors to dengue virus serotype 3, while HLA-DRB1*11 and DQA1*05:01 could act as resistance factors.
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International Nuclear Information System (INIS)
Bahram, S.; Arnold, D.; Bresnahan, M.; Strominger, J.L.; Spies, T.
1991-01-01
The class 2 region of the human major histocompatibility complex (MHC) may encode several genes controlling the processing of endogenous antigen and the presentation of peptide epitopes by MHC class 1 molecules to cytotoxic T lymphocytes. A previously described peptide supply factor (PSF1) is a member of the multidrug-resistance family of transporters and may pump cytosolic peptides into the membrane-bound compartment where class 1 molecules assemble. A second transporter gene, PSF2, was identified 10 kilobases (kb) from PSF1, near the class 2 DOB gene. The complete sequences of PSF1 and PSF2 were determined from cDNA clones. The translation products are closely related in sequence and predicted secondary structure. Both contain a highly conserved ATP-binding fold and share 25% homology in a hydrophobic domain with a tentative number of eight membrane-spanning segments. Based on the principle dimeric organization of these two domains in other transporters, PSF1 and PSF2 may function as complementary subunits, independently as homodimers, or both. Taken together with previous genetic evidence, the coregulation of PSF1 and PSF2 by γ interferon and the to-some-degree coordinate transcription of these genes suggest a common role in peptide-loading of class 1 molecules, although a distinct function of PSF2 cannot be ruled out
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International Nuclear Information System (INIS)
Patel, S.S.; Thiele, D.L.; Lipsky, P.E.
1987-01-01
The frequency and phenotype of human T cells that mediate major histocompatibility complex (MHC)-unrestricted cytolysis were analyzed. T cell clones were generated by culturing adherent cell-depleted peripheral blood mononuclear cells at a density of 0.3 cell/well with phytohemagglutinin, recombinant interleukin 2 (rIL-2), and irradiated autologous peripheral blood mononuclear cells and/or Epstein-Barr virus-transformed lymphoblastoid cell lines. All of the 198 clones generated by this method were T cells (CD2 + , CD3 + , CD4 + or CD2 + , CD3 + , CD8 + ) that possessed potent lytic activity against K562, an erythroleukemia line sensitive to lysis by human natural killer cells, and Cur, a renal carcinoma cell line resistant to human natural killer activity. Cytolysis, measured by 51 Cr release, was MHC-unrestricted, since the clones were able to lyse MHC class I or class II negative targets, as well as MHC class I and class II negative targets. Although the clones produced tissue necrosis factor/lymphotoxin-like molecules, lysis of Cur of K562 was not mediated by a soluble factor secreted by the clones. These data indicate that the capacity for MHC-unrestricted tumoricidal activity and expression of NKH1 and CD11b, but not CD 16, are properties common to all or nearly all human peripheral blood-derived T cell clones regardless of CD4 or CD8 phenotype
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Directory of Open Access Journals (Sweden)
Erma Primanita Hayuningtyas
2016-04-01
Full Text Available Wabah penyakit koi herpes virus (KHV di Indonesia yang terjadi sejak tahun 2002 merupakan salah satu faktor yang memicu kemerosotan produksi ikan mas budidaya. Pembentukan strain unggul ikan mas tahan KHV dapat menjadi solusi bagi permasalahan tersebut. Pemilihan genotip ikan mas tahan KHV dengan marka molekuler gen major histocompatibility complex class II (MHC-II, khususnya pada alel Cyca DAB 1*05 akan membantu dalam kegiatan seleksi. Penelitian ini bertujuan untuk mengetahui keberadaan gen MHC-II pada populasi dasar G0 ikan mas strain Rajadanu dan hubungannya dengan pertumbuhan (bobot. Metode deteksi keberadaan gen MHC-II pada dua kelompok ikan dengan ukuran berbeda dilakukan dengan teknik PCR. Hubungan antara pertumbuhan ikan mas dengan persentase kemunculan gen MHC-II dianalisis dengan menggunakan program SPSS (Statistical Package for the Social Sciences, sehingga diperoleh korelasi di antara keduanya. Hasil penelitian menunjukkan bahwa hubungan antara pertumbuhan dengan persentase keberadaan gen MHC-II berkorelasi negatif dengan nilai R = -0,742. Hal ini mengindikasikan bahwa semakin cepat pertumbuhan populasi ikan mas maka semakin sedikit persentase individu yang mempunyai gen MHC-II pada setiap populasi ikan mas. Sehingga populasi ikan mas yang pertumbuhannya lambat memiliki tingkat persentase positif MHC-II lebih tinggi (85,71%-100% dibandingkan populasi ikan mas yang pertumbuhannya cepat (42,86%-85,71%.
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Directory of Open Access Journals (Sweden)
Christine Grossen
2014-06-01
Full Text Available The major histocompatibility complex (MHC is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex. At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2, Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus. We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8% to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection.
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Grossen, Christine; Keller, Lukas; Biebach, Iris; Croll, Daniel
2014-01-01
The major histocompatibility complex (MHC) is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex). At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2), Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus). We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8%) to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection. PMID:24945814
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DEFF Research Database (Denmark)
Salomonsen, J; Eriksson, H; Skjødt, K
1991-01-01
The polymorphic B-G region of the chicken major histocompatibility complex has previously been shown to mediate an "adjuvant effect" on the humoral response to other erythrocyte alloantigens. We demonstrate here that B-G molecules purified with monoclonal antibodies exert this adjuvant effect...... on the production of alloantibodies to chicken class I (B-F) molecules, when the two are in the same liposome. The adjuvant effect may in part be mediated by antibodies, since the antibody response to B-G molecules occurs much faster than the response to B-F molecules, and conditions in which antibodies to B......-G are present increase the speed of the response to B-F molecules. We also found that the presence of B-G molecules in separate liposomes results in a lack of response to B-F molecules. In the light of this and other data, we consider the possible roles for the polymorphic B-G molecules, particularly...
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DNA polymorphism of HLA class II genes in systemic lupus erythematosus
DEFF Research Database (Denmark)
Cowland, J B; Andersen, V; Halberg, P
1994-01-01
We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) genes: HLA-DRB, -DQA, -DQB, -DPB in 24 Danish patients with systemic lupus erythematosus (SLE) and in 102 healthy Danes. A highly significant increase of the frequency of the DR3......- and DRw6-associated 7.00 kb DRB TaqI DNA fragment was found in SLE patients compared to normal controls (83.3% vs 35.5%; RR = 9.1, p 1*0501-associated 4.56 kb DQA TaqI fragment and the DRB3*01/03-associated 9.79 kb TaqI fragment were also found to be significantly...... increased in SLE patients (70.8% vs 29.7%; RR = 5.8, p 1%; RR = 4.3, p
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DEFF Research Database (Denmark)
Lamberth, K; Claesson, M H
2001-01-01
Early apoptosis in Jurkat T-lymphoma cells was induced by agonistic anti-Fas Ab or by anisomycin which activates the stress kinases SAPK/JNK. Apoptosis was inhibited by ligation of major histocompatibility complex class I antigens (MHC-I). MHC-I ligation induced upregulation of the anti......-apoptotic Bcl-2 protein and stabilized the mitochondrial membrane potential (Deltapsim). MHC-I ligation also prevented downregulation of Bcl-2 and destabilization of Deltapsim induced by anti-Fas Ab treatment or anisomycin exposure. Studies on three different Jurkat cell mutants deficient for src p56(lck), ZAP......-70 kinase, or TCR/CD3 gamma-chain showed that the cells undergo apoptosis after Fas ligation. Anisomycin exposure induced apoptosis in the src p56(lck)-deficient cell line but not in the two other mutant cell lines. Simultaneous cross-linking of MHC-I and Fas ligation inhibited apoptosis in the ZAP...
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The major histocompatibility complex in the chicken
DEFF Research Database (Denmark)
Guillemot, F; Kaufman, J F; Skjoedt, K
1989-01-01
The chicken B complex is the first non-mammalian MHC characterized at the molecular level. It differs from the human HLA and murine H-2 complexes in the small size of the class I (B-F) and class II (B-L) genes and their close proximity. This proximity accounts for the absence of recombination...
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López Solís, Remigio O; Weis, Ulrike Kemmerling; Ceballos, Alicia Ramos; Salas, Gustavo Hoecker
2003-12-01
Two inbred mouse strains, A/Snell and A.Swiss, which were produced as congenic with regard to the H-2 histocompatibility gene complex, are homozygous for two different groups of isoproterenol-induced salivary polypeptides (IISP). These polypeptides, which have been considered as markers of the hypertrophic growth of the parotid acinar cells, are members of the complex family of salivary proline-rich proteins (PRP) on the basis of both their massive accumulation in the parotid acinar cells in response to chronic isoproterenol, secretory character, high solubility in trichloroacetic acid and metachromatic staining by Coomassie blue. IISP expressed in both mouse strains were identified by unidimensional SDS-polyacrylamide electrophoresis and Coomassie blue staining both in parotid gland homogenates and in whole salivas obtained from mice repeatedly stimulated at 24-h intervals with isoproterenol. Parotid glands from 40 mice (20 A/Snell and 20 A.Swiss) and salivas from 270 mice (200 A/Snell and 70 A.Swiss) were analyzed. One of the congenic strains (A/Snell) expressed five IISP (Mr 65, 61, 51.5, 38, and 37 kDa) and the other strain (A.Swiss) expressed six IISP (Mr 59, 57, 54.5, 46, 36, and 34 kDa). No inter-individual intra-strain variations were observed, thus defining strain-associated patterns of IISP (PRP). Copyright 2003 Wiley-Liss, Inc.
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Ditchkoff, S S; Lochmiller, R L; Masters, R E; Hoofer, S R; Van Den Bussche, R A
2001-03-01
Good-genes hypotheses predict that development of secondary sexual characters can be an honest advertisement of heritable male quality. We explored this hypothesis using a cervid model (adult, male white-tailed deer, Odocoileus virginianus) to determine whether antler development could provide an honest signal of a male's genetic quality and condition to adversaries. We compared antler, morphometric, hormonal, and parasitic data collected from hunter-harvested deer to characteristics of the Mhc-DRB (Odvi), the most widely studied gene of the major histocompatibility complex (MHC) in Artiodactyla. We detected associations between genetic characteristics at Odvi-DRB and antler development and body mass, suggesting that antler development and body mass may be associated with pathogen resistance in deer and thus may be an honest signal of genetic quality. We also detected associations between Odvi-DRB characteristics and serum testosterone during the breeding season, suggesting that certain MHC characteristics may help deer cope with stresses related to breeding activity. In addition, we observed a negative relationship between degree of antler development and overall abundance of abomasal helminths. Our observations provide support for the hypothesis that antler development in white-tailed deer is an honest signal of quality.
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MH2c: Characterization of major histocompatibility α-helices - an information criterion approach.
Hischenhuber, B; Frommlet, F; Schreiner, W; Knapp, B
2012-07-01
Fitting Toolbox and Statistic Toolbox of Matlab Nature of problem: Major histocompatibility (MH) proteins share a similar overall structure. However, identical MH alleles which present different peptides differ by subtle conformational alterations. One hypothesis is that such conformational differences could be another level of T cell regulation. By this software package we present a reliable and systematic way to compare different MH structures to each other. Solution method: We tested several fitting approaches on all available experimental crystal structures of MH to obtain an overall picture of how to describe MH helices. For this purpose we transformed all complexes into the same space and applied splines and polynomials of several degrees to them. To draw a general conclusion which method fits them best we employed the "corrected Akaike Information Criterion". The software is applicable for all kinds of helices of biomolecules. Running time: Depends on the data, for a single stationary structure the runtime should not exceed a few seconds.
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Ruiz-López, María José; Monello, Ryan J; Schuttler, Stephanie G; Lance, Stacey L; Gompper, Matthew E; Eggert, Lori S
2014-12-01
Major Histocompatibility Complex (MHC) variability plays a key role in pathogen resistance, but its relative importance compared to environmental and demographic factors that also influence resistance is unknown. We analyzed the MHC II DRB exon 2 for 165 raccoons (Procyon lotor) in Missouri (USA). For each animal we also determined the presence of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to two highly virulent pathogens, canine distemper virus (CDV) and parvovirus. We investigated the role of MHC polymorphism and other demographic and environmental factors previously associated with predicting seroconversion. In addition, using an experimental approach, we studied the relative importance of resource availability and contact rates. We found important associations between IgG antibody presence and several MHC alleles and supertypes but not between IgM antibody presence and MHC. No effect of individual MHC diversity was found. For CDV, supertype S8, one allele within S8 (Prlo-DRB(∗)222), and a second allele (Prlo-DRB(∗)204) were positively associated with being IgG+, while supertype S4 and one allele within the supertype (Prlo-DRB(∗)210) were negatively associated with being IgG+. Age, year, and increased food availability were also positively associated with being IgG+, but allele Prlo-DRB(∗)222 was a stronger predictor. For parvovirus, only one MHC allele was negatively associated with being IgG+ and age and site were stronger predictors of seroconversion. Our results show that negative-frequency dependent selection is likely acting on the raccoon MHC and that while the role of MHC in relation to other factors depends on the pathogen of interest, it may be one of the most important factors predicting successful immune response. Copyright © 2014 Elsevier B.V. All rights reserved.
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1994-01-01
Taking advantage of our understanding of the peptide specificity of the major histocompatibility complex class I-b molecule M3a, we sought to determine why these molecules are poorly represented on the cell surface. To this end we constructed a chimeric molecule with the alpha 1 and alpha 2 domains of M3a and alpha 3 of Ld thereby allowing use of available monoclonal antibodies to quantify surface expression. Transfected, but not control, B10.CAS2 (H-2M3b) cells were lysed readily by M3a-restricted monoclonal cytotoxic T lymphocytes. Thus, the chimera bound, trafficked, and presented endogenous mitochondrial peptides. However, despite high levels of M3a-Ld mRNA, transfectants were negative by surface staining. This finding was consistent with inefficient trafficking to the cell surface. Incubation at 26 degrees C, thought to permit trafficking of unoccupied heavy (H) chains, resulted in detectable cell surface expression of chimeric molecules. Incubation with exogenous peptide at 26 degrees C (but not at 37 degrees C) greatly enhanced expression of M3a-Ld molecules in a dose- dependent manner, suggesting stabilization of unoccupied molecules. Stable association of beta 2-microglobulin with the chimeric H chain was observed in labeled cell lysates only in the presence of exogenous specific peptide, indicating that peptide is required for the formation of a ternary complex. These results indicate that surface expression of M3a-Ld is limited largely by the steady-state availability of endogenous peptides. Since most known M3a-binding peptides are N- formylated, native M3a may normally be expressed at high levels only during infection by intracellular bacteria. PMID:8270862
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DEFF Research Database (Denmark)
Merkle, Patrick S.; Irving, Melita; Hongjian, Song
2017-01-01
from molecular dynamics simulations. Using a biological assay based on TCR gene-engineered primary human T cells, we did not observe a significant effect of β2m on T-cell cytotoxicity, suggesting an alternate role for β2m binding. Overall, we show that binding of β2m to the TCR occurs in vitro and......T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR-pMHC interface, and their effects on TCR conformation and dynamics...... are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR. Our results demonstrate that while TCR...
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Directory of Open Access Journals (Sweden)
Piyumali Sandareka Arachchi
2016-11-01
Full Text Available Background: Helicobacter pylori has been identified as a group I carcinogenic bacteria that infect the gastric mucosa leading to gastritis, peptic ulcer disease, lymphoma and gastric cancer. Pathogenesis of H. pylori depends on the virulence of the strain, host immune response and modulating factors like smoking and diet. Objective: This study aimed to assess the association of selected HLA (Human Leukocyte Antigen alleles; HLA-DQA1*0102, HLA-DQA1*0103 and HLA-DQB1*0301, with the presence of H. pylori infection and disease severity among dyspeptic patients. Methods: Gastric tissue samples from 100 dyspeptic patients, who underwent upper gastrointestinal endoscopy at a tertiary care hospital, were collected. Presence of HLA alleles was confirmed using Polymerase Chain Reaction (PCR. H. pylori infection was determined using PCR and Histology. The histological interpretation was done according to the ‘Sydney classification’. Statistical analysis was done with the Statistical Package of Social Sciences (SPSS (version 22; SPSS, Inc., Chicago, Illinois, USA. Results: Respective percentages of HLA-DQA1*0102, HLA-DQA1*0103 and HLA-DQB1*0301 were 39%, 31% and 20%. Of the 25 samples positive for H. pylori infection respectively 56% (14/25, 36% (9/25 and 12% (3/25 were positive for HLA-DQA1*0102, HLA-DQA1*0103 and HLA-DQB1*0301 alleles. Considering the association with H. pylori infection, only HLA-DQA1*0102 showed significant association (p=0.044. No significant association was found between the HLA alleles and the histological severity among the H. pylori infected patients. Conclusion: In conclusion, HLA-DQA1*0102 allele has a significant association with H. pylori infection while HLA-DQA1*0103 and HLA-DQB1*0301 shows no significant association in a Sri Lankan dyspeptic patient population.
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DEFF Research Database (Denmark)
Skov, S; Nielsen, M; Bregenholt, S
1998-01-01
Activation of Janus tyrosine kinases (Jak) and Signal transducers and activators of transcription (Stat) after ligation of major histocompatibility complex class I (MHC-I) was explored in Jurkat T cells. Cross-linking of MHC-I mediated tyrosine phosphorylation of Tyk2, but not Jak1, Jak2, and Jak3......-probe derived from the interferon-gamma activated site (GAS) in the c-fos promoter, a common DNA sequence for Stat protein binding. An association between hSIE and Stat-3 after MHC-I ligation was directly demonstrated by precipitating Stat-3 from nuclear extracts with biotinylated hSIE probe and avidin......-coupled agarose. To investigate the function of the activated Stat-3, Jurkat T cells were transiently transfected with a Stat-3 isoform lacking the transactivating domain. This dominant-negative acting Stat-3 isoform significantly inhibited apoptosis induced by ligation of MHC-I. In conclusion, our data suggest...
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Miller, Hilary C; O'Meally, Denis; Ezaz, Tariq; Amemiya, Chris; Marshall-Graves, Jennifer A; Edwards, Scott
2015-05-07
Major histocompatibility complex (MHC) genes are a central component of the vertebrate immune system and usually exist in a single genomic region. However, considerable differences in MHC organization and size exist between different vertebrate lineages. Reptiles occupy a key evolutionary position for understanding how variation in MHC structure evolved in vertebrates, but information on the structure of the MHC region in reptiles is limited. In this study, we investigate the organization and cytogenetic location of MHC genes in the tuatara (Sphenodon punctatus), the sole extant representative of the early-diverging reptilian order Rhynchocephalia. Sequencing and mapping of 12 clones containing class I and II MHC genes from a bacterial artificial chromosome library indicated that the core MHC region is located on chromosome 13q. However, duplication and translocation of MHC genes outside of the core region was evident, because additional class I MHC genes were located on chromosome 4p. We found a total of seven class I sequences and 11 class II β sequences, with evidence for duplication and pseudogenization of genes within the tuatara lineage. The tuatara MHC is characterized by high repeat content and low gene density compared with other species and we found no antigen processing or MHC framework genes on the MHC gene-containing clones. Our findings indicate substantial differences in MHC organization in tuatara compared with mammalian and avian MHCs and highlight the dynamic nature of the MHC. Further sequencing and annotation of tuatara and other reptile MHCs will determine if the tuatara MHC is representative of nonavian reptiles in general. Copyright © 2015 Miller et al.
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Strandh, Maria; Westerdahl, Helena; Pontarp, Mikael; Canbäck, Björn; Dubois, Marie-Pierre; Miquel, Christian; Taberlet, Pierre; Bonadonna, Francesco
2012-11-07
Mate choice for major histocompatibility complex (MHC) compatibility has been found in several taxa, although rarely in birds. MHC is a crucial component in adaptive immunity and by choosing an MHC-dissimilar partner, heterozygosity and potentially broad pathogen resistance is maximized in the offspring. The MHC genotype influences odour cues and preferences in mammals and fish and hence olfactory-based mate choice can occur. We tested whether blue petrels, Halobaena caerulea, choose partners based on MHC compatibility. This bird is long-lived, monogamous and can discriminate between individual odours using olfaction, which makes it exceptionally well suited for this analysis. We screened MHC class I and II B alleles in blue petrels using 454-pyrosequencing and quantified the phylogenetic, functional and allele-sharing similarity between individuals. Partners were functionally more dissimilar at the MHC class II B loci than expected from random mating (p = 0.033), whereas there was no such difference at the MHC class I loci. Phylogenetic and non-sequence-based MHC allele-sharing measures detected no MHC dissimilarity between partners for either MHC class I or II B. Our study provides evidence of mate choice for MHC compatibility in a bird with a high dependency on odour cues, suggesting that MHC odour-mediated mate choice occurs in birds.
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Directory of Open Access Journals (Sweden)
Kia J Langford-Smith
Full Text Available Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM:blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan. We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.
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Langford-Smith, Kia J; Sandiford, Zara; Langford-Smith, Alex; Wilkinson, Fiona L; Jones, Simon A; Wraith, J Ed; Wynn, Robert F; Bigger, Brian W
2013-01-01
Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.
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Influence of the HLA class II polymorphism in chronic Chagas' disease.
Fernandez-Mestre, M T; Layrisse, Z; Montagnani, S; Acquatella, H; Catalioti, F; Matos, M; Balbas, O; Makhatadze, N; Dominguez, E; Herrera, F; Madrigal, A
1998-04-01
Chagas' disease or American trypanosomiasis due to Trypanosoma cruzi has existed at least since the time of the Inca empire and contributes significantly to cardiovascular morbidity and mortality in several countries of this continent. Due to the fundamental role of human class II molecules polymorphic residues in the control of the immune response, a study was designed to define by DNA typing HLA class II alleles in a sample of 67 serologically positive individuals with and without cardiomyopathy and in 156 healthy controls of similar ethnic origin. Genomic DNA extraction, PCR amplification of the HLA-DRB1 and DQB1 second exon regions and hybridization to labelled specific probes were carried out following the 11th International Histocompatibility Workshop reference protocol. Comparison of DRB1 and DQB1 allele frequencies among the patients and control subjects showed a decreased frequency of DRB1*14 and DQB1*0303 in the patients, suggesting independent protective effects to the chronic infection in this population. Allele frequencies comparison between patients with and without cardiomyopathy showed a higher frequency of DRB1*01, DRB1*08 and DQB1*0501 and a decreased frequency of DRB1*1501 in the patients with arrhythmia and congestive heart failure. The results suggest that HLA Class II genes may be associated with the development of a chronic infection and with heart damage in Chagas' disease.
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Directory of Open Access Journals (Sweden)
Tetiana Haniastuti
2012-09-01
Full Text Available Background: Dental caries is a bacterial infection which causes destruction of the hard tissues of the tooth. Exposure of the dentin to the oral environment as a result of caries inevitably results in a cellular response in the pulp. The major histocompatibility complex (MHC is a group of genes that code for cell-surface histocompatibility antigens. Cells expressing class II MHC molecules participate in the initial recognition and the processing of antigenic substances to serve as antigen-presenting cells. Purpose: The aim of the study was to elucidate the alteration in the distribution of class II MHC antigen-expressing cells in human dental pulp as carious lesions progressed toward the pulp. Methods: Fifteen third molars with caries at the occlusal site at various stages of decay and 5 intact third molars were extracted and used in this study. Before decalcifying with 10% EDTA solution (pH 7.4, all the samples were observed by micro-computed tomography to confirm the lesion condition three-dimensionally. The specimens were then processed for cryosection and immunohistochemistry using an anti-MHC class II monoclonal antibody. Results: Class II MHC antigen-expressing cells were found both in normal and carious specimens. In normal tooth, the class II MHC-immunopositive cells were observed mainly at the periphery of the pulp tissue. In teeth with caries, class II MHC-immunopositive cells were located predominantly subjacent to the carious lesions. As the caries progressed, the number of class II MHC antigen-expressing cells was increased. Conclusion: The depth of carious lesions affects the distribution of class II MHC antigen-expressing cells in the dental pulp.Latar belakang: Karies merupakan penyakit infeksi bakteri yang mengakibatkan destruksi jaringan keras gigi. Dentin yang terbuka akibat karies akan menginduksi respon imun seluler pada pulpa. Kompleks histokompatibilitas utama (MHC merupakan sekumpulan gen yang mengkode histokompatibilitas
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Colussi, S; Prearo, M; Bertuzzi, S A; Scanzio, T; Peletto, S; Favaro, L; Modesto, P; Maniaci, M G; Ru, G; Desiato, R; Acutis, P L
2015-01-01
Major histocompatibility complex (MHC) loci encode glycoproteins that bind to foreign peptides and initiate immune responses through their interaction with T cells. MHC class II molecules are heterodimers consisting of α and β chains encoded by extremely variable genes; variation in exon 2 is responsible for the majority of observed polymorphisms, mostly concentrated in the codons specifying the peptide-binding region. Lactococcus garvieae is the causative agent of lactococcosis, a warm-water bacterial infection pathogenic for cultured freshwater and marine fish. It causes considerable economic losses, limiting the profitability and development of fish industries in general and the intensive production of rainbow trout, Oncorhynchus mykiss (Walbaum), in particular. The disease is currently controlled with vaccines and antibiotics; however, vaccines have short-term efficacy, and increasing concerns regarding antibiotic residues have called for alternative strategies. To explore the involvement of the MHC class II β-1 domain as a candidate gene for resistance to lactococcosis, we exposed 400 rainbow trout to naturally contaminated water. One single nucleotide polymorphism (SNP) and one haplotype were associated with resistance (P trout resistant to lactococcosis. © 2014 John Wiley & Sons Ltd.
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DEFF Research Database (Denmark)
Kornum, Birgitte Rahbek; Burgdorf, Kristoffer Sølvsten; Holm, Anja
2017-01-01
Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune...... reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4(+) T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy...
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Grogan, Kathleen E; Sauther, Michelle L; Cuozzo, Frank P; Drea, Christine M
2017-10-01
Across species, diversity at the major histocompatibility complex (MHC) is critical to individual disease resistance and, hence, to population health; however, MHC diversity can be reduced in small, fragmented, or isolated populations. Given the need for comparative studies of functional genetic diversity, we investigated whether MHC diversity differs between populations which are open, that is experiencing gene flow, versus populations which are closed, that is isolated from other populations. Using the endangered ring-tailed lemur ( Lemur catta ) as a model, we compared two populations under long-term study: a relatively "open," wild population ( n = 180) derived from Bezà Mahafaly Special Reserve, Madagascar (2003-2013) and a "closed," captive population ( n = 121) derived from the Duke Lemur Center (DLC, 1980-2013) and from the Indianapolis and Cincinnati Zoos (2012). For all animals, we assessed MHC-DRB diversity and, across populations, we compared the number of unique MHC-DRB alleles and their distributions. Wild individuals possessed more MHC-DRB alleles than did captive individuals, and overall, the wild population had more unique MHC-DRB alleles that were more evenly distributed than did the captive population. Despite management efforts to maintain or increase genetic diversity in the DLC population, MHC diversity remained static from 1980 to 2010. Since 2010, however, captive-breeding efforts resulted in the MHC diversity of offspring increasing to a level commensurate with that found in wild individuals. Therefore, loss of genetic diversity in lemurs, owing to small founder populations or reduced gene flow, can be mitigated by managed breeding efforts. Quantifying MHC diversity within individuals and between populations is the necessary first step to identifying potential improvements to captive management and conservation plans.
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Semler, Matthew R; Wiseman, Roger W; Karl, Julie A; Graham, Michael E; Gieger, Samantha M; O'Connor, David H
2017-11-13
Pig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to that of rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to infer Mane-A and Mane-B haplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313 Mane-A, Mane-B, and Mane-I sequences that defined 86 Mane-A and 106 Mane-B MHC-I haplotypes. Pacific Biosciences technology allows us to resolve these Mane-A and Mane-B haplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease.
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DEFF Research Database (Denmark)
Brorsson, C.; Hansen, Niclas Tue; Hansen, Kasper Lage
2009-01-01
genes. We have developed a novel method that combines single nucleotide polymorphism (SNP) genotyping data with protein-protein interaction (ppi) networks to identify disease-associated network modules enriched for proteins encoded from the MHC region. Approximately 2500 SNPs located in the 4 Mb MHC......To develop novel methods for identifying new genes that contribute to the risk of developing type 1 diabetes within the Major Histocompatibility Complex (MHC) region on chromosome 6, independently of the known linkage disequilibrium (LD) between human leucocyte antigen (HLA)-DRB1, -DQA1, -DQB1...... region were analysed in 1000 affected offspring trios generated by the Type 1 Diabetes Genetics Consortium (T1DGC). The most associated SNP in each gene was chosen and genes were mapped to ppi networks for identification of interaction partners. The association testing and resulting interacting protein...
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Zhao, Y-K; Jia, C-M; Yuan, G-J; Liu, W; Qiu, Y; Zhu, Q-G
2015-06-29
We investigated the expression and clinical value of the soluble major histocompatibility complex class I-related chain A (sMICA) molecule in the serum of patients with renal tumors. Sixty patients diagnosed with renal tumors were enrolled in the experimental group, whereas 20 healthy volunteers served as the control group. The sMICA levels were measured via enzyme-linked immunosorbent assay, and the results were analyzed in combination with data from pathol-ogy examination. The experimental group had a statistically significant higher sMICA level (P < 0.05) than the control group. The sMICA level was higher in patients with malignant tumors than in those with be-nign tumors. We also observed a positive relationship among different tumor-node-metastasis (TNM) pathological stages with more advanced diseases exhibiting higher sMICA levels. As a tumor-associated antigen, MICA has a close relationship with renal tumorigenesis and immune es-cape. Our results indicated that sMICA levels were related to tumor pathol-ogy, TNM stage, and metastasis. Therefore, sMICA might be a potential marker for tumor characteristics, prognosis, and recurrence prediction.
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Directory of Open Access Journals (Sweden)
Ottaviani Diego
2008-05-01
Full Text Available Abstract Background The major histocompatibility complex (MHC is essential for human immunity and is highly associated with common diseases, including cancer. While the genetics of the MHC has been studied intensively for many decades, very little is known about the epigenetics of this most polymorphic and disease-associated region of the genome. Methods To facilitate comprehensive epigenetic analyses of this region, we have generated a genomic tiling array of 2 Kb resolution covering the entire 4 Mb MHC region. The array has been designed to be compatible with chromatin immunoprecipitation (ChIP, methylated DNA immunoprecipitation (MeDIP, array comparative genomic hybridization (aCGH and expression profiling, including of non-coding RNAs. The array comprises 7832 features, consisting of two replicates of both forward and reverse strands of MHC amplicons and appropriate controls. Results Using MeDIP, we demonstrate the application of the MHC array for DNA methylation profiling and the identification of tissue-specific differentially methylated regions (tDMRs. Based on the analysis of two tissues and two cell types, we identified 90 tDMRs within the MHC and describe their characterisation. Conclusion A tiling array covering the MHC region was developed and validated. Its successful application for DNA methylation profiling indicates that this array represents a useful tool for molecular analyses of the MHC in the context of medical genomics.
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Directory of Open Access Journals (Sweden)
Weicai Chen
Full Text Available Major histocompatibility complex (MHC genes are the most polymorphic genes in vertebrates and encode molecules that play a crucial role in pathogen resistance. As a result of their diversity, they have received much attention in the fields of evolutionary and conservation biology. Here, we described the genetic variation of MHC class II B (MHCIIB exon 2 in a wild population of Hume's pheasant (Syrmaticus humiae, which has suffered a dramatic decline in population over the last three decades across its ranges in the face of heavy exploitation and habitat loss. Twenty-four distinct alleles were found in 73 S. humiae specimens. We found seven shared alleles among four geographical groups as well as six rare MHCIIB alleles. Most individuals displayed between one to five alleles, suggesting that there are at least three MHCIIB loci of the Hume's pheasant. The dN ⁄ dS ratio at putative antigen-binding sites (ABS was significantly greater than one, indicating balancing selection is acting on MHCIIB exon 2. Additionally, recombination and gene conversion contributed to generating MHCIIB diversity in the Hume's pheasant. One to three recombination events and seventy-five significant gene conversion events were observed within the Hume's pheasant MHCIIB loci. The phylogenetic tree and network analysis revealed that the Hume's pheasant alleles do not cluster together, but are scattered through the tree or network indicating a trans-species evolutionary mode. These findings revealed the evolution of the Hume's pheasant MHC after suffering extreme habitat fragmentation.
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Directory of Open Access Journals (Sweden)
Kevin Y Urayama
2013-12-01
Full Text Available The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL, is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2-5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (xMHC, an approximately 7.6 megabase region that is well-known for its high density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA. First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C and class II (HLA-DR, HLA-DQ, and HLA-DP molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk.
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Bentley, Carol; Yates, Jenna; Salimi, Maryam; Greig, Jenny; Wiblin, Sarah; Hassanali, Tasneem; Banham, Alison H.
2017-01-01
Therapeutic monoclonal antibodies targeting cell surface or secreted antigens are among the most effective classes of novel immunotherapies. However, the majority of human proteins and established cancer biomarkers are intracellular. Peptides derived from these intracellular proteins are presented on the cell surface by major histocompatibility complex class I (MHC-I) and can be targeted by a novel class of T-cell receptor mimic (TCRm) antibodies that recognise similar epitopes to T-cell receptors. Humoural immune responses to MHC-I tetramers rarely generate TCRm antibodies and many antibodies recognise the α3 domain of MHC-I and β2 microglobulin (β2m) that are not directly involved in presenting the target peptide. Here we describe the production of functional chimeric human-murine HLA-A2-H2Dd tetramers and modifications that increase their bacterial expression and refolding efficiency. These chimeric tetramers were successfully used to generate TCRm antibodies against two epitopes derived from wild type tumour suppressor p53 (RMPEAAPPV and GLAPPQHLIRV) that have been used in vaccination studies. Immunisation with chimeric tetramers yielded no antibodies recognising the human α3 domain and β2m and generated TCRm antibodies capable of specifically recognising the target peptide/MHC-I complex in fully human tetramers and on the cell surface of peptide pulsed T2 cells. Chimeric tetramers represent novel immunogens for TCRm antibody production and may also improve the yield of tetramers for groups using these reagents to monitor CD8 T-cell immune responses in HLA-A2 transgenic mouse models of immunotherapy. PMID:28448627
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Parmar, Drashti R; Mitra, Siuli; Bhadouriya, Snehalata; Rao, Tirupathi; Kunteepuram, Vaishnavi; Gaur, Ajay
2017-12-01
The major histocompatibility complex (MHC), in vertebrate animals, is a multi-genic protein complex that encodes various receptors. During a disease, MHC interacts with the antigen and triggers a cascade of adaptive immune responses to overcome a disease outbreak. The MHC is very important region from immunological point of view, but it is poorly characterized among Indian leopards. During this investigation, we examined genetic diversity for MHC class I (MHC-I) and MHC class II-DRB (MHC-II) among wild and captive Indian leopards. This study estimated a pool of 9 and 17 alleles for MHC-I and MHC-II, respectively. The wild group of individuals showed higher nucleotide diversity and amino acid polymorphism compared to the captive group. A phylogenetic comparison with other felids revealed a clustering in MHC-I and interspersed presence in MHC-II sequences. A test for selection also revealed a deviation from neutrality at MHC-II DRB loci and higher non-synonymous substitution rate (dN) among the individuals from wild group. Further, the wild individuals showed higher dN for both MHC I and II genes compared to the group that was bred under captive conditions. These findings suggest the role of micro-evolutionary forces, such as pathogen-mediated selection, to cause MHC variations among the two groups of Indian leopards, because the two groups have been bred in two different environments for a substantial period of time. Since, MHC diversity is often linked with the quality of immunological health; the results obtained from this study fill the gap of knowledge on disease predisposition among wild and captive Indian leopards.
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DEFF Research Database (Denmark)
Oleksiewicz, M.B.; Kristensen, B.; Ladekjaer-Mikkelsen, A.S.
2002-01-01
The extracellular domains of swine leukocyte antigen class I (SLA-I, major histocompatibility complex protein class 1) were cloned and sequenced for two haplotypes (114 and H7) which do not share any alleles based on serological typing, and which are the most important in Danish farmed pigs....... The extracellular domain of SLA-I was connected to porcine beta2 microglobulin by glycine-rich linkers. The engineered sin.-le-chain proteins, consisting of fused SLA-I and beta2 microglobulin, were overexpressed as inclusion bodies in Escherichia coli. Also, variants were made of the single-chain proteins......, by linking them through glycine-rich linkers to peptides representing T-cell epitopes from classical swine fever virus (CSFV) and foot-and-mouth disease virus (FMDV). An in vitro refold assay was developed, using a monoclonal anti-SLA antibody (PT85A) to gauge refolding. The single best-defined, SLA...
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Directory of Open Access Journals (Sweden)
Pan Hui-Juan
2007-09-01
Full Text Available Abstract Background Giant panda is rare and endangered species endemic to China. The low rates of reproductive success and infectious disease resistance have severely hampered the development of captive and wild populations of the giant panda. The major histocompatibility complex (MHC plays important roles in immune response and reproductive system such as mate choice and mother-fetus bio-compatibility. It is thus essential to understand genetic details of the giant panda MHC. Construction of a bacterial artificial chromosome (BAC library will provide a new tool for panda genome physical mapping and thus facilitate understanding of panda MHC genes. Results A giant panda BAC library consisting of 205,800 clones has been constructed. The average insert size was calculated to be 97 kb based on the examination of 174 randomly selected clones, indicating that the giant panda library contained 6.8-fold genome equivalents. Screening of the library with 16 giant panda PCR primer pairs revealed 6.4 positive clones per locus, in good agreement with an expected 6.8-fold genomic coverage of the library. Based on this BAC library, we constructed a contig map of the giant panda MHC class II region from BTNL2 to DAXX spanning about 650 kb by a three-step method: (1 PCR-based screening of the BAC library with primers from homologous MHC class II gene loci, end sequences and BAC clone shotgun sequences, (2 DNA sequencing validation of positive clones, and (3 restriction digest fingerprinting verification of inter-clone overlapping. Conclusion The identifications of genes and genomic regions of interest are greatly favored by the availability of this giant panda BAC library. The giant panda BAC library thus provides a useful platform for physical mapping, genome sequencing or complex analysis of targeted genomic regions. The 650 kb sequence-ready BAC contig map of the giant panda MHC class II region from BTNL2 to DAXX, verified by the three-step method, offers a
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Directory of Open Access Journals (Sweden)
Christos Iacovakis
Full Text Available A study was conducted in order to determine the occurrence of European Brown Hare Syndrome virus (EBHSV in Denmark and possible relation between disease pathogenesis and Major Histocompatibility Complex (MHC host genotype. Liver samples were examined from 170 brown hares (hunted, found sick or dead, collected between 2004 and 2009. Macroscopical and histopathological findings consistent with EBHS were detected in 24 (14.1% hares; 35 (20.6% had liver lesions not typical of the syndrome, 50 (29.4% had lesions in other tissues and 61 (35.9% had no lesions. Sixty five (38.2% of 170 samples were found to be EBHSV-positive (RT-PCR, VP60 gene. In order to investigate associations between viral pathogenesis and host genotype, variation within the exon 2 DQA gene of MHC was assessed. DQA exon 2 analysis revealed the occurrence of seven different alleles in Denmark. Consistent with other populations examined so far in Europe, observed heterozygosity of DQA (H o = 0.1180 was lower than expected (H e = 0.5835. The overall variation for both nucleotide and amino acid differences (2.9% and 14.9%, respectively were lower in Denmark than those assessed in other European countries (8.3% and 16.9%, respectively. Within the peptide binding region codons the number of nonsynonymous substitutions (dN was much higher than synonymous substitutions (dS, which would be expected for MHC alleles under balancing selection. Allele frequencies did not significantly differ between EBHSV-positive and -negative hares. However, allele Leeu-DQA*30 was detected in significantly higher (P = 0.000006 frequency among the positive hares found dead with severe histopathological lesions than among those found sick or apparently healthy. In contrast, the latter group was characterized by a higher frequency of the allele Leeu-DQA*14 as well as the proportion of heterozygous individuals (P = 0.000006 and P = 0.027. These data reveal a polarisation between EBHSV
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Kiemnec-Tyburczy, Karen M.; Richmond, Jonathan Q.; Savage, Anna E.; Zamudio, Kelly R.
2010-01-01
Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II ??1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class II?? exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class II?? loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the ??1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations. ?? 2010 Springer-Verlag.
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Cruz, E; Vieira, J; Gonçalves, R; Alves, H; Almeida, S; Rodrigues, P; Lacerda, R; Porto, G
2004-07-01
Variability in T-lymphocyte numbers is partially explained by a genetic regulation. From studies in animal models, it is known that the Major Histocompatibility Complex (MHC) is involved in this regulation. In humans, this has not been shown yet. The objective of the present study was to test the hypothesis that genes in the MHC region influence the regulation of T-lymphocyte numbers. Two approaches were used. Association studies between T-cell counts (CD4(+) and CD8(+)) or total lymphocyte counts and HLA class I alleles (A and B) or mutations in the HFE (C282Y and H63D), the hemochromatosis gene, in an unrelated population (n = 264). A second approach was a sibpair correlation analysis of the same T-cell counts in relation to HLA-HFE haplotypes in subjects belonging to 48 hemochromatosis families (n = 456 sibpairs). In the normal population, results showed a strong statistically significant association of the HLA-A*01 with high numbers of CD8(+) T cells and a less powerful association with the HLA-A*24 with low numbers of CD8(+) T cells. Sibpair correlations revealed the most significant correlation for CD8(+) T-cell numbers for sibpairs with HLA-HFE-identical haplotypes. This was not observed for CD4(+) T cells. These results show that the MHC region is involved in the genetic regulation of CD8(+) T-cell numbers in humans. Identification of genes responsible for this control may have important biological and clinical implications.
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Directory of Open Access Journals (Sweden)
Kevin Y Urayama
Full Text Available The extended major histocompatibility complex (xMHC is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs in childhood BCP-ALL cases (n=567 enrolled in the Northern California Childhood Leukemia Study (NCCLS compared with population controls (n=892. Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036, located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046. Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.
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Glasner, Ariella; Oiknine-Djian, Esther; Weisblum, Yiska; Diab, Mohammad; Panet, Amos; Wolf, Dana G; Mandelboim, Ofer
2017-11-15
NK cells are innate lymphocytes that participate in many immune processes encompassing cancer, bacterial and fungal infection, autoimmunity, and even pregnancy and that specialize in antiviral defense. NK cells express inhibitory and activating receptors and kill their targets when activating signals overpower inhibitory signals. The NK cell inhibitory receptors include a uniquely diverse array of proteins named killer cell immunoglobulin-like receptors (KIRs), the CD94 family, and the leukocyte immunoglobulin-like receptor (LIR) family. The NK cell inhibitory receptors recognize mostly major histocompatibility complex (MHC) class I (MHC-I) proteins. Zika virus has recently emerged as a major threat due to its association with birth defects and its pandemic potential. How Zika virus interacts with the immune system, and especially with NK cells, is unclear. Here we show that Zika virus infection is barely sensed by NK cells, since little or no increase in the expression of activating NK cell ligands was observed following Zika infection. In contrast, we demonstrate that Zika virus infection leads to the upregulation of MHC class I proteins and consequently to the inhibition of NK cell killing. Mechanistically, we show that MHC class I proteins are upregulated via the RIGI-IRF3 pathway and that this upregulation is mediated via beta interferon (IFN-β). Potentially, countering MHC class I upregulation during Zika virus infection could be used as a prophylactic treatment against Zika virus. IMPORTANCE NK cells are innate lymphocytes that recognize and eliminate various pathogens and are known mostly for their role in controlling viral infections. NK cells express inhibitory and activating receptors, and they kill or spare their targets based on the integration of inhibitory and activating signals. Zika virus has recently emerged as a major threat to humans due to its pandemic potential and its association with birth defects. The role of NK cells in Zika virus
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Pimentel-Santos, F M; Matos, M; Ligeiro, D; Mourão, A F; Ribeiro, C; Costa, J; Santos, H; Barcelos, A; Pinto, P; Cruz, M; Sousa, E; Santos, R A; Fonseca, J E; Trindade, H; Guedes-Pinto, H; Branco, J C
2013-12-01
Human leukocyte antigen (HLA)-B27 is the mostly known major histocompatibility complex (MHC) gene associated with ankylosing spondylitis (AS). Nonetheless, there is substantial evidence that other MHC genes appear to be associated with the disease, although it has not yet been established whether these associations are driven by direct associations or by linkage disequilibrium (LD) mechanisms. We aimed to investigate the contributions of HLA class I and II alleles and B27-haplotypes for AS in a case-control study. A total of 188 HLA-B27 AS cases and 189 HLA-B27 healthy controls were selected and typed for HLA class I and II by the Luminex polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. Allelic and haplotypic distributions were estimated by maximum likelihood method using Arlequin v3.11 and statistical analysis were performed by Stata10.1. No associations were found between non-HLA-B27 loci and AS susceptibility, but several associations were observed for phenotypic features of the disease. DRB1*08 was identified as a risk factor for uveitis and DQB1*04 seems to provide protection for AS severity (functional, metrological and radiological indexes). A*02/B27/C*02/DRB1*01/DQB1*05 [P<0.0001; odds ratio (OR) = 39.06; 95% confidence interval (CI) (2.34-651)] is the only haplotype that seems to confer susceptibility to AS. Moreover, the haplotype A*02/B27/C*01/DRB1*08/DQB1*04 seems to provide protection for disease functional and radiological repercussions. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 might play some role in AS susceptibility and severity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Directory of Open Access Journals (Sweden)
Christina Reinauer
2017-05-01
Full Text Available Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA DR and DQ haplotypes in a cohort with early-onset (age < 5 years, long term type 1 diabetes (T1D and explored their influence on clinical and laboratory parameters. Methods: Intermediate resolution HLA-DRB1, DQA1 and DQB1 typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis. Results: Genetic variability was low, 44.6% (104/233 of early-onset T1D patients carried the highest-risk genotype HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01/DRB1*04-DQA1*03:01-DQB1*03:02 (HLA-DRB1*04 denoting 04:01/02/04/05, and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest (n = 83, moderate (n = 106 and low risk (n = 6 genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years, metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each p > 0.05. Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes. Conclusion: In this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation.
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Directory of Open Access Journals (Sweden)
Miguel Álvaro-Benito
2018-05-01
Full Text Available The major histocompatibility complex of class II (MHCII immunopeptidome represents the repertoire of antigenic peptides with the potential to activate CD4+ T cells. An understanding of how the relative abundance of specific antigenic epitopes affects the outcome of T cell responses is an important aspect of adaptive immunity and offers a venue to more rationally tailor T cell activation in the context of disease. Recent advances in mass spectrometric instrumentation, computational power, labeling strategies, and software analysis have enabled an increasing number of stratified studies on HLA ligandomes, in the context of both basic and translational research. A key challenge in the case of MHCII immunopeptidomes, often determined for different samples at distinct conditions, is to derive quantitative information on consensus epitopes from antigenic peptides of variable lengths. Here, we present the design and benchmarking of a new algorithm [peptide landscape antigenic epitope alignment utility (PLAtEAU] allowing the identification and label-free quantification (LFQ of shared consensus epitopes arising from series of nested peptides. The algorithm simplifies the complexity of the dataset while allowing the identification of nested peptides within relatively short segments of protein sequences. Moreover, we apply this algorithm to the comparison of the ligandomes of cell lines with two different expression levels of the peptide-exchange catalyst HLA-DM. Direct comparison of LFQ intensities determined at the peptide level is inconclusive, as most of the peptides are not significantly enriched due to poor sampling. Applying the PLAtEAU algorithm for grouping of the peptides into consensus epitopes shows that more than half of the total number of epitopes is preferentially and significantly enriched for each condition. This simplification and deconvolution of the complex and ambiguous peptide-level dataset highlights the value of the PLAt
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Directory of Open Access Journals (Sweden)
Alasaad Samer
2012-09-01
Full Text Available Abstract Background Hybridization between closely related wild and domestic species is of great concern because it can alter the evolutionary integrity of the affected populations. The high allelic variability of Major Histocompatibility Complex (MHC loci usually excludes them from being used in studies to detect hybridization events. However, if a the parental species don’t share alleles, and b one of the parental species possesses an exceptionally low number of alleles (to facilitate analysis, then even MHC loci have the potential to detect hybrids. Results By genotyping the exon2 of the MHC class II DRB1 locus, we were able to detect hybridization between domestic goats (Capra hircus and free-ranging Iberian ibex (Capra pyrenaica hispanica by molecular means. Conclusions This is the first documentation of a Capra pyrenaica × Capra hircus hybridization, which presented us the opportunity to test the applicability of MHC loci as new, simple, cost-effective, and time-saving approach to detect hybridization between wild species and their domesticated relatives, thus adding value to MHC genes role in animal conservation and management.
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Stewart, Patricia W.; Chapes, Stephen K.
2003-01-01
Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.
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Dutta, Sankhadeep; Chakraborty, Chandraditya; Mandal, Ranajit Kumar; Basu, Partha; Biswas, Jaydip; Roychoudhury, Susanta; Panda, Chinmay Kumar
2015-07-01
The aim of this study was to understand the association of human papillomavirus (HPV) type 16/18 infection and polymorphisms in the HLA-DQB1 (rs6457617) and IL-1β -511 (rs16944) loci with the development of uterine cervical cancer (CaCx). The distribution of HLA-DQB1 G > A and IL-1β -511 C/T polymorphisms was determined in HPV-negative cervical swabs from normal women (N = 111) and compared with cervical swabs of HPV-cleared normal women (once HPV infected followed by natural clearance of the infection, N = 86), HPV16/18-positive cervical intraepithelial neoplasia (CIN, N = 41) and CaCx biopsies (N = 107). The A-allele containing genotypes (i.e. G/A and A/A) of HLA-DQB1 was significantly associated with CaCx compared with HPV-negative [OR = 2.56(1.42-4.62), p = 0.001] or HPV-cleared [OR = 2.07(1.12-3.87), p = 0.01] normal women, whereas the T-allele containing genotypes (i.e. C/T and T/T) of IL-1β showed increased risk of CIN [OR = 3.68(0.97-16.35), p = 0.03; OR = 3.59(0.92-16.38), p = 0.03] and CaCx development [OR = 2.03(1.03-5.2), p = 0.02; OR = 2.25(0.96-5.31), p = 0.04] compared with HPV-negative or HPV-cleared normal women. Considering these two loci together, it was evident that the T- and A-alleles rendered significantly increased susceptibility for development of CIN and CaCx compared with HPV-negative and HPV-cleared normal women. Moreover, the T-allele of IL-1β showed increased susceptibility for CIN [OR = 3.62(0.85-17.95), p = 0.04] and CaCx [OR = 2.39(0.91-6.37), p = 0.05] development compared with the HPV-cleared women, even in the presence of the HLA-DQB1 G-allele. Thus, our data suggest that persistent HPV16/18 infection in the cervix due to the presence of the HLA-DQB1 A-allele and chronic inflammation due to the presence of the IL-1β -511 T-allele might predispose women to CaCx development.
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Evidence for multiple major histocompatibility class II X-box binding proteins.
Celada, A; Maki, R
1989-01-01
The X box is a loosely conserved DNA sequence that is located upstream of all major histocompatibility class II genes and is one of the cis-acting regulatory elements. Despite the similarity between all X-box sequences, each promoter-proximal X box in the mouse appears to bind a separate nuclear factor.
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Directory of Open Access Journals (Sweden)
Carvalho Adriana
2003-01-01
Full Text Available Esclerose múltipla (EM é doença inflamatória desmielinizante do sistema nervoso central (SNC de natureza autoimune, mediada por linfócitos Th1. A produção de autoanticorpos séricos para proteína básica da mielina (MBP, proteolipídeo PLP e sequência da glicoproteína de oligodendrócito MOG 92-106, foi determinada em 54 indivíduos saudáveis e 26 pacientes com EM expressando ou não o alelo de suscetibilidade HLA-DQB1*0602. Independentemente da expressão do alelo DQB1*0602, todos os pacientes apresentaram produção marcante (p< 0,0001 de autoanticorpos isotipo IgG para MBP e MOG 92-106, e do isotipo IgA para PLP e MOG 92-106. Os resultados sugerem que outros alelos HLA da classe II exerçam influência na suscetibilidade à EM e no reconhecimento imunológico dos antígenos encefalitogênicos, determinando o padrão de resposta autoimune e contribuindo na manutenção e/ou controle da inflamação no SNC.
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Ross, Ian; Boulle, Andrew; Soule, Steven; Levitt, Naomi; Pirie, Fraser; Karlsson, Anders; Mienie, Japie; Yang, Ping; Wang, Hongjie; She, Jin-Xiong; Winter, William; Schatz, Desmond
2010-09-01
We sought to determine whether autoimmunity is the predominant cause of Addison's disease in South Africa and whether human leucocyte antigen (HLA) DQ association exists. We compiled a national registry of patients from primary care, referral centres and private practices. A total of 144 patients, 94 of European descent, 34 Mixed Ancestry, 5 Asian and 11 Black Africans (mean age 45.9 years, range 2.7-88 years; mean duration of disease 13.1 years, range 0-50 years) and controls were matched for gender and ethnicity. All potential causes were investigated. Fifty one per cent of cases (74 patients) were autoimmune in aetiology. Either 21-hydroxylase autoantibodies (72 patients, 50% of entire patient group) or adrenocortical autoantibodies (35 patients, 24%) were present, while 23% of patients had both. None of the Asian (n = 5) or Black (n = 11) patients had evidence of autoimmune disease. Overall 8% of patients had tuberculosis, 4% adrenoleucodystrophy, 1% adrenocorticotrophic hormone resistance syndrome and 6% X-linked adrenal hypoplasia. In those with autoimmune disease primary hypothyroidism (47%), premature ovarian failure (8%) and type 1 diabetes (7%) were the most prevalent accompanying autoimmune conditions. HLA DQB1*0201 alleles predominated in the autoimmune group (DQB1*0201: 65%vs 43% of controls P = 0.017) with the *0201/*0302 heterozygous genotype being the most prevalent (28%vs 8%P = 0.02). While autoimmunity accounts for at least half of patients with Addison's disease in South Africa and is associated with HLA DQB1*0201, none of the Black Africans or Asians in this cohort had adrenal autoantibodies. Moreover, 21-hydroxylase autoantibodies were detectable in a higher proportion than adrenocortical autoantibodies, especially in those patients with a long history after disease onset.
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Kamath, Pauline L; Getz, Wayne M
2011-05-18
Major Histocompatibility Complex (MHC) genes are central to vertebrate immune response and are believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and trans-species polymorphisms at these loci. In equids, the organization and variability of this gene family has been described, however the full extent of diversity and selection is unknown. As selection is not expected to act uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for species adaptations. We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA), DRA and DQA, in the genus Equus with the addition of novel alleles identified in plains zebra (E. quagga, formerly E. burchelli). We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele lineages. To our knowledge, DRA allelic diversity was discovered to be higher than has ever been observed in vertebrates. Evidence was also found to support a duplication of the DQA locus. Selection analyses, evaluated in terms of relative rates of nonsynonymous to synonymous mutations (dN/dS) averaged over the gene region, indicated that the majority of codon sites were conserved and under purifying selection (dN
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Directory of Open Access Journals (Sweden)
Getz Wayne M
2011-05-01
Full Text Available Abstract Background Major Histocompatibility Complex (MHC genes are central to vertebrate immune response and are believed to be under balancing selection by pathogens. This hypothesis has been supported by observations of extremely high polymorphism, elevated nonsynonymous to synonymous base pair substitution rates and trans-species polymorphisms at these loci. In equids, the organization and variability of this gene family has been described, however the full extent of diversity and selection is unknown. As selection is not expected to act uniformly on a functional gene, maximum likelihood codon-based models of selection that allow heterogeneity in selection across codon positions can be valuable for examining MHC gene evolution and the molecular basis for species adaptations. Results We investigated the evolution of two class II MHC genes of the Equine Lymphocyte Antigen (ELA, DRA and DQA, in the genus Equus with the addition of novel alleles identified in plains zebra (E. quagga, formerly E. burchelli. We found that both genes exhibited a high degree of polymorphism and inter-specific sharing of allele lineages. To our knowledge, DRA allelic diversity was discovered to be higher than has ever been observed in vertebrates. Evidence was also found to support a duplication of the DQA locus. Selection analyses, evaluated in terms of relative rates of nonsynonymous to synonymous mutations (dN/dS averaged over the gene region, indicated that the majority of codon sites were conserved and under purifying selection (dN dS. However, the most likely evolutionary codon models allowed for variable rates of selection across codon sites at both loci and, at the DQA, supported the hypothesis of positive selection acting on specific sites. Conclusions Observations of elevated genetic diversity and trans-species polymorphisms supported the conclusion that balancing selection may be acting on these loci. Furthermore, at the DQA, positive selection was
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Schizophrenia risk from complex variation of complement component 4
Sekar, Aswin; Bialas, Allison R.; de Rivera, Heather; Davis, Avery; Hammond, Timothy R.; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matthew; van Doren, Vanessa; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert E.; Daly, Mark J.; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven A.; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; de Haan, Lieuwe
2016-01-01
Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging
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S. V. Koshkin
2017-01-01
Full Text Available Sixty patients with different clinical symptoms of secondary syphilis (ulcer chancres, pustular syphilis, hypertrophic papules, widespread leukoderma and alopecia were examined in order to study the distribution pattern of histocompatibility antigens of the first class in patients with secondary syphilis of the skin and mucous membranes. As a result of the study, the presence of an associative relationship between the distribution pattern of histocompatibility antigens of the first class and various clinical manifestations in patients with secondary syphilis was established.
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Pugliese, Alberto; Boulware, David; Yu, Liping; Babu, Sunanda; Steck, Andrea K; Becker, Dorothy; Rodriguez, Henry; DiMeglio, Linda; Evans-Molina, Carmella; Harrison, Leonard C; Schatz, Desmond; Palmer, Jerry P; Greenbaum, Carla; Eisenbarth, George S; Sosenko, Jay M
2016-04-01
The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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Barrionuevo, Paula; Cassataro, Juliana; Delpino, M. Victoria; Zwerdling, Astrid; Pasquevich, Karina A.; Samartino, Clara García; Wallach, Jorge C.; Fossati, Carlos A.; Giambartolomei, Guillermo H.
2008-01-01
The strategies that allow Brucella abortus to survive inside macrophages for prolonged periods and to avoid the immunological surveillance of major histocompatibility complex class II (MHC-II)-restricted gamma interferon (IFN-γ)-producing CD4+ T lymphocytes are poorly understood. We report here that infection of THP-1 cells with B. abortus inhibited expression of MHC-II molecules and antigen (Ag) processing. Heat-killed B. abortus (HKBA) also induced both these phenomena, indicating the independence of bacterial viability and involvement of a structural component of the bacterium. Accordingly, outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, inhibited both MHC-II expression and Ag processing to the same extent as HKBA. Moreover, a synthetic lipohexapeptide that mimics the structure of the protein lipid moiety also inhibited MHC-II expression, indicating that any Brucella lipoprotein could down-modulate MHC-II expression and Ag processing. Inhibition of MHC-II expression and Ag processing by either HKBA or lipidated Omp19 (L-Omp19) depended on Toll-like receptor 2 and was mediated by interleukin-6. HKBA or L-Omp19 also inhibited MHC-II expression and Ag processing of human monocytes. In addition, exposure to the synthetic lipohexapeptide inhibited Ag-specific T-cell proliferation and IFN-γ production of peripheral blood mononuclear cells from Brucella-infected patients. Together, these results indicate that there is a mechanism by which B. abortus may prevent recognition by T cells to evade host immunity and establish a chronic infection. PMID:17984211
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DEFF Research Database (Denmark)
Poudrier, J; Owens, T
1994-01-01
We have examined signaling roles for CD54 intercellular adhesion molecule 1 and major histocompatibility complex (MHC) II as contact ligands during T help for B cell activation. We used a T helper 1 (Th1)-dependent helper system that was previously shown to be contact as well as interleukin 2 (IL-2......) dependent to demonstrate the relative roles of CD54, MHC II, and CD40 signaling in the events leading to the induction of B cell proliferation and responsiveness to IL-2. Paraformaldehyde-fixed activated Th1-induced expression of IL-2R alpha, IL-2R beta, and B7, and upregulated MHC II and CD54 on B cells...... resulted in the upregulated expression of MHC II and of CD54 and B7, respectively, analogous to the effect of fixed activated Th1 cells. B7 expression was further enhanced by co-cross-linking CD54 and MHC II. Cross-linking of CD40 achieved comparable effects. Strikingly, cross-linking ligation of CD54...
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Sun Chongran
2010-08-01
Full Text Available Abstract Background The relationship between functional improvements in ischemic rats given a neural stem cell (NSC transplant and the modulation of the class I major histocompatibility complex (MHC mediated by NSC-derived neurotrophins was investigated. Methods The levels of gene expression of nerve growth factor (NGF, brain-derived neurotropic factor (BDNF and neurotrophin-3 (NT-3 were assayed from cultures of cortical NSC from Sprague-Dawley rat E16 embryos. The levels of translated NGF in spent culture media from NSC cultures and the cerebral spinal fluid (CSF of rats with and without NGF injection or NSC transplant were also measured. Results We found a significant increase of NGF, BDNF and NT-3 transcripts and NGF proteins in both the NSC cultures and the CSF of the rats. The immunochemical staining for MHC in brain sections and the enzyme-linked immunosorbent assay of CSF were carried out in sham-operated rats and rats with surgically induced focal cerebral ischemia. These groups were further divided into animals that did and did not receive NGF administration or NSC transplant into the cisterna magna. Our results show an up-regulation of class I MHC in the ischemic rats with NGF and NSC administration. The extent of caspase-III immunoreactivity was comparable among three arms in the ischemic rats. Conclusion Readouts of somatosensory evoked potential and the trap channel test illustrated improvements in the neurological function of ischemic rats treated with NGF administration and NSC transplant.
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Comparative analysis of minor histocompatibility antigens genotyping methods
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A. S. Vdovin
2016-01-01
Full Text Available The wide range of techniques could be employed to find mismatches in minor histocompatibility antigens between transplant recipients and their donors. In the current study we compared three genotyping methods based on polymerase chain reaction (PCR for four minor antigens. Three of the tested methods: allele-specific PCR, restriction fragment length polymorphism and real-time PCR with TaqMan probes demonstrated 100% reliability when compared to Sanger sequencing for all of the studied polymorphisms. High resolution melting analysis was unsuitable for genotyping of one of the tested minor antigens (HA-1 as it has linked synonymous polymorphism. Obtained data could be used to select the strategy for large-scale clinical genotyping.
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Typing of human fetal organs for the histocompatibility antigens A, B and DR.
Tuch, B E; Doran, T J; Messel, N; Turtle, J R
1985-01-01
In the transplantation of human fetal pancreatic explants into diabetic man, the importance of matching the histocompatibility antigens of donor and recipient to decrease the chances of rejection is unknown. Before this question can be answered human fetuses must be tissue typed. We have shown that lymphocytes harvested from fetal liver, thymus, bone marrow and spleen can be successfully HLA DR typed in 64% and A and B typed in 57% of 58 fetuses aged 15 wk or more. Typing should ideally be carried out on unseparated T and B cells. Best results were achieved if all four of the above organs were available and more than one million viable cells were able to be harvested for typing. Whilst the DR antigens could be typed from all tissues, the A and B antigens could be typed, with few exceptions only from thymus, spleen and bone marrow. The efficacy of matching the histocompatibility antigens of recipient and donor fetuses, especially the DR antigens can now be tested in the human diabetic being transplanted with pancreatic explants.
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Holder, Angela L; Kennedy, Lorna J; Ollier, William E R; Catchpole, Brian
2015-10-15
Administration of insulin for treatment of diabetes mellitus in dogs can stimulate an immune response, with a proportion of animals developing anti-insulin antibodies (AIA). For an IgG antibody response to occur, this would require B cell presentation of insulin peptides by major histocompatibility complex (MHC) class II molecules, encoded by dog leukocyte antigen (DLA) genes, in order to receive T-cell help for class switching. DLA genes are highly polymorphic in the dog population and vary from breed to breed. The aim of the present study was to evaluate AIA reactivity in diabetic dogs of different breeds and to investigate whether DLA genes influence AIA status. Indirect ELISA was used to determine serological reactivity to insulin in diabetic dogs, treated with either a porcine or bovine insulin preparation. DLA haplotypes for diabetic dogs were determined by sequence-based typing of DLA-DRB1, -DQA1 and -DQB1 loci. Significantly greater insulin reactivity was seen in treated diabetic dogs (n=942) compared with non-diabetic dogs (n=100). Relatively few newly diagnosed diabetic dogs (3/109) were found to be AIA positive, although this provides evidence that insulin autoantibodies might be involved in the pathogenesis of the disease in some cases. Of the diabetic dogs treated with a bovine insulin preparation, 52.3% (182/348) were AIA positive, compared with 12.6% (75/594) of dogs treated with a porcine insulin preparation, suggesting that bovine insulin is more immunogenic. Breeds such as dachshund, Cairn terrier, miniature schnauzer and Tibetan terrier were more likely to develop AIA, whereas cocker spaniels were less likely to develop AIA, compared with crossbreed dogs. In diabetic dogs, DLA haplotype DRB1*0015--DQA1*006--DQB1*023 was associated with being AIA positive, whereas the haplotype DLA-DRB1*006--DQA1*005--DQB1*007 showed an association with being AIA negative. These research findings suggest that DLA genes influence AIA responses in treated diabetic
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Strategies for future histocompatible stem cell therapy
DEFF Research Database (Denmark)
Nehlin, Jan; Barington, Torben
2009-01-01
Stem cell therapy based on the safe and unlimited self-renewal of human pluripotent stem cells is envisioned for future use in tissue or organ replacement after injury or disease. A gradual decline of regenerative capacity has been documented among the adult stem cell population in some body organs...... during the aging process. Recent progress in human somatic cell nuclear transfer and inducible pluripotent stem cell technologies has shown that patient-derived nuclei or somatic cells can be reprogrammed in vitro to become pluripotent stem cells, from which the three germ layer lineages can be generated......, genetically identical to the recipient. Once differentiation protocols and culture conditions can be defined and optimized, patient-histocompatible pluripotent stem cells could be directed towards virtually every cell type in the human body. Harnessing this capability to enrich for given cells within...
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Miller, Marcia M.; Taylor, Robert L.
2016-01-01
Nearly all genes presently mapped to chicken chromosome 16 (GGA 16) have either a demonstrated role in immune responses or are considered to serve in immunity by reason of sequence homology with immune system genes defined in other species. The genes are best described in regional units. Among these, the best known is the polymorphic major histocompatibility complex-B (MHC-B) region containing genes for classical peptide antigen presentation. Nearby MHC-B is a small region containing two CD1 genes, which encode molecules known to bind lipid antigens and which will likely be found in chickens to present lipids to specialized T cells, as occurs with CD1 molecules in other species. Another region is the MHC-Y region, separated from MHC-B by an intervening region of tandem repeats. Like MHC-B, MHC-Y is polymorphic. It contains specialized class I and class II genes and c-type lectin-like genes. Yet another region, separated from MHC-Y by the single nucleolar organizing region (NOR) in the chicken genome, contains olfactory receptor genes and scavenger receptor genes, which are also thought to contribute to immunity. The structure, distribution, linkages and patterns of polymorphism in these regions, suggest GGA 16 evolves as a microchromosome devoted to immune defense. Many GGA 16 genes are polymorphic and polygenic. At the moment most disease associations are at the haplotype level. Roles of individual MHC genes in disease resistance are documented in only a very few instances. Provided suitable experimental stocks persist, the availability of increasingly detailed maps of GGA 16 genes combined with new means for detecting genetic variability will lead to investigations defining the contributions of individual loci and more applications for immunogenetics in breeding healthy poultry. PMID:26740135
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Quantifying the energetics of cooperativity in a ternary protein complex
DEFF Research Database (Denmark)
Andersen, Peter S; Schuck, Peter; Sundberg, Eric J
2002-01-01
and mathematical modeling to describe the energetics of cooperativity in a trimolecular protein complex. As a model system for quantifying cooperativity, we studied the ternary complex formed by the simultaneous interaction of a superantigen with major histocompatibility complex and T cell receptor, for which...... a structural model is available. This system exhibits positive and negative cooperativity, as well as augmentation of the temperature dependence of binding kinetics upon the cooperative interaction of individual protein components in the complex. Our experimental and theoretical analysis may be applicable...... to other systems involving cooperativity....
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Directory of Open Access Journals (Sweden)
Sarrah Castillo
Full Text Available The major histocompatibility complex (MHC presents a unique system to explore links between genetic diversity and pathogens, as diversity within MHC is maintained in part by pathogen driven selection. While the majority of wildlife MHC studies have investigated species that are of conservation concern, here we characterize MHC variation in a common and broadly distributed species, the North American raccoon (Procyon lotor. Raccoons host an array of broadly distributed wildlife diseases (e.g., canine distemper, parvovirus and raccoon rabies virus and present important human health risks as they persist in high densities and in close proximity to humans and livestock. To further explore how genetic variation influences the spread and maintenance of disease in raccoons we characterized a fragment of MHC class II DRA exon 3 (250 bp and DRB exon 2 (228 bp. MHC DRA was found to be functionally monomorphic in the 32 individuals screened; whereas DRB exon 2 revealed 66 unique alleles among the 246 individuals screened. Between two and four alleles were observed in each individual suggesting we were amplifying a duplicated DRB locus. Nucleotide differences between DRB alleles ranged from 1 to 36 bp (0.4-15.8% divergence and translated into 1 to 21 (1.3-27.6% divergence amino acid differences. We detected a significant excess of nonsynonymous substitutions at the peptide binding region (P = 0.005, indicating that DRB exon 2 in raccoons has been influenced by positive selection. These data will form the basis of continued analyses into the spatial and temporal relationship of the raccoon rabies virus and the immunogenetic response in its primary host.
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Bartnes, K; Hannestad, K
2000-04-01
Peptide epitopes derived from immunoglobulin variable regions represent tumour-specific antigens on B-cell neoplasms and can be recognized by syngeneic, major histocompatibility complex (MHC) class II-restricted T cells. Immunoglobulin peptide/MHC class II complexes may also be involved in autoimmunity and CD4+ T-cell-mediated B-cell regulation. Thus, the IgG2a(b) H-chain allopeptide gamma2a(b) 435-451 presented on I-Ad mimics the epitope implicated in herpes simplex virus-induced autoimmune stromal keratitis and is the target of T helper 1 (Th1) clones that suppress IgG2a(b) production in vivo. We here report that spleen and thymus cells constitutively present the autologous gamma2a(b) epitope to a gamma2a(b) 435-451/I-A(d) reactive T-cell hybridoma as a function of the animal housing conditions (specific pathogen-free or not) and the serum levels of IgG2a(b). Constitutive presentation in the spleen was predominantly performed by dendritic cells. Whereas spleen cells poorly presented native IgG2a(b) to a gamma2a(b) 435-451/I-A(d) reactive T-cell hybridoma, IgG2a(b) in the form of immune complexes were presented > 200-fold more efficiently owing to internalization via low-affinity FcgammaR on macrophages. The antigenicity could also be improved by homotypic aggregation and by targeting IgG2a(b) to complement receptors on the A20 B-cell lymphoma. Mice without detectable IgG2a(b)-containing immune complexes typically exhibited minimal constitutive presentation. Nevertheless, native IgG2a(b) can sensitize antigen-presenting cells in vivo, as mice that were devoid of immune complexes and carried an IgG2a(b)-producing tumour did present constitutively, even at physiological IgG2a(b) serum levels. Whereas the amounts of IgG released from most B-cell lymphomas may be too low to allow spontaneous priming of tumour-specific MHC class II-restricted T cells, administration of tumour immunoglobulin in aggregated form might improve the efficacy of idiotype vaccination.
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Parasar, Parveen; Wilhelm, Amanda; Rutigliano, Heloisa M; Thomas, Aaron J; Teng, Lihong; Shi, Bi; Davis, William C; Suarez, Carlos E; New, Daniel D; White, Kenneth L; Davies, Christopher J
2016-08-01
Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-classical MHC-I isoforms, we expressed the MHC proteins in murine P815 and human K562 (MHC-I deficient) cells. Following antibiotic selection, stably transfected cell lines were stained with H1A or W6/32 antibodies to detect expression of the MHC-I proteins by flow cytometry. Two non-classical proteins (BoLA-NC1*00501 and BoLA-NC3*00101) were expressed on the cell surface in both cell lines. Surprisingly, the BoLA-NC4*00201 protein was expressed on the cell membrane of human K562 but not mouse P815 cells. Two non-classical proteins (BoLA-NC1*00401, which lacks a transmembrane domain, and BoLA-NC2*00102) did not exhibit cell surface expression. Nevertheless, Western blot analyses demonstrated expression of the MHC-I heavy chain in all transfected cell lines. Ammonium-sulfate precipitation of proteins from culture supernatants showed that BoLA-NC1*00401 was secreted and that all surface expressed proteins where shed from the cell membrane by the transfected cells. Interestingly, the surface expressed MHC-I proteins were present in culture supernatants at a much higher concentration than BoLA-NC1*00401. This comprehensive study shows that bovine non-classical MHC-I proteins BoLA-NC1*00501, BoLA-NC3*00101, and BoLA-NC4*00201 are expressed as surface isoforms with the latter reaching the cell membrane only in K562 cells. Furthermore, it demonstrated that BoLA-NC1*00401 is a secreted isoform and that significant quantities of membrane associated MHC-I proteins can be shed from the cell membrane. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Directory of Open Access Journals (Sweden)
Wilson Anthony B
2011-05-01
Full Text Available Abstract Background Both natural and sexual selection are thought to influence genetic diversity, but the study of the relative importance of these two factors on ecologically-relevant traits has traditionally focused on species with conventional sex-roles, with male-male competition and female-based mate choice. With its high variability and significance in both immune function and olfactory-mediated mate choice, the major histocompatibility complex (MHC/MH is an ideal system in which to evaluate the relative contributions of these two selective forces to genetic diversity. Intrasexual competition and mate choice are both reversed in sex-role reversed species, and sex-related differences in the detection and use of MH-odor cues are expected to influence the intensity of sexual selection in such species. The seahorse, Hippocampus abdominalis, has an exceptionally highly developed form of male parental care, with female-female competition and male mate choice. Results Here, we demonstrate that the sex-role reversed seahorse has a single MH class II beta-chain gene and that the diversity of the seahorse MHIIβ locus and its pattern of variation are comparable to those detected in species with conventional sex roles. Despite the presence of only a single gene copy, intralocus MHIIβ allelic diversity in this species exceeds that observed in species with multiple copies of this locus. The MHIIβ locus of the seahorse exhibits a novel expression domain in the male brood pouch. Conclusions The high variation found at the seahorse MHIIβ gene indicates that sex-role reversed species are capable of maintaining the high MHC diversity typical in most vertebrates. Whether such species have evolved the capacity to use MH-odor cues during mate choice is presently being investigated using mate choice experiments. If this possibility can be rejected, such systems would offer an exceptional opportunity to study the effects of natural selection in isolation
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Bahr, Angela; Wilson, Anthony B
2011-05-10
Both natural and sexual selection are thought to influence genetic diversity, but the study of the relative importance of these two factors on ecologically-relevant traits has traditionally focused on species with conventional sex-roles, with male-male competition and female-based mate choice. With its high variability and significance in both immune function and olfactory-mediated mate choice, the major histocompatibility complex (MHC/MH) is an ideal system in which to evaluate the relative contributions of these two selective forces to genetic diversity. Intrasexual competition and mate choice are both reversed in sex-role reversed species, and sex-related differences in the detection and use of MH-odor cues are expected to influence the intensity of sexual selection in such species. The seahorse, Hippocampus abdominalis, has an exceptionally highly developed form of male parental care, with female-female competition and male mate choice. Here, we demonstrate that the sex-role reversed seahorse has a single MH class II beta-chain gene and that the diversity of the seahorse MHIIβ locus and its pattern of variation are comparable to those detected in species with conventional sex roles. Despite the presence of only a single gene copy, intralocus MHIIβ allelic diversity in this species exceeds that observed in species with multiple copies of this locus. The MHIIβ locus of the seahorse exhibits a novel expression domain in the male brood pouch. The high variation found at the seahorse MHIIβ gene indicates that sex-role reversed species are capable of maintaining the high MHC diversity typical in most vertebrates.Whether such species have evolved the capacity to use MH-odor cues during mate choice is presently being investigated using mate choice experiments. If this possibility can be rejected, such systems would offer an exceptional opportunity to study the effects of natural selection in isolation, providing powerful comparative models for understanding the
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Directory of Open Access Journals (Sweden)
Kush Shrivastava
2015-10-01
Full Text Available Aim: To study the major histocompatibility complex (MHC Class II DRB1 gene polymorphism in Rohilkhandi goat using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and nucleotide sequencing techniques. Materials and Methods: DNA was isolated from 127 Rohilkhandi goats maintained at sheep and goat farm, Indian Veterinary Research Institute, Izatnagar, Bareilly. A 284 bp fragment of exon 2 of DRB1 gene was amplified and digested using BsaI and TaqI restriction enzymes. Population genetic parameters were calculated using Popgene v 1.32 and SAS 9.0. The genotypes were then sequenced using Sanger dideoxy chain termination method and were compared with related breeds/species using MEGA 6.0 and Megalign (DNASTAR software. Results: TaqI locus showed three and BsaI locus showed two genotypes. Both the loci were found to be in Hardy–Weinberg equilibrium (HWE, however, population genetic parameters suggest that heterozygosity is still maintained in the population at both loci. Percent diversity and divergence matrix, as well as phylogenetic analysis revealed that the MHC Class II DRB1 gene of Rohilkhandi goats was found to be in close cluster with Garole and Scottish blackface sheep breeds as compared to other goat breeds included in the sequence comparison. Conclusion: The PCR-RFLP patterns showed population to be in HWE and absence of one genotype at one locus (BsaI, both the loci showed excess of one or the other homozygote genotype, however, effective number of alleles showed that allelic diversity is present in the population. Sequence comparison of DRB1 gene of Rohilkhandi goat with other sheep and goat breed assigned Rohilkhandi goat in divergence with Jamanupari and Angora goats.
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Weg-Remers, S; Brenden, M; Schwarz, E; Witzel, K; Schneider, P M; Guerra, L K; Rehfeldt, I R; Lima, M T; Hartmann, D; Petzl-Erler, M L; de Messias, I J; Mauff, G
1997-10-01
Population genetic studies of the major histocompatibility complex (MHC) class III region, comprising C2, BF and C4 phenotypes, and molecular genetic data are rarely available for populations other than Caucasoids. We have investigated three Amerindian populations from Southern Brazil: 131 Kaingang from Ivaí (KIV), 111 Kaingang (KRC) and 100 Guarani (GRC) from Rio das Cobras. Extended MHC haplotypes were derived after standard C2, BF, C4 phenotyping and restriction fragment length polymorphism (RFLP) analysis with TaqI, together with HLA data published previously by segregation analysis. C2 and BF frequencies corresponded to other Amerindian populations. C4B*Q0 frequency was high in the GRC (0.429) but low in the Kaingang. Unusual C4 alleles were found, viz. C4A*58, A*55 and C4B*22 (presumably non-Amerindian) and aberrant C4A*3 of Amerindian origin occurring with a frequency of 0.223 in the GRC. C4A*3 bands of homo- and heterozygous individuals carrying this variant were Rodgers 1 positive and Chido 1,3 positive, showed a C4A specific lysis type and a C4A like alpha-chain. Polymerase chain reaction studies and sequencing showed that this is based on a C4A*3 duplication with a regular C4A*3 and a partially converted C4A*0304 carrying the C4B specific epitopes Ch 6 and Ch 1,3. Associations of class III haplotypes with particular RFLP patterns were similar to those reported for Caucasoids. The previously described association between combined C4A and CYP21P deletions and the 6.4 kb TaqI fragment was not seen in these Amerindians. This fragment occurred within a regular two locus gene structure in the Kaingang, representing a "short" gene at C4 locus I. C4 and CYP21 duplications were frequently observed. The distribution of extended MHC haplotypes provides evidence for a close relationship between the KIV and KRC and a larger genetic distance between the two Kaingang groups and the GRC.
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Razali, Haslina; O'Connor, Emily; Drews, Anna; Burke, Terry; Westerdahl, Helena
2017-07-28
High-throughput sequencing enables high-resolution genotyping of extremely duplicated genes. 454 amplicon sequencing (454) has become the standard technique for genotyping the major histocompatibility complex (MHC) genes in non-model organisms. However, illumina MiSeq amplicon sequencing (MiSeq), which offers a much higher read depth, is now superseding 454. The aim of this study was to quantitatively and qualitatively evaluate the performance of MiSeq in relation to 454 for genotyping MHC class I alleles using a house sparrow (Passer domesticus) dataset with pedigree information. House sparrows provide a good study system for this comparison as their MHC class I genes have been studied previously and, consequently, we had prior expectations concerning the number of alleles per individual. We found that 454 and MiSeq performed equally well in genotyping amplicons with low diversity, i.e. amplicons from individuals that had fewer than 6 alleles. Although there was a higher rate of failure in the 454 dataset in resolving amplicons with higher diversity (6-9 alleles), the same genotypes were identified by both 454 and MiSeq in 98% of cases. We conclude that low diversity amplicons are equally well genotyped using either 454 or MiSeq, but the higher coverage afforded by MiSeq can lead to this approach outperforming 454 in amplicons with higher diversity.
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Aït-Azzouzene, D; Langkopf, A; Cohen, J; Bleux, C; Gendron, M C; Kanellopoulos-Langevin, C
1998-05-01
Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regulation of expression of the polymorphic major histocompatibility complex (MHC) at the fetal-maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation, the absence of polymorphic MHC molecules on the early embryo, as well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class la gene H-2Kb under the control of a housekeeping gene promoter, the hydroxy-methyl-glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H-2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one-cell stage with the pHMG-Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal-maternal interface and in various transgenic mouse models.
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DEFF Research Database (Denmark)
Rognan, D; Lauemoller, S L; Holm, A
1999-01-01
A simple and fast free energy scoring function (Fresno) has been developed to predict the binding free energy of peptides to class I major histocompatibility (MHC) proteins. It differs from existing scoring functions mainly by the explicit treatment of ligand desolvation and of unfavorable protein...... coordinates of the MHC-bound peptide have first been determined with an accuracy of about 1-1.5 A. Furthermore, it may be easily recalibrated for any protein-ligand complex.......) and of a series of 16 peptides to H-2K(k). Predictions were more accurate for HLA-A2-binding peptides as the training set had been built from experimentally determined structures. The average error in predicting the binding free energy of the test peptides was 3.1 kJ/mol. For the homology model-derived equation...
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International Nuclear Information System (INIS)
Pretell, J.O.; Cone, R.E.
1985-01-01
Previous studies in our laboratory demonstrated that several treatments that inhibited the ability of cells to stimulate the mixed lymphocyte reaction (MLR) also blocked the shedding of histocompatibility antigens and Ia antigens from murine spleen cells. In the present studies, one of these treatments, ultraviolet radiation (UV), was shown to cause an initial loss in the density of H-2K, IA, and IE antigens prior to the block in shedding observed after culture of these cells. Further analysis revealed that the UV-induced loss of antigens could be prevented by the presence of colchicine during irradiation. Biosynthetic analyses revealed the IA antigen synthesis was also inhibited in the UV-irradiated cells. Examination of the effects of a second agent, 12-0-tetradecanoylphorbol-13-acetate (TPA) on the turnover of histocompatibility antigens revealed that the biosynthesis and shedding of these antigens were accelerated by this agent. However, addition of TPA to UV-irradiated cells did not result in a reversal of the UV-induced block in biosynthesis of IA antigens. Results of immune function assays correlated with the biochemical studies: UV-irradiation inhibited the generation of the MLR, but TPA enhanced this reaction, and addition of TPA to mixed lymphocyte cultures with UV-irradiated stimulators did not reverse the UV-induced inhibition. These results suggest that, although the turnover of histocompatibility antigens may be affected by TPA and UV in an antagonistic fashion, additional factors other than the expression of histocompatibility antigens are operating in the inhibition of stimulation of an MLR by UV radiation or its enhancement by TPA
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Hamada, K; Gleason, S L; Levi, B Z; Hirschfeld, S; Appella, E; Ozato, K
1989-01-01
Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, bu...
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DEFF Research Database (Denmark)
Hokland, M; Basse, P; Justesen, J
1989-01-01
IFN proteins are a family of lymphokines with anti-viral effects. Several other effects of IFNs have also been described, including enhancement of natural killer (NK) cell activity, enhancement of cytotoxic T-lymphocyte activity, and enhancement of the expression of major histocompatibility compl...... to the classical anti-viral mechanism. This concept proposes that the MHC-enhancing effect of IFNs is a vital part of the immunological defense against virus infections and an integral part of the anti-viral effects of IFN proteins. Udgivelsesdato: 1988-Nov...
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Imputing amino acid polymorphisms in human leukocyte antigens.
Directory of Open Access Journals (Sweden)
Xiaoming Jia
Full Text Available DNA sequence variation within human leukocyte antigen (HLA genes mediate susceptibility to a wide range of human diseases. The complex genetic structure of the major histocompatibility complex (MHC makes it difficult, however, to collect genotyping data in large cohorts. Long-range linkage disequilibrium between HLA loci and SNP markers across the major histocompatibility complex (MHC region offers an alternative approach through imputation to interrogate HLA variation in existing GWAS data sets. Here we describe a computational strategy, SNP2HLA, to impute classical alleles and amino acid polymorphisms at class I (HLA-A, -B, -C and class II (-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1 loci. To characterize performance of SNP2HLA, we constructed two European ancestry reference panels, one based on data collected in HapMap-CEPH pedigrees (90 individuals and another based on data collected by the Type 1 Diabetes Genetics Consortium (T1DGC, 5,225 individuals. We imputed HLA alleles in an independent data set from the British 1958 Birth Cohort (N = 918 with gold standard four-digit HLA types and SNPs genotyped using the Affymetrix GeneChip 500 K and Illumina Immunochip microarrays. We demonstrate that the sample size of the reference panel, rather than SNP density of the genotyping platform, is critical to achieve high imputation accuracy. Using the larger T1DGC reference panel, the average accuracy at four-digit resolution is 94.7% using the low-density Affymetrix GeneChip 500 K, and 96.7% using the high-density Illumina Immunochip. For amino acid polymorphisms within HLA genes, we achieve 98.6% and 99.3% accuracy using the Affymetrix GeneChip 500 K and Illumina Immunochip, respectively. Finally, we demonstrate how imputation and association testing at amino acid resolution can facilitate fine-mapping of primary MHC association signals, giving a specific example from type 1 diabetes.
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Directory of Open Access Journals (Sweden)
Amal A. Mohamed
2017-07-01
Full Text Available The major histocompatibility complex class I-related gene A (MICA is an antigen induced by stress and performs an integral role in immune responses as an anti-infectious and antitumor agent. This work was designed to investigate whether (SNP rs2596542C/T in MICA promoter region is predictive of liver cirrhosis (LC and hepatocellular carcinoma (HCC or not. Forty-seven healthy controls and 94 HCV-infected patients, subdivided into 47 LC and 47 HCC subjects were enrolled in this study. SNP association was studied using real time PCR and soluble serum MICA concentration was measured using ELISA. Results showed that heterozygous genotype rs2596542CT was significantly (P = 0.022 distributed between HCC and LC related CHC patients. The sMICA was significantly higher (P = 0.0001 among HCC and LC. No significant association (P = 0.56 between rs2596542CT genotypes and sMICA levels was observed. Studying SNP rs2596542C/T association with HCC and LC susceptibility revealed that statistical significant differences (P = 0.013, P = 0.027 were only observed between SNP rs2596542C/T and each of HCC and LC, respectively, versus healthy controls, indicating that the rs2596542C/T genetic variation is not a significant contributor to HCC development in LC patients. Moreover, the T allele was considered a risk factor for HCC and LC vulnerability in HCV patients (OR = 1.93 and 2.1, respectively, while the C allele contributes to decreasing HCC risk. Therefore, SNP (rs2596542C/T in MICA promoter region and sMICA levels might be potential useful markers in the assessment of liver disease progression to LC and HCC.
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Ferrero, Mariana C.; Hielpos, M. Soledad; Carvalho, Natalia B.; Barrionuevo, Paula; Corsetti, Patricia P.; Giambartolomei, Guillermo H.; Oliveira, Sergio C.
2014-01-01
Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-α), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1β (IL-1β), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID:24478078
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New recombinants within the MHC (B-complex) of the chicken
DEFF Research Database (Denmark)
Koch, C; Skjødt, K; Toivanen, A
1983-01-01
In a search for genetic recombinations within the major histocompatibility complex (MHC) of the chicken, the B-complex, the offspring from matings between heterozygous B15/B21 and B4/B6 animals were analysed by red cell agglutination. Among the progeny, 8,912 informative typings were performed...... followed B-F/B-L. The mapping distance between the two loci B-F and B-G is in the range of 0.04 centimorgan. The lack of recombinants separating individual B-F loci in this study and in the studies of others might indicate that chicken MHC is less complex than those of mammalian species, but alternative...
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Parsa, A T; Chi, J H; Hurley, P T; Jeyapalan, S A; Bruce, J N
2001-09-01
Acquired immunity has been demonstrated in Fischer rats bearing syngeneic 9L tumors after herpes simplex virus (HSV) thymidine kinase (TK) gene transfection and ganciclovir treatment. The nature of this immunity in rats and its relevance to the HSV TK/ganciclovir protocol for human subjects remain to be determined. In this study, levels of major histocompatibility complex (MHC) Class I and II antigen expression were measured before and after HSV TK transfection, in an effort to document immunomodulatory changes caused by gene therapy. Tumor cells from the 9L gliosarcoma cell line, three primary human glioma cultures, and the human glioma cell line U87 MG were transduced with HSV TK vector-containing supernatant from fibroblast-producing cells (titer of 5 x 10(6) colony-forming units/ml) and selected in G418 medium for neomycin resistance. Clones were pooled or individually selected for cell-killing assays with ganciclovir, to confirm TK expression (10(3) cells/well in a 96-well dish). Northern analyses using MHC Class I and Class II complementary deoxyribonucleic acid probes were performed on blots containing total ribonucleic acid from wild-type tumor cells and HSV TK transfectants. A beta-actin complementary deoxyribonucleic acid probe served as an internal control. Cell surface expression was confirmed with flow cytometry. The induction of MHC Class I was tested for cycloheximide and genistein sensitivity. All cell cultures exhibited increases in MHC Class I but not MHC Class II expression, as determined by Northern analysis densitometry and flow cytometry. Cycloheximide treatment did not diminish the up-regulation of MHC Class I after retroviral transfection, implicating a signal transduction pathway that does not require ongoing protein synthesis. Genistein pretreatment of cell cultures did diminish the up-regulation of MHC Class I, implicating a tyrosine kinase in the signaling cascade. Induction of MHC Class I in rat and human glioma cells after HSV TK
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Laher, Faatima; Ranasinghe, Srinika; Porichis, Filippos; Mewalal, Nikoshia; Pretorius, Karyn; Ismail, Nasreen; Buus, Søren; Stryhn, Anette; Carrington, Mary; Walker, Bruce D; Ndung'u, Thumbi; Ndhlovu, Zaza M
2017-04-01
Immune control of viral infections is heavily dependent on helper CD4 + T cell function. However, the understanding of the contribution of HIV-specific CD4 + T cell responses to immune protection against HIV-1, particularly in clade C infection, remains incomplete. Recently, major histocompatibility complex (MHC) class II tetramers have emerged as a powerful tool for interrogating antigen-specific CD4 + T cells without relying on effector functions. Here, we defined the MHC class II alleles for immunodominant Gag CD4 + T cell epitopes in clade C virus infection, constructed MHC class II tetramers, and then used these to define the magnitude, function, and relation to the viral load of HIV-specific CD4 + T cell responses in a cohort of untreated HIV clade C-infected persons. We observed significantly higher frequencies of MHC class II tetramer-positive CD4 + T cells in HIV controllers than progressors ( P = 0.0001), and these expanded Gag-specific CD4 + T cells in HIV controllers showed higher levels of expression of the cytolytic proteins granzymes A and B. Importantly, targeting of the immunodominant Gag41 peptide in the context of HLA class II DRB1*1101 was associated with HIV control ( r = -0.5, P = 0.02). These data identify an association between HIV-specific CD4 + T cell targeting of immunodominant Gag epitopes and immune control, particularly the contribution of a single class II MHC-peptide complex to the immune response against HIV-1 infection. Furthermore, these results highlight the advantage of the use of class II tetramers in evaluating HIV-specific CD4 + T cell responses in natural infections. IMPORTANCE Increasing evidence suggests that virus-specific CD4 + T cells contribute to the immune-mediated control of clade B HIV-1 infection, yet there remains a relative paucity of data regarding the role of HIV-specific CD4 + T cells in shaping adaptive immune responses in individuals infected with clade C, which is responsible for the majority of HIV
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International Nuclear Information System (INIS)
Hodes, R.J.; Hathcock, K.S.; Singer, A.
1983-01-01
In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways
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Kwun, Jean; Farris, Alton B; Song, Hyunjin; Mahle, William T; Burlingham, William J; Knechtle, Stuart J
2015-12-01
Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.
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Identification of a Novel UTY‐Encoded Minor Histocompatibility Antigen
DEFF Research Database (Denmark)
Mortensen, B. K.; Rasmussen, A. H.; Larsen, Malene Erup
2012-01-01
Minor histocompatibility antigens (mHags) encoded by the Y‐chromosome (H‐Y‐mHags) are known to play a pivotal role in allogeneic haematopoietic cell transplantation (HCT) involving female donors and male recipients. We present a new H‐Y‐mHag, YYNAFHWAI (UTY139–147), encoded by the UTY gene...... obtained post‐HCT from male recipients of female donor grafts. In one of these recipients, a CD8+ T cell response was observed against a peptide stretch encoded by the UTY gene. Another bioinformatics tool, HLArestrictor, was used to identify the optimal peptide and HLA‐restriction element. Using peptide....../HLA tetramers, the specificity of the CD8+ T cell response was successfully validated as being HLA‐A*24:02‐restricted and directed against the male UTY139–147 peptide. Functional analysis of these T cells demonstrated male UTY139–147 peptide‐specific cytokine secretion (IFNγ, TNFα and MIP‐1β) and cytotoxic...
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Williams, R; Chen, Y-F; Endres, R; Middleton, D; Trucco, M; Williams, J Dunn; Knowler, W
2009-12-01
A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high-resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only five allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two 'private' alleles, B*5102 and B*4005, which are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the six most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high-frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members.
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Reference free phasing and representation of complex variation
DEFF Research Database (Denmark)
Jensen, Jacob Malte
2017-01-01
High throughput sequencing has revolutionized our ability to interrogate genomes and entire human genomes are sequenced daily across the world. Mapping of short reads to a reference genome has enhanced our ability to detect genetic variation and is currently the most widely used technology....... Therefore, new methods for detecting variation that reduce reference bias are needed including ways of representing genomes that account for the variability within and between populations. The major histocompatibility complex (MHC) region is one of the most diverse and complex regions of the human genome...... to detect and call variation in humans. However, it has become evident that mapping of short reads to a single reference genome is subject to ascertainment bias (reference bias). This bias is especially pronounced in complex regions of the genome and particularly hampers detection of structural variation...
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Endocrine autoimmune disease: genetics become complex.
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.
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Waldburger, Jean-Marc; Palmer, Gaby; Seemayer, Christian; Lamacchia, Celine; Finckh, Axel; Christofilopoulos, Panayiotis; Baeten, Dominique; Reith, Walter; Gabay, Cem
2011-11-01
To determine the regulation of class II major histocompatibility complex (MHC) expression in fibroblast-like synoviocytes (FLS) in order to investigate their role as nonprofessional antigen-presenting cells in collagen-induced arthritis (CIA). Expression of class II MHC, class II MHC transactivator (CIITA), and Ciita isoforms PI, PIII, and PIV was examined by real-time quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry in human synovial tissues, arthritic mouse joints, and human and murine FLS. CIA was induced in mice in which isoform PIV of Ciita was knocked out (PIV(-/-) ), in PIV(-/-) mice transgenic for CIITA in the thymus (K14 CIITA), and in their control littermates. HLA-DRA, total CIITA, and CIITA PIII messenger RNA levels were significantly increased in synovial tissue samples from patients with rheumatoid arthritis compared with the levels in tissue from patients with osteoarthritis. Human FLS expressed surface class II MHC via CIITA PIII and PIV, while class II MHC expression in murine FLS was entirely mediated by PIV. Mice with a targeted deletion of CIITA PIV lack CD4+ T cells and were protected against CIA. The expression of CIITA was restored in the thymus of PIV(-/-) K14 CIITA-transgenic mice, which had a normal CD4+ T cell repertoire and normal surface levels of class II MHC on professional antigen-presenting cells, but did not induce class II MHC on FLS. Synovial inflammation and immune responses against type II collagen were similar in PIV(-/-) K14 CIITA-transgenic mice and control mice with CIA, but bone erosion was significantly reduced in the absence of PIV. Overexpression of class II MHC is tightly correlated with CIITA expression in arthritic synovium and in FLS. Selective targeting of Ciita PIV in peripheral tissues abrogates class II MHC expression by murine FLS but does not protect against inflammation and autoimmune responses in CIA. Copyright © 2011 by the American College of Rheumatology.
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Aliesky, Holly; Banuelos, Bianca; Magana, Jessica; Williams, Robert W.; Rapoport, Basil
2014-01-01
Graves' hyperthyroidism is caused by antibodies to the TSH receptor (TSHR) that mimic thyroid stimulation by TSH. Stimulating TSHR antibodies and hyperthyroidism can be induced by immunizing mice with adenovirus expressing the human TSHR A-subunit. Prior analysis of induced Graves' disease in small families of recombinant inbred (RI) female mice demonstrated strong genetic control but did not resolve trait loci for TSHR antibodies or elevated serum T4. We investigated the genetic basis for induced Graves' disease in female mice of two large RI families and combined data with earlier findings to provide phenotypes for 178 genotypes. TSHR antibodies measured by inhibition of TSH binding to its receptor were highly significantly linked in the BXD set to the major histocompatibility region (chromosome 17), consistent with observations in 3 other RI families. In the LXS family, we detected linkage between T4 levels after TSHR-adenovirus immunization and the Ig heavy chain variable region (Igvh, chromosome 12). This observation is a key finding because components of the antigen binding region of Igs determine antibody specificity and have been previously linked to induced thyroid-stimulating antibodies. Data from the LXS family provide the first evidence in mice of a direct link between induced hyperthyroidism and Igvh genes. A role for major histocompatibility genes has now been established for genetic susceptibility to Graves' disease in both humans and mice. Future studies using arrays incorporating variation in the complex human Ig gene locus will be necessary to determine whether Igvh genes are also linked to Graves' disease in humans. PMID:25051451
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Directory of Open Access Journals (Sweden)
Haichong Wu
2018-02-01
Full Text Available IFN-τ, a type I interferon produced by the trophoblasts of ruminants, has various important immune functions, including effects on the expression of major histocompatibility complex (MHC class I (MHC-I. A previous study has reported that IFN-τ promotes the expression of MHC-I molecules on endometrial cells. However, the immunological mechanisms by which IFN-τ regulates MHC-I molecules remain unknown. Here, we investigated which microRNA (miRNAs may be involved in the regulation of MHC-I molecule expression and function in bovine endometrial epithelial cells (bEECs. By using TargetScan 6.2 and http://www.microRNA.org, two miRNAs were suggested to target the 3′UTR of the bovine MHC-I heavy chain: bta-miR-148b and bta-miR-152. Dual luciferase reporter and miRNA mimic/inhibitor assays suggested that bta-miR-148b/152 were negatively correlated with bovine MHC-I heavy chain genes. The function of the MHC-I heavy chain was then investigated using qRT-PCR, ELISA, western blotting, immunofluorescence, and RNA interference assays in primary bEECs and an endometrial epithelial cell line (BEND. The results demonstrated that bta-miR-148b/152 could promote TLR4-triggered inflammatory responses by targeting the bovine MHC-I heavy chain, and the MHC-I molecule negatively regulated TLR4-induced inflammatory reactions may through the Fps-SHP-2 pathway. Our discovery offers novel insight into negative regulation of the TLR4 pathway and elucidates the mechanism by which bovine MHC-I molecules control congenital inflammatory reactions.
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DEFF Research Database (Denmark)
Owens, T; Fazekas de St Groth, B
1987-01-01
two monoclonal antibodies, KJ16-133.18 and F23.1, that recognize a determinant encoded by the T cell receptor V beta 8 gene family. These antibodies were used to select two clones of T cells with surface phenotype Thy-1.2+, L3T4+, Lyt-2-, KJ16-133.18+, F23.1+, IA-, IE-. One of these clones (E9.D4......The recognition of many class II major histocompatibility complex (MHC)-associated antigens by T cells requires the participation of the L3T4 molecule. It has been proposed that this molecule acts to stabilize low affinity binding to antigen in association with MHC and thereby increases the avidity...... of T cell/antigen interactions. By using antibodies against the T cell antigen receptor (TCR) to activate T cells, thereby circumventing the requirement for antigen presenting cells and MHC-associated antigen, we have been able to study the function of L3T4 in the absence of class II MHC. We have used...
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Haplotype specific alteration of diabetes MHC risk by olfactory receptor gene polymorphism.
Jahromi, Mohamed M
2012-12-01
Evidence for genes associated with risk for Type 1 diabetes (T1D) in the extended region of the major histocompatibility complex (MHC) genes is accumulating. The aim of this study was to investigate the association pattern of the extended MHC region with T1D susceptibility to identify effects independent of well established DR/DQ genes. A total of 394 Europid families with T1D were genotyped for the single nucleotide polymorphism (SNP) in the olfactory receptor family 14, subfamily J, member 1 (OR14J1) gene, rs9257691, in the MHC telomeric region. The OR provides "an internal depiction of our external world" through the capture of odorant molecules in the main OR system by several large families of G-protein coupled receptors (GPCR). These receptors transduce and chemosignals into the central nervous system (CNS). This SNP was chosen to identify its association with T1D. Interestingly, OR14J1C allele was significantly associated with T1D that seems to go with DRB1*0401, Χ(2)=10.9, p=0.0003. However, by fixing both genes of DR*0401-DQB1*0302, high risk, the association of T1D with OR14J1C still existed, Χ(2)=7.4, p=0.005. The occurrence of association of the OR14J1C allele with T1D patients with DRB1*401/DQB1*0302 is an independent risk for T1D. As an accumulative report suggests the role of OR in the pathogenesis of diabetic microvascular and other diabetic complications, undoubtedly, this haplotype specific alteration of T1D risk is an independent risk for the disease and can address the promising MHC-linked gene other than DR/DQ. Moreover, there is nothing to hinder for that this might be a signal that identifies the role of OR gene in the pathogenesis of T1D in patients who are prone to diabetic complications. Copyright © 2012. Published by Elsevier B.V.
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Complex Movement Disorders at Disease Onset in Childhood Narcolepsy with Cataplexy
Plazzi, Giuseppe; Pizza, Fabio; Palaia, Vincenzo; Franceschini, Christian; Poli, Francesca; Moghadam, Keivan K.; Cortelli, Pietro; Nobili, Lino; Bruni, Oliviero; Dauvilliers, Yves; Lin, Ling; Edwards, Mark J.; Mignot, Emmanuel; Bhatia, Kailash P.
2011-01-01
Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of…
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DEFF Research Database (Denmark)
Pedersen, L O; Stryhn, A; Holter, T L
1995-01-01
of class I molecules are involved in peptide binding, whereas most of class I molecules are involved in beta 2m binding. We propose that mouse beta 2m interacts with the minor peptide binding (i.e. the "empty") fraction with a lower affinity than human beta 2m does, whereas mouse and human beta 2m interact......The function of major histocompatibility complex (MHC) class I molecules is to sample peptides derived from intracellular proteins and to present these peptides to CD8+ cytotoxic T lymphocytes. In this paper, biochemical assays addressing MHC class I binding of both peptide and beta 2-microglobulin...... (beta 2m) have been used to examine the assembly of the trimolecular MHC class I/beta 2m/peptide complex. Recombinant human beta 2m and mouse beta 2ma have been generated to compare the binding of the two beta 2m to mouse class I. It is frequently assumed that human beta 2m binds to mouse class I heavy...
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International Nuclear Information System (INIS)
Chu, Fuliang; Lou, Zhiyong; Gao, Bin; Bell, John I.; Rao, Zihe; Gao, George F.
2005-01-01
Crystallization of the first rhesus macaque MHC class I complex. Simian immunodeficiency virus (SIV) infection in rhesus macaques has been used as the best model for the study of human immunodeficiency virus (HIV) infection in humans, especially in the cytotoxic T-lymphocyte (CTL) response. However, the structure of rhesus macaque (or any other monkey model) major histocompatibility complex class I (MHC I) presenting a specific peptide (the ligand for CTL) has not yet been elucidated. Here, using in vitro refolding, the preparation of the complex of the rhesus macaque MHC I allele (Mamu-A*01) with human β 2 m and an immunodominant peptide, CTPYDINQM (Gag-CM9), derived from SIV Gag protein is reported. The complex (45 kDa) was crystallized; the crystal belongs to space group I422, with unit-cell parameters a = b = 183.8, c = 155.2 Å. The crystal contains two molecules in the asymmetric unit and diffracts X-rays to 2.8 Å resolution. The structure is being solved by molecular replacement and this is the first attempt to determined the crystal structure of a peptide–nonhuman primate MHC complex
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Faulks, L K; Östman, Ö
2016-04-01
This study assessed the major histocompatibility complex (MHC) and neutral genetic variation and structure in two percid species, perch Perca fluviatilis and zander Sander lucioperca, in a unique brackish ecosystem, the Baltic Sea. In addition, to assess the importance of MHC diversity to disease susceptibility in these populations, comparisons were made to an introduced, disease susceptible, P. fluviatilis population in Australia. Eighty-three MHC class II B exon 2 variants were amplified: 71 variants from 92 P. fluviatilis samples, and 12 variants from 82 S. lucioperca samples. Microsatellite and MHC data revealed strong spatial genetic structure in S. lucioperca, but not P. fluviatilis, across the Baltic Sea. Both microsatellite and MHC data showed higher levels of genetic diversity in P. fluviatilis from the Baltic Sea compared to Australia, which may have facilitated the spread of an endemic virus, EHNV in the Australian population. The relatively high levels of genetic variation in the Baltic Sea populations, together with spatial genetic structure, however, suggest that there currently seems to be little risk of disease epidemics in this system. To ensure this remains the case in the face of ongoing environmental changes, fisheries and habitat disturbance, the conservation of local-scale genetic variation is recommended. © 2016 The Fisheries Society of the British Isles.
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DEFF Research Database (Denmark)
Hombrink, Pleun; Hadrup, Sine R; Bakker, Arne
2011-01-01
the technical feasibility of high-throughput analysis of antigen-specific T-cell responses in small patient samples. However, the high-sensitivity of this approach requires the use of potential epitope sets that are not solely based on MHC binding, to prevent the frequent detection of T-cell responses that lack......T-cell recognition of minor histocompatibility antigens (MiHA) plays an important role in the graft-versus-tumor (GVT) effect of allogeneic stem cell transplantation (allo-SCT). However, the number of MiHA identified to date remains limited, making clinical application of MiHA reactive T......MHC-tetramer-based enrichment and multi-color flow cytometry. Using this approach, 71 peptide-reactive T-cell populations were generated. The isolation of a T-cell line specifically recognizing target cells expressing the MAP4K1(IMA) antigen demonstrates that identification of MiHA through this approach is in principle...
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PeptX: Using Genetic Algorithms to optimize peptides for MHC binding
Directory of Open Access Journals (Sweden)
Ribarics Reiner
2011-06-01
Full Text Available Abstract Background The binding between the major histocompatibility complex and the presented peptide is an indispensable prerequisite for the adaptive immune response. There is a plethora of different in silico techniques for the prediction of the peptide binding affinity to major histocompatibility complexes. Most studies screen a set of peptides for promising candidates to predict possible T cell epitopes. In this study we ask the question vice versa: Which peptides do have highest binding affinities to a given major histocompatibility complex according to certain in silico scoring functions? Results Since a full screening of all possible peptides is not feasible in reasonable runtime, we introduce a heuristic approach. We developed a framework for Genetic Algorithms to optimize peptides for the binding to major histocompatibility complexes. In an extensive benchmark we tested various operator combinations. We found that (1 selection operators have a strong influence on the convergence of the population while recombination operators have minor influence and (2 that five different binding prediction methods lead to five different sets of "optimal" peptides for the same major histocompatibility complex. The consensus peptides were experimentally verified as high affinity binders. Conclusion We provide a generalized framework to calculate sets of high affinity binders based on different previously published scoring functions in reasonable runtime. Furthermore we give insight into the different behaviours of operators and scoring functions of the Genetic Algorithm.
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International Nuclear Information System (INIS)
Xu, Xiulong; Rao, Geetha S; Groh, Veronika; Spies, Thomas; Gattuso, Paolo; Kaufman, Howard L; Plate, Janet; Prinz, Richard A
2011-01-01
Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51 Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC) and ELISA, respectively. Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68%) pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production
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Directory of Open Access Journals (Sweden)
Kaufman Howard L
2011-05-01
Full Text Available Abstract Background Major histocompatibility complex class I-related chain A and B (MICA/B are two stress-inducible ligands that bind the immunoreceptor NKG2D and play an important role in mediating the cyotoxicity of NK and T cells. In this study, we sought to study MICA/B expression in pancreatic cancer and to determine whether and how genotoxic drugs such as gemcitabine can affect MICA/B expression and natural killer cytotoxity. Methods Seven pancreatic cancer cell lines were analyzed for MICA/B expression by flow cytometry and for their sensitivity to NK-92 cell killing by a 51Cr release assay. MICA/B expression in tumor tissues and sera of pancreatic cancer was analyzed by immunohistochemical staining (IHC and ELISA, respectively. Results Two MICA/B-positive cell lines were sensitive to the cytotoxic activity of NK-92 cells. Other two MICA/B-positive cell lines and three MICA/B-negative cell lines were resistant to NK-92 cell killing. MICA/B expression was positive in 17 of 25 (68% pancreatic ductal adenocarcinomas but not in normal pancreatic ductal epithelial cells. Serum MICA/B levels were significantly elevated in patients with pancreatic adenocarcinomas but did not correlate with the stage of pancreatic cancer and patient survival. Gemcitabine therapy led to increased serum MICA levels in 6 of 10 patients with detectable serum MICA. Allopurinol, an inhibitor of xanthine oxidoreductase that converts xanthine to uric acid, blocked uric acid production, MICA/B expression, and sensitivity to NK-92 cell killing toward a PANC-1 cancer cell line exposed to radiation and two genotoxic drugs, gemcitabine and 5-fluorouracil. Conclusions The levels of MICA/B expression in serum and tissue of pancreatic cancer are elevated. DNA damage-induced MICA/B expression is mediated through increased uric acid production.
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Hattotuwagama, Channa K; Doytchinova, Irini A; Flower, Darren R
2007-01-01
Quantitative structure-activity relationship (QSAR) analysis is a cornerstone of modern informatics. Predictive computational models of peptide-major histocompatibility complex (MHC)-binding affinity based on QSAR technology have now become important components of modern computational immunovaccinology. Historically, such approaches have been built around semiqualitative, classification methods, but these are now giving way to quantitative regression methods. We review three methods--a 2D-QSAR additive-partial least squares (PLS) and a 3D-QSAR comparative molecular similarity index analysis (CoMSIA) method--which can identify the sequence dependence of peptide-binding specificity for various class I MHC alleles from the reported binding affinities (IC50) of peptide sets. The third method is an iterative self-consistent (ISC) PLS-based additive method, which is a recently developed extension to the additive method for the affinity prediction of class II peptides. The QSAR methods presented here have established themselves as immunoinformatic techniques complementary to existing methodology, useful in the quantitative prediction of binding affinity: current methods for the in silico identification of T-cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate computational prediction of peptide-MHC affinity. We have reviewed various human and mouse class I and class II allele models. Studied alleles comprise HLA-A*0101, HLA-A*0201, HLA-A*0202, HLA-A*0203, HLA-A*0206, HLA-A*0301, HLA-A*1101, HLA-A*3101, HLA-A*6801, HLA-A*6802, HLA-B*3501, H2-K(k), H2-K(b), H2-D(b) HLA-DRB1*0101, HLA-DRB1*0401, HLA-DRB1*0701, I-A(b), I-A(d), I-A(k), I-A(S), I-E(d), and I-E(k). In this chapter we show a step-by-step guide into predicting the reliability and the resulting models to represent an advance on existing methods. The peptides used in this study are available from the AntiJen database (http://www.jenner.ac.uk/AntiJen). The PLS method
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HLA: The Major Histocompatibility Complex of Man
1991-01-01
be used in conjunction with asthma, hay fever, urticaria, and eczema have been solid organ transplantations. Numerous new ap- sought but have not been...IgE levels are controlled by a second. non-HLA-linked Raum (1981) and Svejgaard (1983) have reported ex- locus (or loci). Atopic patients showed an...Products Asia-Oceania ttistocompatibility Workshop Conference. Sapporo. Japan . Hlokkaido University Press. 1986. Alper. CA.. Awdeh. Z.L.. Raum. D.D
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Histocompatibility Testing for Organ Transplantation Purposes in Albania: A Single Center Experience
Directory of Open Access Journals (Sweden)
Erkena Shyti
2014-06-01
Full Text Available Background: Histocompatibility testing (HT which includes donor-recipient human leukocyte antigen (HLA matching, cross-match testing (XMT and anti-HLA antibody searching are crucial examinations in solid organ transplantation aiming to avoid the hyperacute graft rejection and also to predict the immunological outcome of the graft. Aims: The aim of this study was to analyse the tissue typing data collected at the Laboratory of Immunology and Histocompatibility of the University Hospital Center of Tirana, Albania, in order to define those actions that should be taken for improvements in the situation of kidney transplantation in Albania. Design: Descriptive study. Methods: The donor/recipient cross-match testing was performed through a standard complement-dependent cytotoxicity (CDC assay using separated donor T and B cells that were tested in parallel with the recipient serum sample. All recipient sera were screened for anti-Class I and anti-Class II HLA antibodies using a bead based Luminex anti-HLA antibody screening test. In the case of detected positivity, an allele-specific anti-HLA antibody determination was conducted with the respective Luminex anti-Class I and Class II HLA antibody determination kits. Results: A total of 174 recipients and 202 donors were typed for the purpose of living donor kidney transplantation at our laboratory between January 2006 and December 2012. The mean age and female gender proportion of patients were 34.9 years and 34.5%, respectively, and 48.0 years and 65.3% for the donors, respectively. Here, 25.9% of the patients reported a positive complement-dependent cytotoxicity cross-match test and/or a positive anti-HLA antibody testing result. Eighteen patients that were negative for the complement-dependent cytotoxicity cross-match test were positive for anti-HLA antibodies. Conclusion: The predominant causes of end-stage renal disease (ESRD in our patient population are chronic pyelonephritis and
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Nakajima, Nakako Izumi; Niimi, Atsuko; Isono, Mayu; Oike, Takahiro; Sato, Hiro; Nakano, Takashi; Shibata, Atsushi
2017-08-01
Immunotherapy is expected to be promising as a next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such levels of ligand expression are not effectively recognized by the native immune system due to tumor microenvironmental adaptation. Studies have demonstrated that natural-killer group 2, member D (NKG2D), a major activating immunoreceptor, responds to DNA damage. The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) (members of NKG2D ligands) expression after DNA damage is associated with NK cell-mediated killing of cancer cells. However, the regulation of DNA damage-induced MICA/B expression has not been fully elucidated in the context of the types of cancer cell lines. In the present study, we found that MICA/B expression varied between cancer cell lines after DNA damage. Screening in terms of chromatin remodeling identified that inhibitors related to chromatin relaxation via post-translational modification on histone H3K9, i.e. HDAC, Suv39 or G9a inhibition, restored DNA damage-dependent MICA/B expression in insensitive cells. In addition, we revealed that the restored MICA/B expression was dependent on ATR as well as E2F1, a transcription factor. We further revealed that low‑dose treatment of an HDAC inhibitor was sufficient to restore MICA/B expression in insensitive cells. Finally, we demonstrated that HDAC inhibition restored DNA damage‑dependent cytotoxic NK activity against insensitive cells. Thus, the present study revealed that DNA damage‑dependent MICA/B expression in insensitive cancer cells can be restored by chromatin relaxation via the HDAC/Suv39/G9a pathway. Collectively, manipulation of chromatin status by therapeutic cancer drugs may potentiate the antitumor effect by enhancing immune activation following radiotherapy and DNA damage-associated chemotherapy.
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Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Bae, Sang-Cheol
2014-01-01
Genetic variations of human leukocyte antigen (HLA) genes within the major histocompatibility complex (MHC) locus are strongly associated with disease susceptibility and prognosis for many diseases, including many autoimmune diseases. In this study, we developed a Korean HLA reference panel for imputing classical alleles and amino acid residues of several HLA genes. An HLA reference panel has potential for use in identifying and fine-mapping disease associations with the MHC locus in East Asian populations, including Koreans. A total of 413 unrelated Korean subjects were analyzed for single nucleotide polymorphisms (SNPs) at the MHC locus and six HLA genes, including HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1. The HLA reference panel was constructed by phasing the 5,858 MHC SNPs, 233 classical HLA alleles, and 1,387 amino acid residue markers from 1,025 amino acid positions as binary variables. The imputation accuracy of the HLA reference panel was assessed by measuring concordance rates between imputed and genotyped alleles of the HLA genes from a subset of the study subjects and East Asian HapMap individuals. Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively. The imputation accuracy was minimally affected by SNP density of a test dataset for imputation. In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.
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Directory of Open Access Journals (Sweden)
Kwangwoo Kim
Full Text Available Genetic variations of human leukocyte antigen (HLA genes within the major histocompatibility complex (MHC locus are strongly associated with disease susceptibility and prognosis for many diseases, including many autoimmune diseases. In this study, we developed a Korean HLA reference panel for imputing classical alleles and amino acid residues of several HLA genes. An HLA reference panel has potential for use in identifying and fine-mapping disease associations with the MHC locus in East Asian populations, including Koreans. A total of 413 unrelated Korean subjects were analyzed for single nucleotide polymorphisms (SNPs at the MHC locus and six HLA genes, including HLA-A, -B, -C, -DRB1, -DPB1, and -DQB1. The HLA reference panel was constructed by phasing the 5,858 MHC SNPs, 233 classical HLA alleles, and 1,387 amino acid residue markers from 1,025 amino acid positions as binary variables. The imputation accuracy of the HLA reference panel was assessed by measuring concordance rates between imputed and genotyped alleles of the HLA genes from a subset of the study subjects and East Asian HapMap individuals. Average concordance rates were 95.6% and 91.1% at 2-digit and 4-digit allele resolutions, respectively. The imputation accuracy was minimally affected by SNP density of a test dataset for imputation. In conclusion, the Korean HLA reference panel we developed was highly suitable for imputing HLA alleles and amino acids from MHC SNPs in East Asians, including Koreans.
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Directory of Open Access Journals (Sweden)
Karin E J Rödström
Full Text Available T cells are crucial players in cell-mediated immunity. The specificity of their receptor, the T cell receptor (TCR, is central for the immune system to distinguish foreign from host antigens. Superantigens are bacterial toxins capable of inducing a toxic immune response by cross-linking the TCR and the major histocompatibility complex (MHC class II and circumventing the antigen specificity. Here, we present the structure of staphylococcal enterotoxin E (SEE in complex with a human T cell receptor, as well as the unligated T cell receptor structure. There are clear structural changes in the TCR loops upon superantigen binding. In particular, the HV4 loop moves to circumvent steric clashes upon complex formation. In addition, a predicted ternary model of SEE in complex with both TCR and MHC class II displays intermolecular contacts between the TCR α-chain and the MHC, suggesting that the TCR α-chain is of importance for complex formation.
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Forlani, Greta; Abdallah, Rawan; Accolla, Roberto S; Tosi, Giovanna
2016-01-20
Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, a key protein in HTLV-1-induced T cell transformation, deregulates diverse cell signaling pathways. Among them, the NF-κB pathway is constitutively activated by Tax-1, which binds to NF-κB proteins and activates the IκB kinase (IKK). Upon phosphorylation-dependent IκB degradation, NF-κB migrates into the nucleus, mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA (class II transactivator), endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-κB pathway by Tax-1 and map the region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with impaired migration of RelA into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-κB activation in both subcellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKγ and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing retention of the inactive p50/RelA/IκB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NF-κB-responsive genes. Thus, CIITA inhibits cytoplasmic and nuclear steps of Tax-1-mediated NF-κB activation. These results, together with our previous finding that CIITA acts as a restriction factor inhibiting Tax-1-promoted HTLV-1 gene expression and replication, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential. HTLV-1 is the causative agent of human adult T cell leukemia-lymphoma (ATLL). The viral
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Heat shock protein-peptide complex-96 (Vitespen for the treatment of cancer
Directory of Open Access Journals (Sweden)
Robert J. Amato
2011-12-01
Full Text Available Heat shock proteins (HSPs are the most abundant and ubiquitous soluble intracellular proteins. Members of the HSP family bind peptides, they include antigenic peptides generated within cells. HSPs also interact with antigen-presenting cells (APCs through CD91 and other receptors, eliciting a cascade of events that includes re-presentation of HSP-chaperoned peptides by major histocompatability complex (MHC, translocation of nuclear factorkappaB (NFkB into the nuclei, and maturation of dendritic cells (DCs. These consequences point to a key role of heat shock proteins in fundamental immunological phenomena such as activation of APCs, indirect presentation (or crosspriming of antigenic peptides, and chaperoning of peptides during antigen presentation. The properties of HSPs also allow them to be used for immunotherapy of cancers and infections in novel ways. This paper reviews the development and clinical trial progress of vitespen, an HSP peptide complex vaccine based on tumor-derived glycoprotein 96.
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Extremely high major histocompatibility complex class IIb gene ...
Indian Academy of Sciences (India)
tial for the genetic management of the captive alligator; thus much research on this ..... protected; at the same time, we must strengthen the education about alligator ... Province, Zoology Practical Skills Training Center in Fuyang. Teachers ...
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Directory of Open Access Journals (Sweden)
Bacellar O.
1998-01-01
Full Text Available It has been shown that HLA class I molecules play a significant role in the regulation of the proliferation of T cells activated by mitogens and antigens. We evaluated the ability of mAb to a framework determinant of HLA class I molecules to regulate T cell proliferation and interferon gamma (IFN-g production against leishmania, PPD, C. albicans and tetanus toxoid antigens in patients with tegumentary leishmaniasis and healthy subjects. The anti-major histocompatibility complex (MHC mAb (W6/32 suppressed lymphocyte proliferation by 90% in cultures stimulated with aCD3, but the suppression was variable in cultures stimulated with leishmania antigen. This suppression ranged from 30-67% and was observed only in 5 of 11 patients. IFN-g production against leishmania antigen was also suppressed by anti-HLA class I mAb. In 3 patients IFN-g levels were suppressed by more than 60%, while in the other 2 cultures IFN-g levels were 36 and 10% lower than controls. The suppression by HLA class I mAb to the proliferative response in leishmaniasis patients and in healthy controls varied with the antigens and the patients or donors tested. To determine whether the suppression is directed at antigen presenting cells (APCs or at the responding T cells, experiments with antigen-primed non-adherent cells, separately incubated with W6/32, were performed. Suppression of proliferation was only observed when the W6/32 mAb was added in the presence of T cells. These data provide evidence that a mAb directed at HLA class I framework determinants can suppress proliferation and cytokine secretion in response to several antigens.
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International Nuclear Information System (INIS)
Arreygue-Garcia, Naela A; Delgado-Rizo, Vidal; Garcia-Iglesias, Trinidad; Hernandez-Flores, Georgina; Toro-Arreola, Susana del; Daneri-Navarro, Adrian; Toro-Arreola, Alicia del; Cid-Arregui, Angel; Gonzalez-Ramella, Oscar; Jave-Suarez, Luis F; Aguilar-Lemarroy, Adriana; Troyo-Sanroman, Rogelio; Bravo-Cuellar, Alejandro
2008-01-01
Cervical cancer is the second most common cancer in women worldwide. NK and cytotoxic T cells play an important role in the elimination of virus-infected and tumor cells through NKG2D activating receptors, which can promote the lysis of target cells by binding to the major histocompatibility complex class I-related chain A (MICA) proteins. Increased serum levels of MICA have been found in patients with epithelial tumors. The aim of this study was to compare the levels of soluble MICA (sMICA) and NKG2D-expressing NK and T cells in blood samples from patients with cervical cancer or precursor lesions with those from healthy donors. Peripheral blood with or without heparin was collected to obtain mononuclear cells or sera, respectively. Serum sMICA levels were measured by ELISA and NKG2D-expressing immune cells were analyzed by flow cytometry. Also, a correlation analysis was performed to associate sMICA levels with either NKG2D expression or with the stage of the lesion. Significant amounts of sMICA were detected in sera from nearly all patients. We found a decrease in the number of NKG2D-expressing NK and T cells in both cervical cancer and lesion groups when compared to healthy donors. Pearson analysis showed a negative correlation between sMICA and NKG2D-expressing T cells; however, we did not find a significant correlation when the analysis was applied to sMICA and NKG2D expression on NK cells. Our results show for the first time that high sMICA levels are found in sera from patients with both cervical cancer and precursor lesions when compared with healthy donors. We also observed a diminution in the number of NKG2D-expressing NK and T cells in the patient samples; however, a significant negative correlation between sMICA and NKG2D expression was only seen in T cells
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Succesful therapy of viral leukemia by transplantation of histocompatibly unmatched marrow
International Nuclear Information System (INIS)
Meredith, R.F.; OKunewick, J.P.; Kuhnert, P.M.; Brozovich, B.J.; Weaver, E.V.
1978-01-01
The therapeutic effectiveness on murine viral-leukemia of allogeneic or hybrid hematopoietic cells transplanted from leukemia-virus resistant donors was evaluated and compared with that of syngeneic cells. Transplantation of syngeneic cells gave no protection to the viral-leukemic mice. Transplantation of spleen cells from allogeneic donors resulted in early deaths of both leukemic and non-leukemic recipients. Transplantation of hybrid spleen cells resulted in no long-term survival of the leukemic mice. However, there were a number of long-term survivors among the leukemic recipients of allogeneic or hybrid marrow cells. Engraftment of allogeneic marrow resulted in a large number of survivors. Hybrid marrow recipients showed an even better survival, but some leukemia relapses. Tests of the longterm survivors revealed that even though they gave no evidence of leukemia they still harbored the active virus. This suggests that the mechanism of protection may be related to some inherent characteristic of the donor cells rendering them refractory to viral transformation. A difference in graft-versus-host (GvH) response between the leukemic and control mice was also found after transplantation of allogeneic cells. While all of the controls died of GvH reaction, none of the leukemic recipients showed severe GvH response, suggesting a possible effect of the leukemia on histocompatibility. No GvH reaction was found with hybrid marrow engraftment, although some of the leukemic recipients reconstituted with F 1 cells did die of leukemic relapse. (author)
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The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex.
Elliott, Tim; Williams, Anthony
2005-10-01
Major histocompatibility complex (MHC) class I complexes present peptides from both self and foreign intracellular proteins on the surface of most nucleated cells. The assembled heterotrimeric complexes consist of a polymorphic glycosylated heavy chain, non-polymorphic beta(2) microglobulin, and a peptide of typically nine amino acids in length. Assembly of the class I complexes occurs in the endoplasmic reticulum and is assisted by a number of chaperone molecules. A multimolecular unit termed the peptide-loading complex (PLC) is integral to this process. The PLC contains a peptide transporter (transporter associated with antigen processing), a thiooxido-reductase (ERp57), a glycoprotein chaperone (calreticulin), and tapasin, a class I-specific chaperone. We suggest that class I assembly involves a process of optimization where the peptide cargo of the complex is edited by the PLC. Furthermore, this selective peptide loading is biased toward peptides that have a longer off-rate from the assembled complex. We suggest that tapasin is the key chaperone that directs this action of the PLC with secondary contributions from calreticulin and possibly ERp57. We provide a framework model for how this may operate at the molecular level and draw parallels with the proposed mechanism of action of human leukocyte antigen-DM for MHC class II complex optimization.
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Energy Technology Data Exchange (ETDEWEB)
Jiang, Jiansheng; Natarajan, Kannan; Boyd, Lisa F.; Morozov, Giora I.; Mage, Michael G.; Margulies, David H. (NIH); (Hebrew)
2017-10-12
Central to CD8+ T cell–mediated immunity is the recognition of peptide–major histocompatibility complex class I (p–MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein–related), a tapasin homolog. TAPBPR remodels the peptide-binding groove of MHC I, resulting in the release of low-affinity peptide. Changes include groove relaxation, modifications of key binding pockets, and domain adjustments. This structure captures a peptide-receptive state of MHC I and provides insights into the mechanism of peptide editing by TAPBPR and, by analogy, tapasin.
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Quinn, Laura L; Williams, Luke R; White, Claire; Forrest, Calum; Zuo, Jianmin; Rowe, Martin
2016-01-01
The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for
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International Nuclear Information System (INIS)
Ayed, Khaled; Gorgi, Youser; Ayed-Jendoubi, Saloua; Bardi, Rafiqa
2004-01-01
Genetic susceptibility to systemetic lupus erythematosus (SLE) varies among populations. Few data exist on associations of HLA class II and class III allels of major histocompatibility complex (MHC) and susceptibility to SLE in Tunisians. We compared HLA-DRBI, DQAI, DQBI and C4 allotypes in 62 Tunisians SLE patients and 100 matched controls. We also assessed the association of specific allels with distinct autoantibody profiles in SLE patients. HLA-DRBI *0301, -DRBI*1501 and C4AQO allels were increased in the SLE patients, while the frequencies of HLA-DRBI*04 and DQBI*03 were decreased. HLA-DQA1*0102 and DQAI*0501 were significantly increased in the SLE patients. HLA-DQBI*0201 and and DQBI*0602 were more frequent in the SLE patients. C4A*QO and C4B*QO were increased in the frequency in the SLE patients compared to the controls, but only C4A null was significantly increased. 11 of 17 SLE patients with the C4 null allele were HLA-DRBI*0301 positive. 3 of the 16 SLE patients with HLA-DRBI*1501 were associated with the HLA-DQBI*0501 rather than DQBI*0602, as has been reported in European SLE patients. The MHC class II allels (DRBI, DQA1, DQB1)and C$ null assosiations noted in other ethnic groups are also found in Tunisians, suggesting shared suspectibility factors across ethnic lines in predisposition to SLE. In contrast to other ethnic groups, MHC class II allels are not associated with the presence of specific autoantibodies in Tunisians SLE patients. (author)
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McLachlan, Sandra M; Lesage, Sylvie; Collin, Roxanne; Banuelos, Bianca; Aliesky, Holly A; Rapoport, Basil
2017-04-01
Thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) develop spontaneously in NOD.H2h4 mice, a phenotype enhanced by dietary iodine. NOD.H2h4 mice were derived by introducing the major histocompatibility class (MHC) molecule I-Ak from B10.A(4R) mice to nonobese diabetic (NOD) mice. Apart from I-Ak, the genes responsible for the NOD.H2h4 phenotype are unknown. Extending serendipitous observations from crossing BALB/c to NOD.H2h4 mice, thyroid autoimmunity was investigated in both genders of the F1, F2, and the second-generation backcross of F1 to NOD.H2h4 (N2). Medium-density linkage analysis was performed on thyroid autoimmunity traits in F2 and N2 progeny. TgAb develop before TPOAb and were measured after 8 and 16 weeks of iodide exposure; TPOAb and thyroiditis were studied at 16 weeks. TgAb, TPOAb, and thyroiditis, absent in BALB/c and F1 mice, developed in most NOD.H2h4 and in more N2 than F2 progeny. No linkages were observed in F2 progeny, probably because of the small number of autoantibody-positive mice. In N2 progeny (equal numbers of males and females), a chromosome 17 locus is linked to thyroiditis and TgAb and is suggestively linked to TPOAb. This locus includes MHC region genes from B10.A(4R) mice (such as I-Ak and Tnf, the latter involved in thyrocyte apoptosis) and genes from NOD mice such as Satb1, which most likely plays a role in immune tolerance. In conclusion, MHC and non-MHC genes, encoded within the chromosome 17 locus from both B10.A(4R) and NOD strains, are most likely responsible for the Hashimoto disease-like phenotype of NOD.H2h4 mice. Copyright © 2017 Endocrine Society.
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HLA class II polymorphism and IDDM susceptibility in the Greek population.
Khalil, I; Spyropoulou, M; Mallet, C; Loste, M N; Douay, C; Laperrière, J; Bartzokas, C; Lepage, V; Charron, D; Stavropoulos, C
1993-06-01
The frequencies of HLA-DQA1, DQB1 and DRB1 alleles were compared between 50 Insulin-Dependent Diabetes Melitus (IDDM) patients and 49 healthy controls in the Greek population. Statistically significant difference in the frequencies of HLA-DQA1*0501-DQB1*0201 (P = 10(-4)), DQA1*0301-DQB1*0201 (P = 0.01) and DQA1*0301-DQB1*0302 (P = 0.001) were observed. The DRB1*0405-DQA1*0301-DQB1*0201 was the only DR, DQ combination significantly associated with the disease. The unexpected increase of DRB1*0405 observed in the Greek IDDM may suggest as reported in Chinese and Japanese IDDM a contribution of DR beta and DQ alpha in susceptibility. Moreover, in contrast to the Asians, in the Greek, the DR beta, DQ alpha are found with the usual DQ beta 57-ve.
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International Nuclear Information System (INIS)
McMahon, Róisín M.; Friis, Lone; Siebold, Christian; Friese, Manuel A.; Fugger, Lars; Jones, E. Yvonne
2011-01-01
The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease
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DEFF Research Database (Denmark)
Røder, Gustav Andreas; Geironson, Linda; Darabi, Anna
2009-01-01
). Using a biochemical peptide-MHC-I-binding assay, recombinant Tpn(1-87) was found to specifically facilitate peptide-dependent folding of HLA-A*0201. Furthermore, we used Tpn(1-87) to generate a monoclonal antibody, alphaTpn(1-87)/80, specific for natural human Tpn and capable of cellular staining of ER......Tapasin (Tpn) is an ER chaperone that is uniquely dedicated to MHC-I biosynthesis. It binds MHC-I molecules, integrates them into peptide-loading complexes, and exerts quality control of the bound peptides; only when an "optimal peptide" is bound will the MHC-I be released and exported to the cell...... surface for presentation to T cells. The exact mechanisms of Tpn quality control and the criteria for being an optimal peptide are still unknown. Here, we have generated a recombinant fragment of human Tpn, Tpn(1-87) (representing the 87 N-terminal and ER-luminal amino acids of the mature Tpn protein...
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Energy Technology Data Exchange (ETDEWEB)
Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor [The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800 (Australia); Anderson, Robert P. [Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute, 1G Royal Parade, Parkville, Victoria 3050 (Australia); Department of Gastroenterology, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050 (Australia); McCluskey, James [Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010 (Australia); Rossjohn, Jamie, E-mail: jamie.rossjohn@med.monash.edu.au [The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800 (Australia)
2007-12-01
The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported.
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International Nuclear Information System (INIS)
Yao, Shugang; Qi, Jianxun; Liu, Jun; Chen, Rong; Pan, Xiaocheng; Li, Xiaoying; Gao, Feng; Xia, Chun
2011-01-01
The equine MHC class I molecule was crystallized in complex with β 2 -microglobulin and a CTL epitope and X-ray diffraction data were collected to 2.3 Å resolution. In order to clarify the structure and the peptide-presentation characteristics of the equine major histocompatibility complex (MHC) class I molecule, a complex of equine MHC class I molecule (ELA-A1 haplotype, 7-6 allele) with mouse β 2 -microglobulin and the cytotoxic T lymphocyte (CTL) epitope Env-RW12 (RVEDVTNTAEYW) derived from equine infectious anaemia virus (EIAV) envelope protein (residues 195–206) was refolded and crystallized. The crystal, which belonged to space group P2 1 , diffracted to 2.3 Å resolution and had unit-cell parameters a = 82.5, b = 71.4, c = 99.8 Å, β = 102.9°. The crystal structure contained two molecules in the asymmetric unit. These results should help to determine the first equine MHC class I molecule structure presenting an EIAV CTL epitope
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Nunes, J M; Riccio, M E; Buhler, S; Di, D; Currat, M; Ries, F; Almada, A J; Benhamamouch, S; Benitez, O; Canossi, A; Fadhlaoui-Zid, K; Fischer, G; Kervaire, B; Loiseau, P; de Oliveira, D C M; Papasteriades, C; Piancatelli, D; Rahal, M; Richard, L; Romero, M; Rousseau, J; Spiroski, M; Sulcebe, G; Middleton, D; Tiercy, J-M; Sanchez-Mazas, A
2010-07-01
During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops. To that aim, an original methodology was developed and used (i) to estimate frequencies by taking into account ambiguous genotypic data, (ii) to test for Hardy-Weinberg equilibrium (HWE) by using a nested likelihood ratio test involving a parameter accounting for HWE deviations, (iii) to test for selective neutrality by using a resampling algorithm, and (iv) to provide explicit graphical representations including allele frequencies and basic statistics for each series of data. A total of 66 data series (1-7 loci per population) were analyzed with this standard approach. Frequency estimates were compliant with HWE in all but one population of mixed stem cell donors. Neutrality testing confirmed the observation of heterozygote excess at all HLA loci, although a significant deviation was established in only a few cases. Population comparisons showed that HLA genetic patterns were mostly shaped by geographic and/or linguistic differentiations in Africa and Europe, but not in America where both genetic drift in isolated populations and gene flow in admixed populations led to a more complex genetic structure. Overall, a fruitful collaboration between HLA typing laboratories and population geneticists allowed finding useful solutions to the problem of estimating gene frequencies and testing basic population diversity statistics on highly complex HLA data (high numbers of alleles and ambiguities), with promising applications in either anthropological, epidemiological, or transplantation studies.
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Major Histocompatibility complex-DMB allelic diversity in old and ...
African Journals Online (AJOL)
recorded all along the DM molecule domains and analyses of the critical ... Other molecules, like NK-cell receptors and Fc receptors, bear this type of ...... codon 242 (except in Mamu-DMB*01 in which Trp changes to a stop codon) in all the.
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International Nuclear Information System (INIS)
Feng, Youjun; Qi, Jianxun; Zhang, Huimin; Wang, Jinzi; Liu, Jinhua; Jiang, Fan; Gao, Feng
2005-01-01
X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β 2 m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides
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Energy Technology Data Exchange (ETDEWEB)
Feng, Youjun [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Qi, Jianxun [Graduate School, Chinese Academy of Sciences, Beijing (China); Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Zhang, Huimin; Wang, Jinzi [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Liu, Jinhua [College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China); Jiang, Fan [Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Gao, Feng, E-mail: gaofeng@im.ac.cn [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China)
2006-01-01
X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β{sub 2}m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides.
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National Research Council Canada - National Science Library
Worsham, Maria J
2007-01-01
.... The major histocompatibility complex (MHC) class I molecules are found on the cell membrane of all cells in the body and are involved in intercellular communications and in complex interactions with the immune...
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National Research Council Canada - National Science Library
Worsham, Maria
2001-01-01
.... The major histocompatibility complex (MHC) class I molecules are found on the cell membrane of all cells in the body and are involved in intercellular communications and in complex interactions with the immune...
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National Research Council Canada - National Science Library
Worsham, Maria J; Raju, Usha; Abrams, Judith
2005-01-01
.... The major histocompatibility complex (MHC) class I molecules are found on the cell membrane of all cells in the body and are involved in intercellular communications and in complex interactions with the immune...
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National Research Council Canada - National Science Library
Worsham, Maria J
2006-01-01
.... The major histocompatibility complex (MHC) class I molecules are found on the cell membrane of all cells in the body and are involved in intercellular communications and in complex interactions with the immune...
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National Research Council Canada - National Science Library
Worsham, Maria
2004-01-01
.... The major histocompatibility complex (MHC) class I molecules are found on the cell membrane of all cells in the body and are involved in intercellular communications and in complex interactions with the immune...
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Sari, Yulia; Haryati, Sri; Prasetyo, Afiono Agung; Hartono, Adnan, Zainal Arifin
2017-02-01
The human leukocyte antigen (HLA)-DQB1 gene polymorphisms may associated with the infection risk of Toxoplasma gondii in HIV patients. The HLA-DQB1*0402 in HIV-1-positive patients could be considered risk factors for developing neurological opportunistic infections, mainly Toxoplasma encephalitis. However, the HLA-DQB1*0402 gene polymorphisms status in the Javanese HIV patients is unknown. This study evaluated the prevalence of HLA-DQB*0402 alleles polymorphisms in Javanese HIV patients with positive anti-Toxoplasma gondii IgM status. Since 2009 our research group performing a molecular epidemiology of blood borne viruses in Central Java Indonesia, by collecting the epidemiological and clinical data from the high risk communities. All blood samples were screened for blood borne pathogens by serological and molecular assays including for HIV and Toxoplasma gondii. The genomic DNA was isolated from the whole blood samples. Genetic polymorphisms of HLA-DQB1*0402 alleles were detected with polymerase chain reaction-sequence-specific primers (PCR-SSPs) technique. The genotypes were defined according to generated fragment patterns in the agarose gel electrophoresis analysis of PCR products. All of the samples were tested at least in duplicate. HLA-DQB1*0402 alleles were detected in 20.8% (16/77) patients and not detected in all HIV positive samples with negative anti-Toxoplasma gondii IgM status (n= 200). The HLA-DQB1*0402 alleles polymorphisms were detected in Javanese HIV patients with positive anti-Toxoplasma gondii IgM. The polymorphisms found may have association with the infection risk of Toxoplasma gondii in HIV patients.
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Energy Technology Data Exchange (ETDEWEB)
Scharf, Louise; Li, Nan-Sheng; Hawk, Andrew J.; Garzón, Diana; Zhang, Tejia; Fox, Lisa M.; Kazen, Allison R.; Shah, Sneha; Haddadian, Esmael J.; Gumperz, Jenny E.; Saghatelian, Alan; Faraldo-Gómez, José D.; Meredith, Stephen C.; Piccirilli, Joseph A.; Adams, Erin J. (Harvard); (UC); (MXPL-G); (UW-MED)
2011-08-24
CD1 molecules function to present lipid-based antigens to T cells. Here we present the crystal structure of CD1c at 2.5 {angstrom} resolution, in complex with the pathogenic Mycobacterium tuberculosis antigen mannosyl-{beta}1-phosphomycoketide (MPM). CD1c accommodated MPM's methylated alkyl chain exclusively in the A pocket, aided by a unique exit portal underneath the {alpha}1 helix. Most striking was an open F pocket architecture lacking the closed cavity structure of other CD1 molecules, reminiscent of peptide binding grooves of classical major histocompatibility complex molecules. This feature, combined with tryptophan-fluorescence quenching during loading of a dodecameric lipopeptide antigen, provides a compelling model by which both the lipid and peptide moieties of the lipopeptide are involved in CD1c presentation of lipopeptides.
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Allogeneic bone marrow grafts in genotyped swine
International Nuclear Information System (INIS)
Vaiman, M.
1974-01-01
The proof of a major histocompatibility complex (MHC) called SL-A enabled to promote bone marrow allografts. A study of the response to that kind of graft in irradiated pig states a number of interesting points. Bone marrow allografting complies with the rule of tissular compatibility with the major histocompatibility complex. The taking of SL-A incompatible bone marrow allografts could not be achieved under the experimental conditions. In spite of the high doses of radiation, 950 to 1050 rads, higher than 1.5 LD 100%, recipients were capable of rejecting their grafts, regularly. SL-A identify ensured 100%, initial achievement. However, animals developed regular fatal disease within a fairly short time. This development could by no means, be ascribed to the sole sequealae of radiation sickness since autografted animals at equal or even higher doses, showed none of the symptome. Assumption of a chronic graft-vs-host reactions, induced by the minor histocompatible systems, was put foreward, but should be confirmed histopathologically [fr
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International Nuclear Information System (INIS)
Stone, W.H.
1976-03-01
During the course of this project we have studied 35 pairs of chimeric cattle twins. It is now clear that fractionated doses of whole-body 60 Co irradiation can cause marked shifts in the proportions of the two erythrocyte populations that make up the chimeric mixture. However, it has not been possible to eliminate one of the two cell types and thus abrogate the acquired immunologic tolerance. The results of our extensive skin-grafting experiments are remarkable because they show that a chimeric twin may mount a sufficient immune response to reject its cotwin's skin while remaining completely tolerant to erythropoietic elements of its cotwin. In conjunction with these studies, we have acquired sufficient data to define a major histocompatibility locus in cattle using alloimmune anti-lymphocyte typing sera as well as the mixed lymphocyte culture technic. This project has also yielded a considerable number of new immunogenetic parameters for cattle, monkeys and birds. Such parameters are useful for basic and applied studies in immunology
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International Nuclear Information System (INIS)
Britt, L.D.; Scharp, D.W.; Lacy, P.E.; Slavin, S.
1982-01-01
Diabetic Lewis rats (AgB1/L) were evaluated as recipients of allogeneic Wistar-Furth (AgB2/2) isolated adult islets without the use of standard recipient immunosuppression. One group was treated with fractionated total lymphoid irradiation (TLI) and Wistar-Furth bone marrow cell reconstitution to proven chimerism prior to islet transplantation. This group returned to a prediabetic state following Wistar-Furth islet transplantation without any evidence of rejection for 100 days posttransplant. A second group of Lewis rats received only TLI without bone marrow treatment. They gave a varying result following islet transplantation with one recipient showing evidence of prolonged islet survival. A third chimeric control group did not receive isolated islets and did not alter their diabetic state. A fourth group was not given TLI nor donor bone marrow cells and uniformly rejected their allogeneic islets by 7 days. Thus, allogeneic adult islets will survive across major rat histocompatibility barriers using TLI and donor bone marrow chimerism as the only form of immunosuppression
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DEFF Research Database (Denmark)
Larsen, S L; Pedersen, L O; Buus, S
1996-01-01
Endocytosed protein antigens are believed to be fragmented in what appears to be a balance between proteolysis and MHC-mediated epitope protection, and the resulting peptide-MHC complexes are transported to the surface of the antigen-presenting cells (APC) and presented to T cells. The events tha...
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Ross, I L; Babu, S; Armstrong, T; Zhang, L; Schatz, D; Pugliese, A; Eisenbarth, G; Baker Ii, P
2014-10-01
Genetic similarities between patients from the United States and South African (SA) Addison's Disease (AD) strengthen evidence for genetic association. SA-AD (n = 73), SA healthy controls (N = 78), and US-AD patients (N = 83) were genotyped for DQA1, DQB1, DRB1, and HLA-B alleles. Serum was tested for the quantity of 21OH-AA and IFNα-AA at the Barbara Davis Center. Although not as profound as in US-AD, in SA-AD 21OH-AA + subjects the predominantly associated risk haplotypes were DRB1*0301-DQB1*0201 (DR3), DRB1*04xx-DQB1*0302 (DR4), and the combined DR3/4 genotype. DQB1*0302 associated DRB1*04xx haplotypes conferred higher risk than those DRB1*04xx haplotypes associated with other DQB1 alleles. We found negative association in 21OH-AA + SA-AD for DQA1*0201-DQB1*0202 and DQA1*0101-DQB1*0501 vs SA controls, and positive association for DQA1*0401-DQB1*0402 vs US-AD. Apart from the class II DR3 haplotype, HLA-B8 did not have an independent effect; however together DR3 and HLA-B8 conferred the highest risk vs 21OH-AA negative SA-AD and SA-controls. HLA-B7 (often with DR4) conferred novel risk in 21OH-AA + SA-AD vs controls. This study represents the first comparison between South African and United States AD populations utilizing genotyping and serology performed at the same center. SA-AD and US-AD 21OH-AA + patients share common HLA risk haplotypes including DR4 (with HLA-B7) and DR3 (with HLA-B8), strengthening previously described HLA associations and implicating similar genetic etiology. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A; Abreu, S
2017-12-01
This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05-DQA1*03:03-DQB1*03:02 (OR = 100.9) and DRB1*04:04-DQA1*03:01-DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.04) as protective. HLA-DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA-DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04-DQA1*03:01-DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1). © 2017 John Wiley & Sons Ltd.
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Balti, Eric V; Ngo-Nemb, Marinette C; Lontchi-Yimagou, Eric; Atogho-Tiedeu, Barbara; Effoe, Valery S; Akwo, Elvis A; Dehayem, Mesmin Y; Mbanya, Jean-Claude; Gautier, Jean-François; Sobngwi, Eugene
2015-01-01
We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A(-) KPD) in comparison to type 2 diabetes (T2D). A(-) KPD and T2D sub-Saharan African patients aged 19-63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. Among the 130 participants, 35 (27%) were women and 57 (44%) were A(-) KPD. DRB1 and DQB1 allele frequencies were similar for both A(-) KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A(-) KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17-1.85], P=0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79-7.42], P=0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39-1.95], P=0.731) and DRB1*03:01-DQB1*02:01 (OR: 1.48 [95%CI: 0.55-3.96], P=0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P>0.05) in A(-) KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A(-) KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A(-) KPD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Complex Mhc-based mate choice in a wild passerine
Bonneaud, Camille; Chastel, Olivier; Federici, Pierre; Westerdahl, Helena; Sorci, Gabriele
2006-01-01
The extreme polymorphism of the vertebrate major histocompatibility complex (Mhc) is famous for protecting hosts against constantly evolving pathogens. Mate choice is often evoked as a means of maintaining Mhc variability through avoidance of partners with similar Mhc alleles or preference for heterozygotes. Evidence for these two hypotheses mostly comes from studies on humans and laboratory mice. Here, we tested these hypotheses in a wild outbred population of house sparrows (Passer domesticus). Females were not more or less closely related to the males they paired with when considering neutral genetic variation. However, males failed to form breeding pairs when they had too few Mhc alleles and when they were too dissimilar from females at Mhc loci (i.e. had no common alleles). Furthermore, pairs did not form at random as Mhc diversity positively correlated in mating pairs. These results suggest that mate choice evolves in response to (i) benefits in terms of parasite resistance acquired from allelic diversity, and (ii) costs associated with the disruption of co-adapted genes. PMID:16600889
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Crystallization and preliminary X-ray structural studies of a Melan-A pMHC–TCR complex
International Nuclear Information System (INIS)
Yuan, Fang; Georgiou, Theonie; Hillon, Theresa; Gostick, Emma; Price, David A.; Sewell, Andrew K.; Moysey, Ruth; Gavarret, Jessie; Vuidepot, Annelise; Sami, Malkit; Bell, John I.; Gao, George F.; Rizkallah, Pierre J.; Jakobsen, Bent K.
2007-01-01
A preliminary X-ray crystal structural study of a soluble cognate T-cell receptor (TCR) in complex with a pMHC presenting the Melan-A peptide (ELAGIGILTV) is reported. The TCR and pMHC were refolded, purified and mixed together to form complexes, which were crystallized using the sitting-drop vapour-diffusion method. Single TCR–pMHC complex crystals were cryocooled and used for data collection. Melanocytes are specialized pigmented cells that are found in all healthy skin tissue. In certain individuals, diseased melanocytes can form malignant tumours, melanomas, which cause the majority of skin-cancer-related deaths. The melanoma-associated antigenic peptides are presented on cell surfaces via the class I major histocompatibility complex (MHC). Among the melanoma-associated antigens, the melanoma self-antigen A/melanoma antigen recognized by T cells (Melan-A/MART-1) has attracted attention because of its wide expression in primary and metastatic melanomas. Here, a preliminary X-ray crystal structural study of a soluble cognate T-cell receptor (TCR) in complex with a pMHC presenting the Melan-A peptide (ELAGIGILTV) is reported. The TCR and pMHC were refolded, purified and mixed together to form complexes, which were crystallized using the sitting-drop vapour-diffusion method. Single TCR–pMHC complex crystals were cryocooled and used for data collection. Diffraction data showed that these crystals belonged to space group P4 1 /P4 3 , with unit-cell parameters a = b = 120.4, c = 81.6 Å. A complete data set was collected to 3.1 Å and the structure is currently being analysed
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Woo, Hye In; Joo, Eun Yeon; Lee, Kyung Wha
2012-01-01
Background Narcolepsy is a neurologic disorder characterized by excessive daytime sleepiness, symptoms of abnormal rapid eye movement (REM) sleep, and a strong association with HLA-DRB1*1501, -DQA1*0102, and -DQB1*0602. Here, we investigated the clinico-physical characteristics of Korean patients with narcolepsy, their HLA types, and the clinical utility of high-resolution PCR with sequence-specific primers (PCR-SSP) as a simple typing method for identifying DRB1*15/16, DQA1, and DQB1 alleles. Methods The study population consisted of 67 consecutively enrolled patients having unexplained daytime sleepiness and diagnosed narcolepsy based on clinical and neurological findings. Clinical data and the results of the multiple sleep latency test and polysomnography were reviewed, and HLA typing was performed using both high-resolution PCR-SSP and sequence-based typing (SBT). Results The 44 narcolepsy patients with cataplexy displayed significantly higher frequencies of DRB1*1501 (Pc= 0.003), DQA1*0102 (Pc=0.001), and DQB1*0602 (Pc=0.014) than the patients without cataplexy. Among patients carrying DRB1*1501-DQB1*0602 or DQA1*0102, the frequencies of a mean REM sleep latency of less than 20 min in nocturnal polysomnography and clinical findings, including sleep paralysis and hypnagogic hallucination were significantly higher. SBT and PCR-SSP showed 100% concordance for high-resolution typing of DRB1*15/16 alleles and DQA1 and DQB1 loci. Conclusions The clinical characteristics and somnographic findings of narcolepsy patients were associated with specific HLA alleles, including DRB1*1501, DQA1*0102, and DQB1*0602. Application of high-resolution PCR-SSP, a reliable and simple method, for both allele- and locus-specific HLA typing of DRB1*15/16, DQA1, and DQB1 would be useful for characterizing clinical status among subjects with narcolepsy. PMID:22259780
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Arnett, F C; Thiagarajan, P; Ahn, C; Reveille, J D
1999-02-01
To determine any HLA associations with anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in a large, retrospectively studied, multiethnic group of 262 patients with primary antiphospholipid antibody syndrome (APS), systemic lupus erythematosus (SLE), or another connective tissue disease. Anti-beta2GPI antibodies were detected in sera using an enzyme-linked immunosorbent assay. HLA class II alleles (DRB1, DQA1, and DQB1) were determined by DNA oligotyping. The HLA-DQB1*0302 (DQ8) allele, typically carried on HLA-DR4 haplotypes, was associated with anti-beta2GPI when compared with both anti-beta2GPI-negative SLE patients and ethnically matched normal controls, especially in Mexican Americans and, to a lesser extent, in whites. Similarly, when ethnic groups were combined, HLA-DQB1*0302, as well as HLA-DQB1*03 alleles overall (DQB1*0301, *0302, and *0303), were strongly correlated with anti-beta2GPI antibodies. The HLA-DR6 (DR13) haplotype DRB1*1302; DQB1*0604/5 was also significantly increased, primarily in blacks. HLA-DR7 was not significantly increased in any of these 3 ethnic groups, and HLA-DR53 (DRB4*0101) was increased in Mexican Americans only. Certain HLA class II haplotypes genetically influence the expression of antibodies to beta2GPI, an important autoimmune response in the APS, but there are variations in HLA associations among different ethnic groups.
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Association study between HLA-DRB, HLA-DQA1, HLA-DQB1 and breast cancer in Iranian women
Directory of Open Access Journals (Sweden)
Amirzargar AA
2010-11-01
Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Based on the reports, high frequency of special alleles of HLA class II genes might be associated with susceptibility to or protective from a particular cancer. These alleles might vary depending on the geographical region. Here we investigate the association between alleles of HLA class II genes and breast cancer in Iranian women."n"nMethods: 100 patients with pathologically proved breast cancer who referred to Cancer Institute, Tehran University of Medical Sciences in Tehran, Iran, were divided to two groups based on ages (40 years old and less/ or more than 40 years old and were randomly selected and compared with a group of 80 healthy blood donor subjects. HLA class II alleles were determined by amplification of DNA with polymerase chain reaction (PCR method followed by HLA-typing using sequence-specific primer (SSP for each allele."n"nResults: The most frequent alleles in the DR and DQ regions in group 1 (40 years old and less in comparison with control group were HLA-DQA1*0301 (p=0.002 and HLA-DQB1*0302 (p>0.05. In contrast HLA-DQA1*0505 (p=0.004 had significantly lower frequency in this group compared with control group. Patients of group two (more than 40 years old had a higher frequencies of HLA
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DEFF Research Database (Denmark)
Svitek, Nicholas; Hansen, Andreas Martin; Steinaa, Lucilla
2014-01-01
Peptide-major histocompatibility complex (p-MHC) class I tetramer complexes have facilitated the early detection and functional characterisation of epitope specific CD8(+) cytotoxic T lymphocytes (CTL). Here, we report on the generation of seven recombinant bovine leukocyte antigens (BoLA) and re...
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Short communication Identification of genetic variation in the major ...
African Journals Online (AJOL)
EXPER
2016-10-31
Oct 31, 2016 ... DRB1 with Hin1I was more frequent in the Kivircik and White .... evolution of class I duplication blocks, diversity and complexity from shark to man. ... The great diversity of major histocompatibility complex class II genes in ...
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International Nuclear Information System (INIS)
Zhang, Jianhua; Chen, Yong; Gao, Feng; Chen, Weihong; Qi, Jianxun; Xia, Chun
2009-01-01
Using a peptide derived from H5N1, a complex of duck MHC class I molecule (DuMHC I) with duck β 2 -microglobulin (Duβ 2 m) was assembled and crystallized. Initial structure analysis indicated that the crystals did not contain the complete DuMHC I complex but instead contained DuMHC I α3-domain and Duβ 2 m subunits. In order to understand the biological properties of the immune systems of waterfowl and to establish a system for structural studies of duck class I major histocompatibility complex (DuMHC I), a complex of DuMHC I with duck β 2 -microglobulin (Duβ 2 m) and the peptide AEIEDLIF (AF8) derived from H5N1 NP residues 251–258 was assembled. The complex was crystallized; the crystals belonged to space group C222 1 , with unit-cell parameters a = 54.7, b = 72.4, c = 102.2 Å, and diffracted to 2.3 Å resolution. Matthews coefficient calculation and initial structure determination by molecular replacement showed that the crystals did not contain the whole DuMHC I complex, but instead contained the DuMHC I α3 domain and a Duβ2m molecule (DuMHC I α3+β2m). Another complex of DuMHC I with the peptide IDWFDGKE derived from a chicken fusion protein also generated the same results. The stable structure of DuMHC I α3+β2m may reflect some unique characteristics of DuMHC I and pave the way for novel MHC structure-related studies in the future
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DEFF Research Database (Denmark)
Røder, Gustav; Kristensen, Ole; Kastrup, Jette S
2008-01-01
, the crystal structure of HLA-B*1501 in complex with a SARS coronavirus-derived nonapeptide (VQQESSFVM) has been determined at high resolution (1.87 A). The peptide is deeply anchored in the B and F pockets, but with the Glu4 residue pointing away from the floor in the peptide-binding groove, making...
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Polymorphism of HLA in the Romanian population.
Reed, E; Ho, E; Lupu, F; McManus, P; Vasilescu, R; Foca-Rodi, A; Suciu-Foca, N
1992-01-01
We have investigated the HLA-class I and class II polymorphism in a population of 83 Romanians using conventional serology together with PCR amplification and oligonucleotide typing of HLA-class II genes. Romanians show a higher frequency of HLA-A11, B13, B18, B37, B39, B51 and DR2 than other European populations. HLA-DRB1*1501 and 1601 account for the high frequency of the serologic specificity DR2. In Romanians, HLA-DR2 is in linkage disequilibrium with HLA-B18 and HLA-Bw52 rather than with HLA-B7 as in the case in other Europeans. Unexpected HLA-DR2 haplotypes include HLA-DRB1*1502, DQA1*0102, DQB1*0601; HLA-DRB1*1602, DQA1*0102, DQB1*0502. Other unusual haplotypes include HLA-DRB1*0405, DQA1*03, DQB1*0302; HLA-DRB1*1305, DQA1*0103, DQB1*0603; and HLA-DRB1*1405, DQA1*0101, DQB1*05032. Analysis of the genetic distance between Romanians and other Europeans who have been studied serologically are consistent with the hypothesis that Romanians descend from Roman ancestors who colonized Dacia between the 1st century B.C. and 1st century A.D.
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The MHC locus and genetic susceptibility to autoimmune and infectious diseases
Matzaraki, Vasiliki; Kumar, Vinod; Wijmenga, Cisca; Zhernakova, Alexandra
2017-01-01
In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic
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Directory of Open Access Journals (Sweden)
Paul M Armistead
Full Text Available Minor histocompatibility antigens (mHA mediate much of the graft vs. leukemia (GvL effect and graft vs. host disease (GvHD in patients who undergo allogeneic stem cell transplantation (SCT. Therapeutic decision making and treatments based upon mHAs will require the evaluation of multiple candidate mHAs and the selection of those with the potential to have the greatest impact on clinical outcomes. We hypothesized that common, immunodominant mHAs, which are presented by HLA-A, B, and C molecules, can mediate clinically significant GvL and/or GvHD, and that these mHAs can be identified through association of genomic data with clinical outcomes.Because most mHAs result from donor/recipient cSNP disparities, we genotyped 57 myeloid leukemia patients and their donors at 13,917 cSNPs. We correlated the frequency of genetically predicted mHA disparities with clinical evidence of an immune response and then computationally screened all peptides mapping to the highly associated cSNPs for their ability to bind to HLA molecules. As proof-of-concept, we analyzed one predicted antigen, T4A, whose mHA mismatch trended towards improved overall and disease free survival in our cohort. T4A mHA mismatches occurred at the maximum theoretical frequency for any given SCT. T4A-specific CD8+ T lymphocytes (CTLs were detected in 3 of 4 evaluable post-transplant patients predicted to have a T4A mismatch.Our method is the first to combine clinical outcomes data with genomics and bioinformatics methods to predict and confirm a mHA. Refinement of this method should enable the discovery of clinically relevant mHAs in the majority of transplant patients and possibly lead to novel immunotherapeutics.
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Understanding type 1 diabetes through genetics: Advances and prospects
Directory of Open Access Journals (Sweden)
Nikhil Tandon
2015-01-01
Full Text Available The largest contribution of type 1 diabetes mellitus (T1DM from a single locus comes from several genes located in the major histocompatibility complex on chromosome 6p21. Because DQB1 is the best single genetic marker for T1DM, it is the gene most often used to identify individuals with a high risk of developing disease. As per the data collected from the All India Institute of Medical Sciences, among the human leukocyte antigen (HLA-DRB1 genes, HLA-DR3 showed strongest association with the disease; however, unlike Caucasians and other populations, DR4 was not significantly increased in these patients. HLA-DR10, 11, 13, and 15 showed a negative association with the disease as they were reduced in these patients. In India, the relative risk of developing T1DM is higher with the DR3-DQ2 haplotypes as compared to DR4-DQ8 haplotypes. Studies have shown that in North India, the relative risk for T1DM is comparatively higher (>30 with the DQ2/DQ8 genotype, but is relatively lower (approximately 18 for the DQ2/DQ2 genotype. In addition, the three sets of HLA-B-DR3 haplotypes, mainly B58-DR3, B50-DR3, and B8-DR3 have shown to have modulated susceptibility for T1DM in India and worldwide. New interventions that will be tested in the future will be conducted through T1DM TrialNet, a collaborative network of clinical centers and experts in diabetes and immunology. These studies will identify unaffected first-degree relatives with beta cell autoantibodies who will be eligible for new interventions.
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Understanding type 1 diabetes through genetics: Advances and prospects.
Tandon, Nikhil
2015-04-01
The largest contribution of type 1 diabetes mellitus (T1DM) from a single locus comes from several genes located in the major histocompatibility complex on chromosome 6p21. Because DQB1 is the best single genetic marker for T1DM, it is the gene most often used to identify individuals with a high risk of developing disease. As per the data collected from the All India Institute of Medical Sciences, among the human leukocyte antigen (HLA)-DRB1 genes, HLA-DR3 showed strongest association with the disease; however, unlike Caucasians and other populations, DR4 was not significantly increased in these patients. HLA-DR10, 11, 13, and 15 showed a negative association with the disease as they were reduced in these patients. In India, the relative risk of developing T1DM is higher with the DR3-DQ2 haplotypes as compared to DR4-DQ8 haplotypes. Studies have shown that in North India, the relative risk for T1DM is comparatively higher (>30) with the DQ2/DQ8 genotype, but is relatively lower (approximately 18) for the DQ2/DQ2 genotype. In addition, the three sets of HLA-B-DR3 haplotypes, mainly B58-DR3, B50-DR3, and B8-DR3 have shown to have modulated susceptibility for T1DM in India and worldwide. New interventions that will be tested in the future will be conducted through T1DM TrialNet, a collaborative network of clinical centers and experts in diabetes and immunology. These studies will identify unaffected first-degree relatives with beta cell autoantibodies who will be eligible for new interventions.
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Parks, Samuel; Avramopoulos, Dimitrios; Mulle, Jennifer; McGrath, John; Wang, Ruihua; Goes, Fernando S; Conneely, Karen; Ruczinski, Ingo; Yolken, Robert; Pulver, Ann E; Pearce, Brad D
2018-05-01
The infections Toxoplasma gondii (T. gondii), cytomegalovirus, and Herpes Simplex Virus Type 1 (HSV1) are common persistent infections that have been associated with schizophrenia and bipolar disorder. The major histocompatibility complex (MHC, termed HLA in humans) region has been implicated in these infections and these mental illnesses. The interplay of MHC genetics, mental illness, and infection has not been systematically examined in previous research. In a cohort of 1636 individuals, we used genome-wide association data to impute 7 HLA types (A, B, C, DRB1, DQA1, DQB1, DPB1), and combined this data with serology data for these infections. We used regression analysis to assess the association between HLA alleles, infections (individually and collectively), and mental disorder status (schizophrenia, bipolar disorder, controls). After Bonferroni correction for multiple comparisons, HLA C∗07:01 was associated with increased HSV1 infection among mentally healthy controls (OR 3.4, p = 0.0007) but not in the schizophrenia or bipolar groups (P > 0.05). For the multiple infection outcome, HLA B∗ 38:01 and HLA C∗12:03 were protective in the healthy controls (OR ≈ 0.4) but did not have a statistically-significant effect in the schizophrenia or bipolar groups. T. gondii had several nominally-significant positive associations, including the haplotypes HLA DRB∗03:01 ∼ HLA DQA∗05:01 ∼ HLA DQB∗02:01 and HLA B∗08:01 ∼ HLA C∗07:01. We identified HLA types that showed strong and significant associations with neurotropic infections. Since some of these associations depended on mental illness status, the engagement of HLA-related pathways may be altered in schizophrenia due to immunogenetic differences or exposure history. Copyright © 2018 Elsevier Inc. All rights reserved.
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HLA diversity in the 1000 genomes dataset.
Directory of Open Access Journals (Sweden)
Pierre-Antoine Gourraud
Full Text Available The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC, only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.
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Directory of Open Access Journals (Sweden)
Yi-Yan Chen
Full Text Available Genetic variation plays a significant role in maintaining the evolutionary potential of a species. Comparing the patterns of adaptive and neutral diversity in extant populations is useful for understanding the local adaptations of a species. In this study, we determined the fine-scale genetic structure of 6 extant populations of the giant panda (Ailuropoda melanoleuca using mtDNA and DNA fingerprints, and then overlaid adaptive variations in 6 functional Aime-MHC class II genes (DRA, DRB3, DQA1, DQA2, DQB1, and DQB2 on this framework. We found that: (1 analysis of the mtDNA and DNA fingerprint-based networks of the 6 populations identified the independent evolutionary histories of the 2 panda subspecies; (2 the basal (ancestral branches of the fingerprint-based Sichuan-derived network all originated from the smallest Xiaoxiangling (XXL population, suggesting the status of a glacial refuge in XXL; (3 the MHC variations among the tested populations showed that the XXL population exhibited extraordinary high levels of MHC diversity in allelic richness, which is consistent with the diversity characteristics of a glacial refuge; (4 the phylogenetic tree showed that the basal clades of giant panda DQB sequences were all occupied by XXL-specific sequences, providing evidence for the ancestor-resembling traits of XXL. Finally, we found that the giant panda had many more DQ alleles than DR alleles (33∶13, contrary to other mammals, and that the XXL refuge showed special characteristics in the DQB loci, with 7 DQB members of 9 XXL-unique alleles. Thus, this study identified XXL as a glacial refuge, specifically harboring the most number of primitive DQB alleles.
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Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology.
Ikenaga, Chiseko; Kubota, Akatsuki; Kadoya, Masato; Taira, Kenichiro; Uchio, Naohiro; Hida, Ayumi; Maeda, Meiko Hashimoto; Nagashima, Yu; Ishiura, Hiroyuki; Kaida, Kenichi; Goto, Jun; Tsuji, Shoji; Shimizu, Jun
2017-09-05
To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers. All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed. The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy. CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis. © 2017 American Academy of Neurology.
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Enhancing Science Kits with the Driving Question Board
Nordine, Jeff; Torres, Ruben
2013-01-01
This article describes the driving question board (DQB), a visual organizer that supports inquiry-based instruction through the use of guiding questions. The DQB is a teaching aid designed to increase student engagement alongside science kits. Information is provided on its application to a lesson on buoyancy, highlighting how it improved…
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National Research Council Canada - National Science Library
Bjorkman, Pamela
2000-01-01
Zn-alpha 2-glycoprotein (ZAG) is a 41 kDa soluble protein whose sequence and domain organization are surprisingly similar to those of the membrane glycoproteins of the major histocompatibility complex (MHC...
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Energy Technology Data Exchange (ETDEWEB)
Stone, W.H.
1976-03-01
During the course of this project we have studied 35 pairs of chimeric cattle twins. It is now clear that fractionated doses of whole-body /sup 60/Co irradiation can cause marked shifts in the proportions of the two erythrocyte populations that make up the chimeric mixture. However, it has not been possible to eliminate one of the two cell types and thus abrogate the acquired immunologic tolerance. The results of our extensive skin-grafting experiments are remarkable because they show that a chimeric twin may mount a sufficient immune response to reject its cotwin's skin while remaining completely tolerant to erythropoietic elements of its cotwin. In conjunction with these studies, we have acquired sufficient data to define a major histocompatibility locus in cattle using alloimmune anti-lymphocyte typing sera as well as the mixed lymphocyte culture technic. This project has also yielded a considerable number of new immunogenetic parameters for cattle, monkeys and birds. Such parameters are useful for basic and applied studies in immunology.
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The peopling of Madeira Archipelago (Portugal) according to HLA genes.
Arnaiz-Villena, A; Reguera, R; Ferri, A; Barbolla, L; Abd-El-Fatah-Khalil, S; Bakhtiyarova, N; Millan, P; Moscoso, J; Mafalda, A; Serrano-Vela, J I
2009-02-01
The Madeira-Porto Santo Archipelago was officially colonized in 1420 by Portuguese settlers. Its importance in Columbus' information for the American discovery and for slave traffic across the Atlantic is unquestionable. Thus, a complex peopling may have given rise to a present-day high admixture of ethnicities according to HLA genes. A sample of 173 healthy unrelated Madeirans was analysed and compared with 6986 HLA chromosomes from other worldwide populations. Genetic distances, neighbour-joining dendrograms and correspondence analyses were used for comparisons. Southern European, North African (including Canary Islands), Jewish and Mediterranean typical HLA alleles were found and genetic distances from Madeirans to these populations were the closest ones. In addition A*24-B*65-DRB1*0102-DQB1*0501 and A*68-B*08-DRB1*0301-DQB1*0201 haplotypes were newly found in Madeira and not found in any other population. Jewish-Armenian-Middle East haplotype (A*33-B*65-DRB1*0102-DQB1*0501) is one of the most common haplotypes; this haplotype is also present in Spaniards and North Africans. Quantitatively, Portuguese, North Africans (Algerians), Spaniards and Canary Islanders (in this order) are the most important parental populations to Madeirans. Results are discussed on the basis of the recorded historical peopling which does not show a noticeable African gene input in present-day Madeiran population according to our data; one of the closest related populations found is the Canary Islanders, suggesting that Guanche (Canary Islands first inhabitants) slaves gene flow is still noticed at present, both in Madeira and in Canary Islands populations.
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International Nuclear Information System (INIS)
Sandalova, Tatyana; Michaëlsson, Jakob; Harris, Robert A.; Ljunggren, Hans-Gustaf; Kärre, Klas; Schneider, Gunter; Achour, Adnane
2005-01-01
Mouse MHC class I H-2Db in complex with human β2m and the LCMV-derived peptide gp33 has been produced and crystallized. Resolution of the structure of this complex combined with the structural comparison with the previously solved crystal structure of H-2Db/mβ2m/gp33 should lead to a better understanding of how the β2m subunit affects the overall conformation of MHC complexes as well as the stability of the presented peptides. β 2 -Microglobulin (β 2 m) is non-covalently linked to the major histocompatibility (MHC) class I heavy chain and interacts with CD8 and Ly49 receptors. Murine MHC class I can bind human β 2 m (hβ 2 m) and such hybrid molecules are often used in structural and functional studies. The replacement of mouse β 2 m (mβ 2 m) by hβ 2 m has important functional consequences for MHC class I complex stability and specificity, but the structural basis for this is unknown. To investigate the impact of species-specific β 2 m subunits on MHC class I conformation, murine MHC class I H-2D b in complex with hβ 2 m and the peptide gp33 derived from lymphocytic choriomeningitis virus (LCMV) has been expressed, refolded in vitro and crystallized. Crystals containing two complexes per asymmetric unit and belonging to the space group P2 1 , with unit-cell parameters a = 68.1, b = 65.2, c = 101.9 Å, β = 102.4°, were obtained
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International Nuclear Information System (INIS)
Johnson, L.L.
1991-01-01
The hypothesis was investigated that suppressor cells may be responsible for maintenance of immunologic tolerance of a minor H3 antigen in mice that express the antigen naturally. Lymphoid cell populations from B6.C-H-24c (HW54) mice, a congenic-resistant strain histoincompatible with H-24b-expressing C57BL/6 (B6) mice only with respect to the H-24 locus, were examined in cell-transfer experiments to see if they contained naturally arising H-24c-specific suppressor cells. The H-24 antigen was chosen for these studies because, unlike most other minor and major histocompatibility (H) antigens, it is not detectable on mature lymphoid cells by any of several functional criteria. Thus transfer of HW54 lymphoid cells to B6 hosts could be done without the complication of inducing hyporesponsiveness de novo in the host, as occurs with other minor H antigens that are expressed on lymphocytes. B6 hosts were given HW54 skin grafts along with HW54 lymphoid cells to assess their tolerance of the H-24c-encoded antigen. The hosts were either (1) normal, nonimmune B6 mice; (2) B6 mice rendered immunodeficient by thymectomy and irradiation (TxB) and repopulated with H-24c-immune B6 lymphocytes; or (3) TxB B6 hosts repopulated with nonimmune B6 lymphocytes. In each case it was found that the additionally infused HW54 lymphoid cells did not suppress the ability of these hosts to reject HW54 skin grafts. In other words, HW54 lymphoid cells appear not to possess suppressive activity specific for the H-24c antigen that might maintain antigen-specific natural tolerance. Additional experiments were performed to determine whether HW54 lymphoid cells can inhibit the ability of sublethally irradiated B6 mice to regain the capacity to reject HW54 skin
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Directory of Open Access Journals (Sweden)
Kirti Pandey
2016-01-01
Conclusion: Our study has generated several promiscuous antigenic peptides capable of binding to major histocompatibility complex class I with high affinity. These epitopes can become part of a postexposure multivalent subunit vaccine upon experimental validation.
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Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk
Dura, P.; Veen, E.M. van; Salomon, J.; Morsche, R.H.M. te; Roelofs, H.M.J.; Kristinsson, J.O.; Wobbes, T.; Witteman, B.J.; Tan, A.C.; Drenth, J.P.H.; Peters, W.H.M.
2013-01-01
Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC;
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Expression of Major histocompatibility complex genes in carp (Cyprinus carpio L.)
Rodrigues, P.N.S.
1996-01-01
The common carp ( Cyprinus carpio L.) has been the experimental animal of choice because many features of the immune system of this Cyprinid fish have been well characterized. The immune system consists of an integrated set of organs containing -
A role for NADPH oxidase in antigen presentation
Directory of Open Access Journals (Sweden)
Gail J Gardiner
2013-09-01
Full Text Available The nicotinamide adenine dinucleotide phosphate (NADPH oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2.-. This radical is an important precursor of hydrogen peroxide (H2O2 and other reactive oxygen species (ROS needed for microbicidal activity during innate immune responses. Inherited defects in NADPH oxidase give rise to chronic granulomatous disease (CGD, a primary immunodeficiency characterized by recurrent infections and granulomatous inflammation. Interestingly, CGD, CGD carrier status, and oxidase gene polymorphisms have all been associated with autoinflammatory and autoimmune disorders, suggesting a potential role for NADPH oxidase in regulating adaptive immune responses. Here, NADPH oxidase function in antigen processing and presentation is reviewed. NADPH oxidase influences dendritic cell (DC crosspresentation by major histocompatibility complex class I molecules (MHC-I through regulation of the phagosomal microenvironment, while in B lymphocytes, NADPH oxidase alters epitope selection by major histocompatibility complex class II molecules (MHC-II.
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International Nuclear Information System (INIS)
Gao, Feng; Bao, Jinku
2013-01-01
A primitive monoclinic crystal of the rhesus macaque MHC class I molecule Mamu-B*17 complexed with an SIVmac239 Env peptide was obtained and belonged to space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. The crystal diffracted to 2.55 Å resolution. Long-term nonprogression during simian immunodeficiency virus (SIV) infection has been strongly associated with the major histocompatibility complex (MHC) class I allele Mamu-B*17. Here, a complex of rhesus macaque Mamu-B*17 with rhesus macaque β 2 -microglobulin (β 2 m) and an immunodominant peptide (SIVmac239 Env241–251; LRCNDTNYSGF; Env LF11) derived from the SIV Env protein was crystallized by the hanging-drop method using PEG 3350 as a precipitating agent. The crystals belonged to the primitive monoclinic space group P2, with unit-cell parameters a = 68.3, b = 45.0, c = 81.5 Å, β = 96.5°. Assuming the presence of one molecule in the asymmetric unit, the Matthews coefficient and solvent content were calculated to be 2.96 Å 3 Da −1 and 58.5%, respectively
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Distribution of HLA-DRB1/DQB1 alleles and DRB1-DQB1 ...
African Journals Online (AJOL)
Marwa Chaouali
2017-03-17
Mar 17, 2017 ... Background: Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by necrotic inflammation leading to hepatocyte destruction. The association of human leukocyte antigens (HLA) with. AIH development and onset is not fully elucidated especially in the Tunisian population. Objectives: ...
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DEFF Research Database (Denmark)
Soares, Milena Botelho Pereira; de Lima, Ricardo Santana; Rocha, Leonardo Lima
2010-01-01
histocompatibility complex molecules) and fibrosis (extracellular matrix components, lysyl oxidase, and tissue inhibitor of metalloproteinase 1). Our results indicate potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets in chronic Chagas disease....
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Directory of Open Access Journals (Sweden)
Edoardo Totè
Full Text Available The ability of detecting the subtle variations occurring, among different individuals, within specific DNA sequences encompassed in highly polymorphic genes discloses new applications in genomics and diagnostics. DQB1 is a gene of the HLA-II DQ locus of the Human Leukocyte Antigens (HLA system. The polymorphisms of the trait of the DQB1 gene including codons 52-57 modulate the susceptibility to a number of severe pathologies. Moreover, the donor-receiver tissue compatibility in bone marrow transplantations is routinely assessed through crossed genotyping of DQB and DQA. For the above reasons, the development of rapid, reliable and cost-effective typing technologies of DQB1 in general, and more specifically of the codons 52-57, is a relevant although challenging task. Quantitative assessment of the fluorescence resonance energy transfer (FRET efficiency between chromophores labelling the opposite ends of gene-specific oligonucleotide probes has proven to be a powerful tool to type DNA polymorphisms with single-nucleotide resolution. The FRET efficiency can be most conveniently quantified by applying a time-resolved fluorescence analysis methodology, i.e. time-correlated single-photon counting, which allows working on very diluted template specimens and in the presence of fluorescent contaminants. Here we present a full in-vitro characterization of the fluorescence responses of two probes when hybridized to oligonucleotide mixtures mimicking all the possible genotypes of the codons 52-57 trait of DQB1 (8 homozygous and 28 heterozygous. We show that each genotype can be effectively tagged by the combination of the fluorescence decay constants extrapolated from the data obtained with such probes.
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HLA genetic profile of Mapuche (Araucanian) Amerindians from Chile.
Rey, Diego; Parga-Lozano, Carlos; Moscoso, Juan; Areces, Cristina; Enriquez-de-Salamanca, Mercedes; Fernández-Honrado, Mercedes; Abd-El-Fatah-Khalil, Sedeka; Alonso-Rubio, Javier; Arnaiz-Villena, Antonio
2013-07-01
Amerindian Mapuche (Araucanians) are now living in Chile and Argentina at both sides of Andean Mountains. They are anthropologically and genetically different from southernmost South America Patagonian Amerindians. Most of the HLA alleles found in our Mapuche sample are frequent or very frequent in North and South America Amerindians: (1) Class I: A*02:01, A*03:01, A*68:01, B*39:09, B*51:01, (2) Class II: DRB1*03:01, DRB1*04:03, DRB1*07:01, DRB1*08:02, DRB1*14:02, DRB1*16:02. One of the nine most frequent extended haplotypes seems to be from European origin, suggesting the existence of a degree of admixture with Europeans in our Mapuche sample. It has been calculated of about 11 % admixture. Three of the extended haplotypes are also found in other Amerindians and five of them are newly found in Mapuche Amerindians: A*68:01-B*39:09-DRB1*08:02-DQB1*04:02; A*68:01-B*51:01-DRB1*04:03-DQB1*03:02; A*29:01-B*08:01-DRB1*03:01-DQB1*02:01; A*02:01-B*15:01-DRB1*04:03-DQB1*03:02; A*33:01-B*14:02-DRB1*07:01-DQB1*03:03. The medical importance of calculating HLA profile is discussed on the diagnostic (HLA and disease) and therapeutical bases of HLA pharmacogenomics and on the construction of a virtual transplantation HLA list profile. Also, anthropological conclusions are drawn.
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Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules
International Nuclear Information System (INIS)
Yamamoto, Junji; Kariyone, Ai; Kano, Kyoichi; Takiguchi, Masafumi; Akiyama, Nobuo
1990-01-01
Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1 -specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the α 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the α 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the α 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules
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The major genetic determinants of HIV-1 control affect HLA class I peptide presentation
Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I. W.; Walker, Bruce D.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.; Heckerman, David; Graham, Robert R.; Plenge, Robert M.; Deeks, Steven G.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Noël P.; Guiducci, Candace; Gupta, Namrata; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Henn, Matthew R.; Le Gall, Sylvie; Streeck, Hendrik; Haas, David W.; Kuritzkes, Daniel R.; Robbins, Gregory K.; Shafer, Robert W.; Gulick, Roy M.; Shikuma, Cecilia M.; Haubrich, Richard; Riddler, Sharon; Sax, Paul E.; Daar, Eric S.; Ribaudo, Heather J.; Agan, Brian; Agarwal, Shanu; Ahern, Richard L.; Allen, Brady L.; Altidor, Sherly; Altschuler, Eric L.; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J.; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C.; Benson, Anne M.; Berger, Judith; Bernard, Nicole F.; Bernard, Annette M.; Birch, Christopher; Bodner, Stanley J.; Bolan, Robert K.; Boudreaux, Emilie T.; Bradley, Meg; Braun, James F.; Brndjar, Jon E.; Brown, Stephen J.; Brown, Katherine; Brown, Sheldon T.; Burack, Jedidiah; Bush, Larry M.; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H.; Carmichael, J. Kevin; Casey, Kathleen K.; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T.; Chez, Nancy; Chirch, Lisa M.; Cimoch, Paul J.; Cohen, Daniel; Cohn, Lillian E.; Conway, Brian; Cooper, David A.; Cornelson, Brian; Cox, David T.; Cristofano, Michael V.; Cuchural, George; Czartoski, Julie L.; Dahman, Joseph M.; Daly, Jennifer S.; Davis, Benjamin T.; Davis, Kristine; Davod, Sheila M.; DeJesus, Edwin; Dietz, Craig A.; Dunham, Eleanor; Dunn, Michael E.; Ellerin, Todd B.; Eron, Joseph J.; Fangman, John J. W.; Farel, Claire E.; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A.; French, Neel K.; Fuchs, Jonathan D.; Fuller, Jon D.; Gaberman, Jonna; Gallant, Joel E.; Gandhi, Rajesh T.; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C.; Gaultier, Cyril R.; Gebre, Wondwoosen; Gilman, Frank D.; Gilson, Ian; Goepfert, Paul A.; Gottlieb, Michael S.; Goulston, Claudia; Groger, Richard K.; Gurley, T. Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W. David; Harrigan, P. Richard; Hawkins, Trevor N.; Heath, Sonya; Hecht, Frederick M.; Henry, W. Keith; Hladek, Melissa; Hoffman, Robert P.; Horton, James M.; Hsu, Ricky K.; Huhn, Gregory D.; Hunt, Peter; Hupert, Mark J.; Illeman, Mark L.; Jaeger, Hans; Jellinger, Robert M.; John, Mina; Johnson, Jennifer A.; Johnson, Kristin L.; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C.; Kauffman, Carol A.; Khanlou, Homayoon; Killian, Robert K.; Kim, Arthur Y.; Kim, David D.; Kinder, Clifford A.; Kirchner, Jeffrey T.; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P. Todd; Kurisu, Wayne; Kwon, Douglas S.; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M.; Lee, David M.; Lee, Jean M. L.; Lee, Marah J.; Lee, Edward T. Y.; Lemoine, Janice; Levy, Jay A.; Llibre, Josep M.; Liguori, Michael A.; Little, Susan J.; Liu, Anne Y.; Lopez, Alvaro J.; Loutfy, Mono R.; Loy, Dawn; Mohammed, Debbie Y.; Man, Alan; Mansour, Michael K.; Marconi, Vincent C.; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N.; Martin, Harold L.; Mayer, Kenneth Hugh; McElrath, M. Juliana; McGhee, Theresa A.; McGovern, Barbara H.; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X.; Menezes, Prema; Mesa, Greg; Metroka, Craig E.; Meyer-Olson, Dirk; Miller, Andy O.; Montgomery, Kate; Mounzer, Karam C.; Nagami, Ellen H.; Nagin, Iris; Nahass, Ronald G.; Nelson, Margret O.; Nielsen, Craig; Norene, David L.; O'Connor, David H.; Ojikutu, Bisola O.; Okulicz, Jason; Oladehin, Olakunle O.; Oldfield, Edward C.; Olender, Susan A.; Ostrowski, Mario; Owen, William F.; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M.; Perlmutter, Aaron M.; Pierce, Michael N.; Pincus, Jonathan M.; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C.; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J.; Rhame, Frank S.; Richards, Constance Shamuyarira; Richman, Douglas D.; Rodes, Berta; Rodriguez, Milagros; Rose, Richard C.; Rosenberg, Eric S.; Rosenthal, Daniel; Ross, Polly E.; Rubin, David S.; Rumbaugh, Elease; Saenz, Luis; Salvaggio, Michelle R.; Sanchez, William C.; Sanjana, Veeraf M.; Santiago, Steven; Schmidt, Wolfgang; Schuitemaker, Hanneke; Sestak, Philip M.; Shalit, Peter; Shay, William; Shirvani, Vivian N.; Silebi, Vanessa I.; Sizemore, James M.; Skolnik, Paul R.; Sokol-Anderson, Marcia; Sosman, James M.; Stabile, Paul; Stapleton, Jack T.; Starrett, Sheree; Stein, Francine; Stellbrink, Hans-Jurgen; Sterman, F. Lisa; Stone, Valerie E.; Stone, David R.; Tambussi, Giuseppe; Taplitz, Randy A.; Tedaldi, Ellen M.; Theisen, William; Torres, Richard; Tosiello, Lorraine; Tremblay, Cecile; Tribble, Marc A.; Trinh, Phuong D.; Tsao, Alice; Ueda, Peggy; Vaccaro, Anthony; Valadas, Emilia; Vanig, Thanes J.; Vecino, Isabel; Vega, Vilma M.; Veikley, Wenoah; Wade, Barbara H.; Walworth, Charles; Wanidworanun, Chingchai; Ward, Douglas J.; Warner, Daniel A.; Weber, Robert D.; Webster, Duncan; Weis, Steve; Wheeler, David A.; White, David J.; Wilkins, Ed; Winston, Alan; Wlodaver, Clifford G.; van't Wout, Angelique; Wright, David P.; Yang, Otto O.; Yurdin, David L.; Zabukovic, Brandon W.; Zachary, Kimon C.; Zeeman, Beth; Zhao, Meng
2010-01-01
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide
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Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Wares, J. P.; Yabsley, M. J.; Altizer, S.
2014-01-01
Roč. 28, č. 5 (2014), s. 957-975 ISSN 0269-7653 Institutional support: RVO:68081766 Keywords : Major histocompatibility complex * Host-parasite relationship * Balancing selection * Microtus montanus * Cestodes * Eimeria * Microsatellites Subject RIV: EG - Zoology Impact factor: 2.517, year: 2014
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Pathogen-mediated selection for MHC variability in wild zebrafish
Czech Academy of Sciences Publication Activity Database
Smith, C.; Ondračková, Markéta; Spence, R.; Adams, S.; Betts, D. S.; Mallon, E.
2011-01-01
Roč. 13, č. 6 (2011), s. 589-605 ISSN 1522-0613 Institutional support: RVO:68081766 Keywords : digenean * frequency-dependent selection * heterozygote advantage * major histocompatibility complex * metazoan parasite * pathogen-driven selection Subject RIV: EG - Zoology Impact factor: 1.029, year: 2011
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CCR5 in Multiple Sclerosis : expression, regulation, and modulation by statins
Kuipers, Hedwich Fardau
2007-01-01
Activation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of major histocompatibility complex (MHC) molecules. This enhanced expression results from increased
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Analysis of two susceptibilitySNPsinHLAregion and evidence of ...
Indian Academy of Sciences (India)
Previous genomewide association studies (GWAS) and meta-analyses have enumerated several genes/loci in major histocompatibility complex region, which are consistently associated with rheumatoid arthritis (RA) in different ethnic populations. Given the genetic heterogeneity of the disease, it is necessary to replicate ...
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Roos, M. T.; van Lier, R. A.; Hamann, D.; Knol, G. J.; Verhoofstad, I.; van Baarle, D.; Miedema, F.; Schellekens, P. T.
2000-01-01
In response to viral infection, unprimed naive CD8(+), major histocompatibility complex class I-restricted, virus-specific T cells clonally expand and differentiate into memory- and effector-type cells. Changes in CD8(+) subset distribution were studied in 17 subjects with acute human
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van den Berg, Timo K.; van der Schoot, C. Ellen
2008-01-01
Self-nonself discrimination is a central property of the immune system. This paradigm was originally established in the context of tissue transplantation, leading to the discovery of major histocompatibility complex molecules as signals of 'self'. However, accumulating evidence has shown that innate
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Indian Academy of Sciences (India)
PRAKASH KUMAR
Although originally described as an intracellular second messenger, sphingosine 1-phosphate (S1P) has recently been shown to ... lysophosphatidic acid; LPS, lipopolysaccharides; mDC, mature DC; MHC, major histocompatibility complex; NK, natural killer; PCR, ..... -the enigmatic lipid class: biochemistry, physiology, and.
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IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN
DEFF Research Database (Denmark)
Lefranc, Marie-Paule; Duprat, E.; Kaas, Quentin
2005-01-01
IMGT, the international ImMunoGeneTics information system® (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins...
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DEFF Research Database (Denmark)
Lefranc, Marie-Paule; Pommié, Christelle; Kaas, Quentin
2005-01-01
IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins...
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Designing bovine T cell vaccines via reverse immunology
DEFF Research Database (Denmark)
Nene, Vishvanath; Svitek, Nicholas; Toye, Philip
2012-01-01
T cell responses contribute to immunity against many intracellular infections. There is, for example, strong evidence that major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes (CTLs) play an essential role in mediating immunity to East Coast fever (ECF), a fatal lymph...
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DEFF Research Database (Denmark)
Wang, Mingjun; Tang, Sheila Tuyet; Stryhn, Anette
2011-01-01
Major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTL) are known to play an important role in the control of Mycobacterium tuberculosis infection so identification of CTL epitopes from M. tuberculosis is of importance for the development of effective peptide...
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State of the art and challenges in sequence based T-cell epitope prediction
DEFF Research Database (Denmark)
Lundegaard, Claus; Hoof, Ilka; Lund, Ole
2010-01-01
Sequence based T-cell epitope predictions have improved immensely in the last decade. From predictions of peptide binding to major histocompatibility complex molecules with moderate accuracy, limited allele coverage, and no good estimates of the other events in the antigen-processing pathway, the...
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In situ behavior of human Langerhans cells in skin organ culture
Rambukkana, A.; Bos, J. D.; Irik, D.; Menko, W. J.; Kapsenberg, M. L.; Das, P. K.
1995-01-01
Epidermal Langerhans cells (ELC) play a critical role in the initiation of cutaneous immune responses. ELC are characterized by the expression of major histocompatibility complex (MHC) class II Ag and a number of adhesion/costimulatory molecules. Evidence suggests that cytokines induced within the
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Bile acids for liver-transplanted patients
DEFF Research Database (Denmark)
Poropat, Goran; Giljaca, Vanja; Stimac, Davor
2010-01-01
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein...
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Bile acids for liver-transplanted patients. Protocol for a Cochrane Review
DEFF Research Database (Denmark)
Chen, W; Gluud, C
2003-01-01
Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease the degree of allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium...
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Common genetic variation and the control of HIV-1 in humans
DEFF Research Database (Denmark)
Fellay, J.; Ge, D.; Shianna, K.V.
2009-01-01
provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies...
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Ribeiro-do-Couto, Laura M.; Poelen, Martien; Hooibrink, Berend; Dormans, Jan A. M. A.; Roholl, Paul J. M.; Boog, Claire J. P.
2003-01-01
Limitations in neonatal natural killer (NK) cell responses may be associated with the less efficient newborn capacity to solve viral infections. Although these limitations have been extensively reported they are poorly characterized. Making use of the major histocompatibility complex (MHC) class I
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Evolution of MHC class I genes in the European badger (Meles meles)
Sin, Yung Wa; Dugdale, Hannah L.; Newman, Chris; Macdonald, David W.; Burke, Terry
The major histocompatibility complex (MHC) plays a central role in the adaptive immune system and provides a good model with which to understand the evolutionary processes underlying functional genes. Trans-species polymorphism and orthology are both commonly found in MHC genes; however, mammalian
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Aguilar-Medina, Maribel; Escamilla-Tilch, Monica; Frías-Castro, Luis Octavio; Romero-Quintana, Geovanni; Estrada-García, Iris; Estrada-Parra, Sergio; Granados, Julio; Arambula Meraz, Eliakym; Sánchez-Schmitz, Guzman; Khader, Shabaana Abdul; Rangel-Moreno, Javier; Ramos-Payán, Rosalío
2017-01-01
Despite the use of multidrug therapy, leprosy remains endemic in some countries. The association of several human leucocyte antigen (HLA) alleles and gene polymorphisms with leprosy has been demonstrated in many populations, but the major immune contributors associated to the spectrum of leprosy have not been defined yet. In this study, genotyping of HLA-A, -B, -DR, and -DQ alleles was performed in leprosy patients (n = 113) and control subjects (n = 117) from the region with the highest incidence for the disease in México. The odds of developing leprosy and lepromatous subtype were 2.12- and 2.74-fold higher in carriers of HLA-A*28, and 2.48- and 4.14-fold higher for leprosy and dimorphic subtype in carriers of DQB1*06. Interestingly, DQB1*07 was overrepresented in healthy individuals, compared to patients with leprosy (OR = 0.08) and the lepromatous subtype (OR = 0.06). These results suggest that HLA-A*28 is a marker for predisposition to leprosy and the lepromatous subtype and DQB1*06 to leprosy and the dimorphic subtype, while DQB1*07 might be a resistance marker in this Mestizo population. © 2016 John Wiley & Sons Ltd/University College London.
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Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.
Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas
2017-10-01
Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.
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Genome complexity in the coelacanth is reflected in its adaptive immune system
Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W.; Hansen, John; Parra, Zuly; Hsu, Ellen; Buonocore, Francesco; Canapa, Adriana; Cheng, Jan-Fang; Amemiya, Chris T.
2014-01-01
We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding α/β and γ/δ T-cell receptors, and CD3, CD4, and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR α/δ locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations.
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DEFF Research Database (Denmark)
Gold, Marielle C.; McLaren, James E.; Reistetter, Joseph A.
2014-01-01
Mucosal-associated invariant T (MAIT) cells express a semi-invariant T cell receptor (TCR) that detects microbial metabolites presented by the nonpolymorphic major histocompatibility complex (MHC)-like molecule MR1. The highly conserved nature of MR1 in conjunction with biased MAIT TCRα chain usa...
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DEFF Research Database (Denmark)
Pedersen, Lasse Eggers; Rasmussen, Michael; Harndahl, Mikkel
The affinity for and stability of peptides bound by major histocompatibility complex (MHC) class I molecules are instrumental factors in presentation of viral epitopes to cytotoxic T lymphocytes (CTLs). In swine, such peptide presentations by swine leukocyte antigens (SLA) are crucial for swine i...
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MHC Region and Its Related Disease Study
DEFF Research Database (Denmark)
Cao, Hongzhi
The major histocompatibility complex (MHC) is one of the most gene dense regions in the human genome and many disorders, including primary immune deficiencies, autoimmune conditions, infections, cancers and mental disorder have been found to be associated with this region. However, due to a high ...
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Autologous peptides constitutively occupy the antigen binding site on Ia
DEFF Research Database (Denmark)
Buus, S; Sette, A; Colon, S M
1988-01-01
Low molecular weight material associated with affinity-purified class II major histocompatibility complex (MHC) molecules of mouse (Ia) had the expected properties of peptides bound to the antigen binding site of Ia. Thus, the low molecular weight material derived from the I-Ad isotype...
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Roos, A.; Schilder-Tol, E. J.; Chand, M. A.; Claessen, N.; Lakkis, F. G.; Pascual, D. W.; Weening, J. J.; Aten, J.
1998-01-01
Susceptibility to induction of both T helper 1- (Th1) and Th2-mediated autoimmunity is multifactorial and involves genetic linkage to the major histocompatibility complex (MHC) class II haplotype. Brown Norway (BN) rats exposed to mercuric chloride develop a Th2-dependent systemic autoimmunity,
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Sprengers, Dave; Sillé, Fenna C. M.; Derkow, Katja; Besra, Gurdyal S.; Janssen, Harry L. A.; Schott, Eckart; Boes, Marianne
2008-01-01
V alpha14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We
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MHC class II B diversity in blue tits : A preliminary study
Rivero-de Aguilar, Juan; Schut, Elske; Merino, Santiago; Martinez, Javier; Komdeur, Jan; Westerdahl, Helena
In this study, we partly characterize major histocompatibility complex (MHC) class II B in the blue tit (Cyanistes caeruleus). A total of 22 individuals from three different European locations: Spain, The Netherlands, and Sweden were screened for MHC allelic diversity. The MHC genes were
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Designing bovine T-cell vaccines via reverse immunology
T-cell responses contribute to immunity against many intra-cellular infections. There is, for example, strong evidence that major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTLs) play an essential role in mediating immunity to East Coast fever (ECF), a fatal lymphop...
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MHC class II-assortative mate choice in European badgers (Meles meles)
Sin, Yung Wa; Annavi, Geetha; Newman, Chris; Buesching, Christina D.; Burke, Terry; Macdonald, David W.; Dugdale, Hannah
The major histocompatibility complex (MHC) plays a crucial role in the immune system, and in some species, it is a target by which individuals choose mates to optimize the fitness of their offspring, potentially mediated by olfactory cues. Under the genetic compatibility hypothesis, individuals are
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DEFF Research Database (Denmark)
Lundegaard, Claus; Lamberth, K; Harndahl, M
2008-01-01
NetMHC-3.0 is trained on a large number of quantitative peptide data using both affinity data from the Immune Epitope Database and Analysis Resource (IEDB) and elution data from SYFPEITHI. The method generates high-accuracy predictions of major histocompatibility complex (MHC): peptide binding...
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Genome-wide expression profiling of complex regional pain syndrome.
Directory of Open Access Journals (Sweden)
Eun-Heui Jin
Full Text Available Complex regional pain syndrome (CRPS is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II and 5 controls (cut-off value: 1.5-fold change and p<0.05. Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1, matrix metalloproteinase 9 (MMP9, alanine aminopeptidase N (ANPEP, l-histidine decarboxylase (HDC, granulocyte colony-stimulating factor 3 receptor (G-CSF3R, and signal transducer and activator of transcription 3 (STAT3 genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR. We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.0±1.23 times and p = 1.4×10(-4. The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression.
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Luoma, Adrienne M; Castro, Caitlin D; Mayassi, Toufic; Bembinster, Leslie A; Bai, Li; Picard, Damien; Anderson, Brian; Scharf, Louise; Kung, Jennifer E; Sibener, Leah V; Savage, Paul B; Jabri, Bana; Bendelac, Albert; Adams, Erin J
2013-12-12
The nature of the antigens recognized by γδ T cells and their potential recognition of major histocompatibility complex (MHC)-like molecules has remained unclear. Members of the CD1 family of lipid-presenting molecules are suggested ligands for Vδ1 TCR-expressing γδ T cells, the major γδ lymphocyte population in epithelial tissues. We crystallized a Vδ1 TCR in complex with CD1d and the self-lipid sulfatide, revealing the unusual recognition of CD1d by germline Vδ1 residues spanning all complementarity-determining region (CDR) loops, as well as sulfatide recognition separately encoded by nongermline CDR3δ residues. Binding and functional analysis showed that CD1d presenting self-lipids, including sulfatide, was widely recognized by gut Vδ1+ γδ T cells. These findings provide structural demonstration of MHC-like recognition of a self-lipid by γδ T cells and reveal the prevalence of lipid recognition by innate-like T cell populations. Copyright © 2013 Elsevier Inc. All rights reserved.
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International Nuclear Information System (INIS)
Yoshimura, N.; Kahan, B.D.
1985-01-01
Antigen-specific suppressor T cells are induced by donor histocompatibility antigen extracted from spleen cells with 3M KCl combined with cyclosporine (Ag-CsA). A single i.v. injection of 5 mg 3M-KCl-extracted donor Buffalo (Buf, RT1b) antigen (Ag) combined with a three day course of CsA prolonged renal allograft survival in Wistar-Furth (WFu, RT1u) hosts to a greater extent (MST 26.5 days) than CsA alone (MST 11.8 days). Peripheral blood lymphocytes (PBL) or spleen cells harvested from Ag-CsA-treated recipients ten days after transplantation inhibited the mixed lymphocyte reaction (MLR) between normal responder WFu cells and irradiated Buf cells (55.6% and 64.4% suppression, respectively, P less than 0.025), but not third-party Brown-Norway (BN, RT1n) stimulator cells (13.6% and -18.3% suppression, respectively, NS). The suppressor effect was not mediated by cytolytic cells; there was neither primary nor secondary cytolytic activity against 51 Cr-labeled Con-A blastoid Buf cells. The suppressor cells were neither adherent to plastic dishes nor to nylon-wool columns. PBL irradiated with 800 rads, but not 1500 rads, suppressed the MLR. A single injection of cyclophosphamide (CY, 25 mg/kg) seven days after transplantation abrogated the suppression induced by Ag-CsA treatment. Moreover, PBL from Ag-CsA recipients failed to suppress the MLR, if depleted either of all T cells by treatment with monoclonal antibody (Mab) W3/13 HLK (pan T cells; % suppression -15.8), or of cytotoxic/suppressor cells with Mab OX-8 (-19.3% suppression) together with rabbit antimouse immunoglobulin and complement
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Geometry Dynamics of α-Helices in Different Class I Major Histocompatibility Complexes
Directory of Open Access Journals (Sweden)
Reiner Ribarics
2015-01-01
Full Text Available MHC α-helices form the antigen-binding cleft and are of particular interest for immunological reactions. To monitor these helices in molecular dynamics simulations, we applied a parsimonious fragment-fitting method to trace the axes of the α-helices. Each resulting axis was fitted by polynomials in a least-squares sense and the curvature integral was computed. To find the appropriate polynomial degree, the method was tested on two artificially modelled helices, one performing a bending movement and another a hinge movement. We found that second-order polynomials retrieve predefined parameters of helical motion with minimal relative error. From MD simulations we selected those parts of α-helices that were stable and also close to the TCR/MHC interface. We monitored the curvature integral, generated a ruled surface between the two MHC α-helices, and computed interhelical area and surface torsion, as they changed over time. We found that MHC α-helices undergo rapid but small changes in conformation. The curvature integral of helices proved to be a sensitive measure, which was closely related to changes in shape over time as confirmed by RMSD analysis. We speculate that small changes in the conformation of individual MHC α-helices are part of the intrinsic dynamics induced by engagement with the TCR.
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Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection
DEFF Research Database (Denmark)
Hoof, Ilka; Kesmir, Can; Lund, Ole
2008-01-01
and the progression rate to AIDS. Chimpanzees control HIV-1 viral replication and develop a chronic infection without progressing to AIDS. A similar course of disease is observed in human long-term non-progressors. Objective: To investigate if long-term non-progressors and chimpanzees have functional similarities...... in their MHC class I repertoire. Methods: We compared the specificity of groups of human MHC molecules associated with different levels of viremia in HIV-1 infected individuals with those of chimpanzee. Results and conclusion: We demonstrate that human MHC with control of HIV-1 viral load share binding motifs...... with chimpanzee MHC. Moreover, we find that chimpanzee and human MHC associated with low viral load are predicted to elicit broader Gag-specific immune responses than human MHC associated with high viral load, thus supporting earlier findings that Gag-specific immune responses are essential for HIV-1 control....
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Genome-wide association study identifies variants associated with autoimmune hepatitis type 1.
de Boer, Ynto S; van Gerven, Nicole M F; Zwiers, Antonie; Verwer, Bart J; van Hoek, Bart; van Erpecum, Karel J; Beuers, Ulrich; van Buuren, Henk R; Drenth, Joost P H; den Ouden, Jannie W; Verdonk, Robert C; Koek, Ger H; Brouwer, Johannes T; Guichelaar, Maureen M J; Vrolijk, Jan M; Kraal, Georg; Mulder, Chris J J; van Nieuwkerk, Carin M J; Fischer, Janett; Berg, Thomas; Stickel, Felix; Sarrazin, Christoph; Schramm, Christoph; Lohse, Ansgar W; Weiler-Normann, Christina; Lerch, Markus M; Nauck, Matthias; Völzke, Henry; Homuth, Georg; Bloemena, Elisabeth; Verspaget, Hein W; Kumar, Vinod; Zhernakova, Alexandra; Wijmenga, Cisca; Franke, Lude; Bouma, Gerd
2014-08-01
Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Analysis of gene expression profile microarray data in complex regional pain syndrome.
Tan, Wulin; Song, Yiyan; Mo, Chengqiang; Jiang, Shuangjian; Wang, Zhongxing
2017-09-01
The aim of the present study was to predict key genes and proteins associated with complex regional pain syndrome (CRPS) using bioinformatics analysis. The gene expression profiling microarray data, GSE47603, which included peripheral blood samples from 4 patients with CRPS and 5 healthy controls, was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in CRPS patients compared with healthy controls were identified using the GEO2R online tool. Functional enrichment analysis was then performed using The Database for Annotation Visualization and Integrated Discovery online tool. Protein‑protein interaction (PPI) network analysis was subsequently performed using Search Tool for the Retrieval of Interaction Genes database and analyzed with Cytoscape software. A total of 257 DEGs were identified, including 243 upregulated genes and 14 downregulated ones. Genes in the human leukocyte antigen (HLA) family were most significantly differentially expressed. Enrichment analysis demonstrated that signaling pathways, including immune response, cell motion, adhesion and angiogenesis were associated with CRPS. PPI network analysis revealed that key genes, including early region 1A binding protein p300 (EP300), CREB‑binding protein (CREBBP), signal transducer and activator of transcription (STAT)3, STAT5A and integrin α M were associated with CRPS. The results suggest that the immune response may therefore serve an important role in CRPS development. In addition, genes in the HLA family, such as HLA‑DQB1 and HLA‑DRB1, may present potential biomarkers for the diagnosis of CRPS. Furthermore, EP300, its paralog CREBBP, and the STAT family genes, STAT3 and STAT5 may be important in the development of CRPS.
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Hamada, K; Gleason, S L; Levi, B Z; Hirschfeld, S; Appella, E; Ozato, K
1989-11-01
Transcription of major histocompatibility complex (MHC) class I genes is regulated by the conserved MHC class I regulatory element (CRE). The CRE has two factor-binding sites, region I and region II, both of which elicit enhancer function. By screening a mouse lambda gt 11 library with the CRE as a probe, we isolated a cDNA clone that encodes a protein capable of binding to region II of the CRE. This protein, H-2RIIBP (H-2 region II binding protein), bound to the native region II sequence, but not to other MHC cis-acting sequences or to mutant region II sequences, similar to the naturally occurring region II factor in mouse cells. The deduced amino acid sequence of H-2RIIBP revealed two putative zinc fingers homologous to the DNA-binding domain of steroid/thyroid hormone receptors. Although sequence similarity in other regions was minimal, H-2RIIBP has apparent modular domains characteristic of the nuclear hormone receptors. Further analyses showed that both H-2RIIBP and the natural region II factor bind to the estrogen response element (ERE) of the vitellogenin A2 gene. The ERE is composed of a palindrome, and half of this palindrome resembles the region II binding site of the MHC CRE. These results indicate that H-2RIIBP (i) is a member of the superfamily of nuclear hormone receptors and (ii) may regulate not only MHC class I genes but also genes containing the ERE and related sequences. Sequences homologous to the H-2RIIBP gene are widely conserved in the animal kingdom. H-2RIIBP mRNA is expressed in many mouse tissues, in agreement with the distribution of the natural region II factor.
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A strategy for bacterial production of a soluble functional human neonatal Fc receptor
DEFF Research Database (Denmark)
Andersen, Jan Terje; Justesen, Sune; Berntzen, Gøril
2008-01-01
The major histocompatibility complex (MHC) class I related receptor, the neonatal Fc receptor (FcRn), rescues immunoglobulin G (IgG) and albumin from lysosomal degradation by recycling in endothelial cells. FcRn also contributes to passive immunity by mediating transport of IgG from mother to fetus...
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DEFF Research Database (Denmark)
Murphy, J. Patrick; Konda, Prathyusha; Kowalewski, Daniel J.
2017-01-01
Class I major histocompatibility complex (MHC-I)-bound peptide ligands dictate the activation and specificity of CD8+ T cells and thus are important for devising T-cell immunotherapies. In recent times, advances in mass spectrometry (MS) have enabled the precise identification of these MHC-I pept...
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Phillips, J. H.; Hori, T.; Nagler, A.; Bhat, N.; Spits, H.; Lanier, L. L.
1992-01-01
Natural killer (NK) cells have been defined as CD3 epsilon-, CD16+ and/or CD56+ lymphocytes that mediate major histocompatibility complex (MHC)-unrestricted cytotoxicity against certain tumors and virus-infected cells. Unlike T lymphocytes, NK cells do not rearrange or productively express T cell
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Evolution of MHC-based technologies used for detection of antigen-responsive T cells
DEFF Research Database (Denmark)
Bentzen, Amalie Kai; Hadrup, Sine Reker
2017-01-01
T cell-mediated recognition of peptide-major histocompatibility complex (pMHC) class I and II molecules is crucial for the control of intracellular pathogens and cancer, as well as for stimulation and maintenance of efficient cytotoxic responses. Such interactions may also play a role in the deve...
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DEFF Research Database (Denmark)
Follin, Elna; Karlsson, Maria; Lundegaard, Claus
2013-01-01
The major histocompatibility complex (MHC) genes are the most polymorphic genes found in the vertebrate genome, and they encode proteins that play an essential role in the adaptive immune response. Many songbirds (passerines) have been shown to have a large number of transcribed MHC class I genes...
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PCR-based isolation of multigene families: lessons from the avian MHC class IIB
Czech Academy of Sciences Publication Activity Database
Burri, R.; Promerová, Marta; Goebel, J.; Fumagalli, L.
2014-01-01
Roč. 14, č. 4 (2014), s. 778-788 ISSN 1755-098X R&D Projects: GA ČR GAP505/10/1871 Institutional support: RVO:68081766 Keywords : Birds * Major histocompatibility complex * Multigene families * PCR bias Subject RIV: EG - Zoology Impact factor: 3.712, year: 2014
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DEFF Research Database (Denmark)
Hald, Jeppe; Rasmussen, N; Claesson, Mogens Helweg
1995-01-01
Tumour-infiltrating lymphocytes (TIL) and tumours from six patients with squamous cell carcinomas of the head and neck (SCCHN) were investigated. The six tumours all expressed major histocompatibility complex (MHC) class I antigens both in vivo and as tumor cell lines grown in vitro. In addition...
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Natural Killer cell recognition of melanoma: new clues for a more effective immunotherapy
Directory of Open Access Journals (Sweden)
Raquel eTarazona
2016-01-01
Full Text Available Natural killer cells participate in the early immune response against melanoma and also contribute to the development of an adequate adaptive immune response by their crosstalk with dendritic cells and cytokine secretion. Melanoma resistance to conventional therapies together with its high immunogenicity justifies the development of novel therapies aimed to stimulate effective immune responses against melanoma. However, melanoma cells frequently escape to CD8 T cell recognition by the down-regulation of major histocompatibility complex class I molecules. In this scenario, Natural killer cells emerge as potential candidates for melanoma immunotherapy due to their capacity to recognize and destroy melanoma cells expressing low levels of major histocompatibility complex class I molecules. In addition, the possibility to combine immune checkpoint blockade with other NK cell potentiating strategies (e.g. cytokine induction of activating receptors has opened new perspectives in the potential use of adoptive NK cell-based immunotherapy in melanoma.
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Gray, Lesley-Ann; D'Antoine, Heather A; Tong, Steven Y C; McKinnon, Melita; Bessarab, Dawn; Brown, Ngiare; Reményi, Bo; Steer, Andrew; Syn, Genevieve; Blackwell, Jenefer M; Inouye, Michael; Carapetis, Jonathan R
2017-12-12
Rheumatic heart disease (RHD) after group A streptococcus (GAS) infections is heritable and prevalent in Indigenous populations. Molecular mimicry between human and GAS proteins triggers proinflammatory cardiac valve-reactive T cells. Genome-wide genetic analysis was undertaken in 1263 Aboriginal Australians (398 RHD cases; 865 controls). Single-nucleotide polymorphisms were genotyped using Illumina HumanCoreExome BeadChips. Direct typing and imputation was used to fine-map the human leukocyte antigen (HLA) region. Epitope binding affinities were mapped for human cross-reactive GAS proteins, including M5 and M6. The strongest genetic association was intronic to HLA-DQA1 (rs9272622; P = 1.86 × 10-7). Conditional analyses showed rs9272622 and/or DQA1*AA16 account for the HLA signal. HLA-DQA1*0101_DQB1*0503 (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.09-1.90; P = 9.56 × 10-3) and HLA-DQA1*0103_DQB1*0601 (OR, 1.27; 95% CI, 1.07-1.52; P = 7.15 × 10-3) were risk haplotypes; HLA_DQA1*0301-DQB1*0402 (OR 0.30, 95%CI 0.14-0.65, P = 2.36 × 10-3) was protective. Human myosin cross-reactive N-terminal and B repeat epitopes of GAS M5/M6 bind with higher affinity to DQA1/DQB1 alpha/beta dimers for the 2-risk haplotypes than the protective haplotype. Variation at HLA_DQA1-DQB1 is the major genetic risk factor for RHD in Aboriginal Australians studied here. Cross-reactive epitopes bind with higher affinity to alpha/beta dimers formed by risk haplotypes, supporting molecular mimicry as the key mechanism of RHD pathogenesis. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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Association of gliadin antibodies, HLA alleles, and schizophrenia in Cuban population patients
Directory of Open Access Journals (Sweden)
José A. Galván
2016-05-01
Full Text Available Introduction: Several lines of evidence have suggested an interesting link between gluten ingestion and schizophrenia. For example, increased levels of gliadin and transglutaminase antibodies have been observed in patients with schizophrenia. Methods: To verify these observations we compared the prevalence of gliadin and transglutaminse antibodies, as well as the presence of the HLA alleles, HLA DQA1*0501-DQB1*02 (DQ2 and HLA-DQA1*0301-DQB1*0302 (DQ8, among patients with schizophrenia and healthy controls. A total of 108 patients with schizophrenia and 60 healthy controls were evaluated. Gliadin antibodies were determined by a visual semiquantitative assay and tissue transglutaminase antibodies were determined both by one-step immunochromatografic assay and ELISA. HLA typing was performed by PCR amplification using sequence-specific primers for each allele. Results: We found a strong association between the presence of gliadin antibodies and schizophrenia (OR 3.488; 95% CI, 1.43-8.44. However, tissue transglutaminase antibodies were not detected in either group neither by immunochromatograpic or ELISA. No significant association was found for the DQ2 or DQ8 heterodimer and the disease, but a significant positive association between schizophrenia and HLA alleles DQA1*0301 and DQB1*02 was present (OR = 2.80; 95% CI, 1.27-6.17, and OR = 2.37, 95% CI, 1.24-4.53, respectively. Conclusions: The present study showed that the presence of gliadin antibodies was not correlated with the presence of HLA DQA1*0301 or DQB1*02 alleles within the group of patients with schizophrenia. Our study replicates the findings that anti-gliadin antibodies are associated with schizophrenia but also suggests that the presence of these antibodies and the HLA alleles DQB1*02 and DQA1*0301 are independently associated with susceptibility to schizophrenia.
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Baker, Peter R.; Baschal, Erin E.; Fain, Pam R.; Triolo, Taylor M.; Nanduri, Priyaanka; Siebert, Janet C.; Armstrong, Taylor K.; Babu, Sunanda R.; Rewers, Marian J.; Gottlieb, Peter A.; Barker, Jennifer M.; Eisenbarth, George S.
2010-01-01
Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. PMID:20631027
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Directory of Open Access Journals (Sweden)
Noemi F. Pereira
2010-05-01
Full Text Available A compatibilidade HLA é o fator mais valorizado na escolha do doador de medula óssea voluntário, preconizando-se a realização de HLA de alta resolução nos locos HLA-A,B,C, DRB1 e DQB1. Tem sido dado preferência para o doador com consanguinidade alélica 8x8 (A,B,C, DRB1. Na presença de incompatibilidade na classe-I sugere-se a busca de doador com compatibilidade DQB1 (9x10. Já as incompatibilidades dos locos DPB1 não constituem critério de exclusão de doador, exceto quando existir presença de anticorpo contra o loco HLA-DP do doador.The HLA system is considered the most important factor in choosing a volunteer bone marrow donor with the recommendation of performing high resolution HLA tests for the HLA-A, B, C, DRB1 and DQB1 loci. A preference has been given for donor 8x8 (A, B, C, DRB1 allele matching. In the presence of class-I incompatibility a search for DQB1 (9x10 donor compatibility is suggested. The incompatibility of the DPB1 locus does not constitute exclusion of the donor, except when there is the presence of antibodies against the HLA-DP locus of the donor.
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C. Vásquez-Carrillo; V. Friesen; L. Hall; M.Z. Peery
2013-01-01
Conserving genetic variation is critical for maintaining the evolutionary potential and viability of a species. Genetic studies seeking to delineate conservation units, however, typically focus on characterizing neutral genetic variation and may not identify populations harboring local adaptations. Here, variation at two major histocompatibility complex (MHC) class II...
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DEFF Research Database (Denmark)
Lundegaard, Claus; Lund, Ole; Nielsen, Morten
2008-01-01
Several accurate prediction systems have been developed for prediction of class I major histocompatibility complex (MHC):peptide binding. Most of these are trained on binding affinity data of primarily 9mer peptides. Here, we show how prediction methods trained on 9mer data can be used for accurate...
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Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Promerová, M.; Poláková, R.; Vinkler, M.; Schnitzer, J.; Munclinger, P.; Babik, W.; Radwan, J.; Bryja, J.; Albrecht, T.
2015-01-01
Roč. 69, č. 3 (2015), s. 459-469 ISSN 0340-5443 R&D Projects: GA MŠk(CZ) EE2.3.30.0048 Institutional support: RVO:67985939 Keywords : extra-pair copulation * major histocompatibility complex * Erythrina erythrina Subject RIV: EH - Ecology, Behaviour Impact factor: 2.382, year: 2015
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Wilson, A. G.; de Vries, N. [=Niek; Pociot, F.; di Giovine, F. S.; van der Putte, L. B.; Duff, G. W.
1993-01-01
The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies
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Sin, Yung Wa; Dugdale, Hannah L.; Newman, Chris; Macdonald, David W.; Burke, Terry
The major histocompatibility complex (MHC) comprises many genes, some of which are polymorphic with numerous alleles. Sequence variation among alleles is most pronounced in exon 2 of the class II genes, which encodes the alpha 1 and beta 1 domains that form the antigen-binding site (ABS) for the
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Czech Academy of Sciences Publication Activity Database
Vlček, Jakub; Hoeck, P. E. A.; Keller, L. F.; Wayhart, J. P.; Dolinová, I.; Štefka, Jan
2016-01-01
Roč. 25, č. 19 (2016), s. 4757-4772 ISSN 0962-1083 R&D Projects: GA ČR GPP506/12/P529 Institutional support: RVO:60077344 Keywords : major histocompatibility complex * Mimus * genetic diversity * population size * trans-species polymorphism Subject RIV: EG - Zoology Impact factor: 6.086, year: 2016
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O'Hagan, Emma; Mallett, Tamara; Convery, Mairead; McKeever, Karl
2015-01-01
Antiglomerular basement membrane (anti-GBM) antibody disease is uncommon in the pediatric population. There are no cases in the literature describing the development of anti-GBM disease following XGP or nephrectomy. We report the case of a 7-year-old boy with no past history of urological illness, treated with antimicrobials and nephrectomy for diffuse, unilateral xanthogranulomatous pyelonephritis (XGP). Renal function and ultrasound scan of the contralateral kidney postoperatively were normal. Three months later, the child represented in acute renal failure with rapidly progressive glomerulonephritis requiring hemodialysis. Renal biopsy showed severe crescentic glomerulonephritis with 95% of glomeruli demonstrating circumferential cellular crescents. Strong linear IgG staining of the glomerular basement membranes was present, in keeping with anti-GBM disease. Circulating anti-GBM antibodies were positive. Treatment with plasma exchange, methylprednisolone, and cyclophosphamide led to normalization of anti-GBM antibody titers. Frequency of hemodialysis was reduced as renal function improved, and he is currently independent of dialysis with estimated glomerular filtration rate 20.7 mls/min/1.73 m 2 . Case studies in the adult literature have reported the development of a rapidly progressive anti-GBM antibody-induced glomerulonephritis following renal surgery where patients expressed HLA DR2/HLA DR15 major histocompatibility (MHC) antigens. Of note, our patient also expresses the HLA DR15 MHC antigen.
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Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Promerová, Marta; Poláková, R.; Vinkler, M.; Schnitzer, J.; Munclinger, P.; Babik, W.; Radwan, J.; Bryja, Josef; Albrecht, Tomáš
2015-01-01
Roč. 69, č. 3 (2015), s. 459-469 ISSN 0340-5443 R&D Projects: GA ČR GAP505/10/1871 Institutional support: RVO:68081766 Keywords : Extra-pair copulation * Mate choice * Sexual selection * Major histocompatibility complex * Indirect benefits * Erythrina erythrina Subject RIV: EG - Zoology Impact factor: 2.382, year: 2015
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Czech Academy of Sciences Publication Activity Database
Čížková, Dagmar; Javůrková, V.; Champagnon, J.; Kreisinger, J.
2012-01-01
Roč. 152, X (2012), s. 231-240 ISSN 0006-3207 R&D Projects: GA AV ČR IAA6093403; GA MŠk LC06073 Institutional support: RVO:68081766 Keywords : Genetic introgression * Hybridization * Major histocompatibility complex * mtDNA * Restocking * Waterfowl Subject RIV: EG - Zoology Impact factor: 3.794, year: 2012
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Czech Academy of Sciences Publication Activity Database
Promerová, Marta; Králová, Tereza; Bryjová, Anna; Albrecht, Tomáš; Bryja, Josef
2013-01-01
Roč. 8, č. 7 (2013), e69135 E-ISSN 1932-6203 R&D Projects: GA ČR GA206/08/1281 Institutional support: RVO:68081766 Keywords : major histocompatibility complex (MHC) * snipe Gallinago-media * Class-I genes * minimal-essential-MHC Subject RIV: EG - Zoology Impact factor: 3.534, year: 2013
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International Nuclear Information System (INIS)
Grana, N.H.; Kao, K.J.
1991-01-01
The use of 8-methoxypsoralen (8-MOP) and UV-A irradiation to inactivate contaminating donor leukocytes in platelet concentrates and to prevent primary alloimmunization against donor class I major histocompatibility (MHC) antigens in mice was investigated. CBA/CaH-T6J mice with the H2k haplotype and BALB/cByJ mice with the H2d haplotype were used as donors and recipients, respectively. The mixed leukocyte reaction between these two strains of mice showed that treatment of spleen cells with 500 ng/mL 8-MOP and 5J/cm2 UV-A inhibited 99% of responder and 92% of stimulator function. There was no measurable loss of platelet aggregating activity after the treatment. After two weekly transfusions of platelets without any treatment, 93% of control mice (n = 15) developed anti-H2k antibody. In contrast, only 33% of mice (n = 15) receiving platelets treated with 8-MOP and UV-A became alloimmunized. After six weekly platelet transfusions, all mice became alloimmunized. Nevertheless, the mean titers of anti-H2k antibody in sera of the treated groups were significantly lower than the control groups. One hour posttransfusion recoveries of 51Cr-labeled donor platelets were also higher in mice transfused with the treated platelets. Thus, the pretreatment of platelet concentrates with 8-MOP and UV-A irradiation effectively reduced the alloantigenicity of class I MHC molecules. The implication of this finding in relation to the mechanism by which donor leukocytes allosensitize recipients is discussed
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DEFF Research Database (Denmark)
Knudsen, S; Mikkelsen, J D; Bang, B
2010-01-01
Narcolepsy with cataplexy (NC) is caused by substantial loss of hypocretin neurons. NC patients carry the HLA-DQB1*0602 allele suggesting that hypocretin neuron loss is due to an autoimmune attack. We tested intravenous immunoglobulin (IVIG) treatment in early onset NC.......Narcolepsy with cataplexy (NC) is caused by substantial loss of hypocretin neurons. NC patients carry the HLA-DQB1*0602 allele suggesting that hypocretin neuron loss is due to an autoimmune attack. We tested intravenous immunoglobulin (IVIG) treatment in early onset NC....
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Patterns of MHC-dependent mate selection in humans and non-human primates: a meta-analysis
Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Abbate, J. L.; Huchard, E.; Havlíček, J.; Garamszegi, L. Z.
2017-01-01
Roč. 26, č. 2 (2017), s. 668-688 ISSN 0962-1083 Institutional support: RVO:68081766 Keywords : major histocompatibility complex * sexual selection * inbreeding avoidance * mating preference * good genes * HLA Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology Impact factor: 6.086, year: 2016
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Female rose bitterling prefer MHC-dissimilar males: experimental evidence
Czech Academy of Sciences Publication Activity Database
Reichard, Martin; Spence, R.; Bryjová, Anna; Bryja, Josef; Smith, C.
2012-01-01
Roč. 7, č. 7 (2012), e40780 E-ISSN 1932-6203 R&D Projects: GA ČR GA206/09/1163 Institutional support: RVO:68081766 Keywords : major histocompatibility complex * mate choice * sexual selection * good genes * reproductive success * compatible genes * polymorphism * evolution Subject RIV: EG - Zoology Impact factor: 3.730, year: 2012
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Directory of Open Access Journals (Sweden)
Kelly Broen
Full Text Available Nonmyeloablative allogeneic stem cell transplantation (SCT can induce remission in patients with renal cell carcinoma (RCC, but this graft-versus-tumor (GVT effect is often accompanied by graft-versus-host disease (GVHD. Here, we evaluated minor histocompatibility antigen (MiHA-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI. One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.
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Lehnert, S J; Helou, L; Pitcher, T E; Heath, J W; Heath, D D
2018-01-01
Post-copulatory sexual selection processes, including sperm competition and cryptic female choice (CFC), can operate based on major histocompatibility (MH) genes. We investigated sperm competition between male alternative reproductive tactics [jack (sneaker) and hooknose (guard)] of Chinook salmon (Oncorhynchus tshawytscha). Using a full factorial design, we examined in vitro competitive fertilization success of paired jack and hooknose males at three time points after sperm activation (0, 15 and 60 s) to test for male competition, CFC and time effects on male fertilization success. We also examined egg-mediated CFC at two MH genes by examining both the relationship between competitive fertilization success and MH divergence as well as inheritance patterns of MH alleles in resulting offspring. We found that jacks sired more offspring than hooknose males at 0 s post-activation; however, jack fertilization success declined over time post-activation, suggesting a trade-off between sperm speed and longevity. Enhanced fertilization success of jacks (presumably via higher sperm quality) may serve to increase sneaker tactic competitiveness relative to dominant hooknose males. We also found evidence of egg-mediated CFC (i.e. female × male interaction) influencing competitive fertilization success; however, CFC was not acting on the MH genes as we found no relationship between fertilization success and MH II β 1 or MH I α 1 divergence and we found no deviations from Mendelian inheritance of MH alleles in the offspring. Our study provides insight into evolutionary mechanisms influencing variation in male mating success within alternative reproductive tactics, thus underscoring different strategies that males can adopt to attain success. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.
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Analysis of Hypoxic and Hypercapnic Ventilatory Response in Healthy Volunteers.
Directory of Open Access Journals (Sweden)
Shmuel Goldberg
Full Text Available A previous study has suggested that the Human Leukocyte Antigen (HLA allele DQB1*06:02 affects hypoxic ventilatory response (HVR but not hypercapnic ventilatory response (HCVR in an Asian population. The current study evaluated the relationship in Caucasians and Asians. In addition we assessed whether gender or polymorphisms in genes participating in the control of breathing affect HVR and HCVR.A re-breathing system was used to measure HVR and HCVR in 551 young adults (56.8% Caucasians, 30% Asians. HLA-DQB1*06:02 and tagged polymorphisms and coding variants in genes participating in breathing (PHOX2B, GPR4 and TASK2/KCNK5 were analyzed. The associations between HVR/HCVR and HLA-DQB1*06:02, genetic polymorphisms, and gender were evaluated using ANOVA or frequentist association testing with SNPTEST.HVR and gender are strongly correlated. HCVR and gender are not. Mean HVR in women was 0.276±0.168 (liter/minute/%SpO2 compared to 0.429±0.266 (liter/minute/%SpO2 in men, p<0.001 (55.4% higher HVR in men. Women had lower baseline minute ventilation (8.08±2.36 l/m vs. 10.00±3.43l/m, p<0.001, higher SpO2 (98.0±1.3% vs. 96.6±1.7%, p<0.001, and lower EtCO2 (4.65±0.68% vs. 4.82±1.02%, p = 0.025. One hundred and two (18.5% of the participants had HLA-DQB1*06:02. No association was seen between HLA-DQB1*06:02 and HVR or HCVR. Genetic analysis revealed point wise, uncorrected significant associations between two TASK2/KCNK5 variants (rs2815118 and rs150380866 and HCVR.This is the largest study to date reporting the relationship between gender and HVR/ HCVR and the first study assessing the association between genetic polymorphisms in humans and HVR/HCVR. The data suggest that gender has a large effect on hypoxic breathing response.
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Czech Academy of Sciences Publication Activity Database
Dráber, Peter; Vonková, Ivana; Štěpánek, Ondřej; Hrdinka, Matouš; Kucová, Markéta; Skopcová, Tereza; Otáhal, Pavel; Angelisová, Pavla; Hořejší, Václav; Yeung, M.; Weiss, A.; Brdička, Tomáš
2011-01-01
Roč. 31, č. 22 (2011), s. 4550-4562 ISSN 0270-7306 R&D Projects: GA MŠk 1M0506; GA ČR GEMEM/09/E011 Institutional research plan: CEZ:AV0Z50520514 Keywords : SCIMP * transmembrane adaptor protein * MHC II Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.527, year: 2011
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Pulpal responses to cavity preparation in aged rat molars
Kawagishi, Eriko; Nakakura-Ohshima, Kuniko; Nomura, Shuichi; Ohshima, Hayato; 大島, 勇人
2006-01-01
The dentin-pulp complex is capable of repair after tooth injuries including dental procedures. However, there are few available data concerning aged changes in pulpal reactions to such injuries. The present study aimed to clarify the capability of defense of aged pulp by investigating the responses of odontoblasts and class II major histocompatibility complex (MHC)-positive cells to cavity preparation in aged rat molars (300-360 d) and comparing the results with those in young adult rats (100...
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Kulski, Jerzy K; Shiina, Takashi; Anzai, Tatsuya; Kohara, Sakae; Inoko, Hidetoshi
2002-12-01
The major histocompatibility complex (MHC) genomic region is composed of a group of linked genes involved functionally with the adaptive and innate immune systems. The class I and class II genes are intrinsic features of the MHC and have been found in all the jawed vertebrates studied so far. The MHC genomic regions of the human and the chicken (B locus) have been fully sequenced and mapped, and the mouse MHC sequence is almost finished. Information on the MHC genomic structures (size, complexity, genic and intergenic composition and organization, gene order and number) of other vertebrates is largely limited or nonexistent. Therefore, we are mapping, sequencing and analyzing the MHC genomic regions of different human haplotypes and at least eight nonhuman species. Here, we review our progress with these sequences and compare the human MHC structure with that of the nonhuman primates (chimpanzee and rhesus macaque), other mammals (pigs, mice and rats) and nonmammalian vertebrates such as birds (chicken and quail), bony fish (medaka, pufferfish and zebrafish) and cartilaginous fish (nurse shark). This comparison reveals a complex MHC structure for mammals and a relatively simpler design for nonmammalian animals with a hypothetical prototypic structure for the shark. In the mammalian MHC, there are two to five different class I duplication blocks embedded within a framework of conserved nonclass I and/or nonclass II genes. With a few exceptions, the class I framework genes are absent from the MHC of birds, bony fish and sharks. Comparative genomics of the MHC reveal a highly plastic region with major structural differences between the mammalian and nonmammalian vertebrates. Additional genomic data are needed on animals of the reptilia, crocodilia and marsupial classes to find the origins of the class I framework genes and examples of structures that may be intermediate between the simple and complex MHC organizations of birds and mammals, respectively.
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Non HLA genetic markers association with type-1 diabetes mellitus ...
African Journals Online (AJOL)
The currently available data identified IDDM1 and IDDM2 as 2 susceptibility loci for type 1 diabetes (T1D). The major histocompatibility complex (MHC)/HLA region referred to as IDDM1 contains several 100 genes known to have a great influence on T1D risk. Within IDDM2, a minisatellite variable number of tandem repeats ...
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Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells.
Desbarats, J; Freed, J H; Campbell, P A; Newell, M K
1996-01-01
The CD4 receptor contributes to T-cell activation by coligating major histocompatibility complex class II on antigen presenting cells with the T-cell receptor (TCR)/CD3 complex, and triggering a cascade of signaling events including tyrosine phosphorylation of intracellular proteins. Paradoxically, CD3 cross-linking prior to TCR stimulation results in apoptotic cell death, as does injection of anti-CD4 antibodies in vivo of CD4 ligation by HIV glycoprotein (gp) 120. In this report we investig...
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IMGT/GeneInfo: enhancing V(D)J recombination database accessibility
Baum, Thierry-Pascal; Pasqual, Nicolas; Thuderoz, Florence; Hierle, Vivien; Chaume, Denys; Lefranc, Marie-Paule; Jouvin-Marche, Evelyne; Marche, Patrice-Noël; Demongeot, Jacques
2004-01-01
IMGT/GeneInfo is a user-friendly online information system that provides information on data resulting from the complex mechanisms of immunoglobulin (IG) and T cell receptor (TR) V(D)J recombinations. For the first time, it is possible to visualize all the rearrangement parameters on a single page. IMGT/GeneInfo is part of the international ImMunoGeneTics information system® (IMGT), a high-quality integrated knowledge resource specializing in IG, TR, major histocompatibility complex (MHC), an...
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Lim, Pek Siew; Hardy, Kristine; Peng, Kaiman; Shannon, Frances M.
2015-01-01
T cell activation involves the recognition of a foreign antigen complexed to the major histocompatibility complex on the antigen presenting T cell to the T cell receptor. This leads to activation of signaling pathways, which ultimately leads to induction of key cytokine genes responsible for eradication of foreign antigens. We used the mouse EL4 T cell as a model system to study genes that are induced as a result of T cell activation using phorbol myristate acetate (PMA) and calcium ionomycin...
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Unrelated Hematopoietic Stem Cell Donor Matching Probability and Search Algorithm
Directory of Open Access Journals (Sweden)
J.-M. Tiercy
2012-01-01
Full Text Available In transplantation of hematopoietic stem cells (HSCs from unrelated donors a high HLA compatibility level decreases the risk of acute graft-versus-host disease and mortality. The diversity of the HLA system at the allelic and haplotypic level and the heterogeneity of HLA typing data of the registered donors render the search process a complex task. This paper summarizes our experience with a search algorithm that includes at the start of the search a probability estimate (high/intermediate/low to identify a HLA-A, B, C, DRB1, DQB1-compatible donor (a 10/10 match. Based on 2002–2011 searches about 30% of patients have a high, 30% an intermediate, and 40% a low probability search. Search success rate and duration are presented and discussed in light of the experience of other centers. Overall a 9-10/10 matched HSC donor can now be identified for 60–80% of patients of European descent. For high probability searches donors can be selected on the basis of DPB1-matching with an estimated success rate of >40%. For low probability searches there is no consensus on which HLA incompatibilities are more permissive, although HLA-DQB1 mismatches are generally considered as acceptable. Models for the discrimination of more detrimental mismatches based on specific amino acid residues rather than specific HLA alleles are presented.
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A glow of HLA typing in organ transplantation
2013-01-01
The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts leading to development of anti-human leukocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication Anti-HLA Abs may be present in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming (SSP), sequence-specific oligonucleotide probing (SSOP), Sequence based typing (SBT) and reference strand-based conformation analysis (RSCA) method. Problems with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complications. PMID:23432791
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100 million years of multigene family evolution: origin and evolution of the avian MHC class IIB
Czech Academy of Sciences Publication Activity Database
Goebel, J.; Promerová, Marta; Bonadonna, F.; McCoy, K. D.; Serbielle, C.; Strandh, M.; Yannic, G.; Burri, R.; Fumagalli, L.
2017-01-01
Roč. 18, č. 460 (2017), s. 1-9 ISSN 1471-2164 R&D Projects: GA ČR GAP505/10/1871 Institutional support: RVO:68081766 Keywords : Birds * Birth -death evolution * Concerted evolution * Gene duplication * Gene conversion * Major histocompatibility complex * Recombination Subject RIV: EG - Zoology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 3.729, year: 2016
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100 million years of multigene family evolution: origin and evolution of the avian MHC class IIB
Czech Academy of Sciences Publication Activity Database
Goebel, J.; Promerová, Marta; Bonadonna, F.; McCoy, K. D.; Serbielle, C.; Strandh, M.; Yannic, G.; Burri, R.; Fumagalli, L.
2017-01-01
Roč. 18, č. 460 (2017), s. 1-9 ISSN 1471-2164 R&D Projects: GA ČR GAP505/10/1871 Institutional support: RVO:68081766 Keywords : Birds * Birth-death evolution * Concerted evolution * Gene duplication * Gene conversion * Major histocompatibility complex * Recombination Subject RIV: EG - Zoology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 3.729, year: 2016
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Steele, Natasha Z R; Carr, Jessie S; Bonham, Luke W; Geier, Ethan G; Damotte, Vincent; Miller, Zachary A; Desikan, Rahul S; Boehme, Kevin L; Mukherjee, Shubhabrata; Crane, Paul K; Kauwe, John S K; Kramer, Joel H; Miller, Bruce L; Coppola, Giovanni; Hollenbach, Jill A; Huang, Yadong; Yokoyama, Jennifer S
2017-03-01
Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999-2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer's Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984-2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate
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Directory of Open Access Journals (Sweden)
Natasha Z R Steele
2017-03-01
Full Text Available Alzheimer disease (AD is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations.Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case-control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls from the San Francisco-based University of California, San Francisco (UCSF Memory and Aging Center (collected between 1999-2015 and 11,381 individuals (5,728 AD, 5,653 CN controls from the Alzheimer's Disease Genetics Consortium (ADGC, a National Institute on Aging (NIA-funded national data repository (reflecting samples collected between 1984-2012. We also examined cerebrospinal fluid (CSF biomarker measures for patients seen between 2005-2007 and longitudinal cognitive data from the Alzheimer's Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10-4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08-1.37] in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE ɛ4. Separate
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Directory of Open Access Journals (Sweden)
Manas Ranjan
2017-12-01
Full Text Available Visceral leishmaniasis is one of the most neglected tropical diseases for which no vaccine exists. In spite of extensive efforts, no successful vaccine is available against this dreadful infectious disease. To support the vaccine development, immunoinformatics approach was applied to search for potential MHC-classII restricted epitopes that can activate the immune cells. Initially, a total of 37 epitopes derived from six, stage dependent over expressed antigens were predicted, which were presented by at least 26 diverse MHC class II alleles including: DRB10101, DRB10301, DRB10401, DRB10404, DRB10405, DRB10701, DRB10802, DRB10901, DRB11101, DRB11302, DRB11501, DRB30101, DRB40101, DRB50101, DPA10103-DPB10401, DPA10103-DPB10201, DPA10201-DPB10101, DPA10103-DPB10301_DPB10401, DPA10301-DPB10402, DPA10201-DPB105021, DQA10102-DQB10602, DQA10401-DQB10402, DQA10501-QB10201, DQA10501-DQB10301, DQA10301-DQB10302 and DQA10101-DQB10501. Based on the population coverage analysis and HLA cross presentation ability, six epitopes namely, FDLFLFSNGAVVWWG (P1, YPVYPFLASNAALLN (P2, VYPFLASNAALLNLI (P3, LALLIMLYALIATQF (P4, LIMLYALIATQFSDD (P5, IMLYALIATQFSDDA (P6 were selected for further analysis. Stimulation with synthetic peptide alone or as a cocktail triggered the intracellular IFN-γ production. Moreover, specific IgG class of antibodies was detected in the serum of active VL cases against P1, P4, P and P6 in order to evaluate peptide effect on humoral immune response. Additionally, most of the peptides, except P2, were found to be non-inducer of CD4+ IL-10 against both active VL as well as treated VL subjects. Peptide immunogenicity was validated in BALB/c mice immunized with cocktail of synthetic peptide emulsified in complete Freund’s adjuvant/incomplete Freund’s adjuvant. The immunized splenocytes induced strong spleen cell proliferation upon parasite re-stimulation. Furthermore, an increased IFN-γ, IL-12, IL-17 and IL-22 production augmented with
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Directory of Open Access Journals (Sweden)
Silvia Pineda
2017-12-01
Full Text Available Transplant rejection is the critical clinical end-point limiting indefinite survival after histocompatibility antigen (HLA mismatched organ transplantation. The predominant cause of late graft loss is antibody-mediated rejection (AMR, a process whereby injury to the organ is caused by donor-specific antibodies, which bind to HLA and non-HLA (nHLA antigens. AMR is incompletely diagnosed as donor/recipient (D/R matching is only limited to the HLA locus and critical nHLA immunogenic antigens remain to be identified. We have developed an integrative computational approach leveraging D/R exome sequencing and gene expression to predict clinical post-transplant outcome. We performed a rigorous statistical analysis of 28 highly annotated D/R kidney transplant pairs with biopsy-confirmed clinical outcomes of rejection [either AMR or T-cell-mediated rejection (CMR] and no-rejection (NoRej, identifying a significantly higher number of mismatched nHLA variants in AMR (ANOVA—p-value = 0.02. Using Fisher’s exact test, we identified 123 variants associated mainly with risk of AMR (p-value < 0.001. In addition, we applied a machine-learning technique to circumvent the issue of statistical power and we found a subset of 65 variants using random forest, that are predictive of post-tx AMR showing a very low error rate. These variants are functionally relevant to the rejection process in the kidney and AMR as they relate to genes and/or expression quantitative trait loci (eQTLs that are enriched in genes expressed in kidney and vascular endothelium and underlie the immunobiology of graft rejection. In addition to current D/R HLA mismatch evaluation, additional mismatch nHLA D/R variants will enhance the stratification of post-tx AMR risk even before engraftment of the organ. This innovative study design is applicable in all solid organ transplants, where the impact of mitigating AMR on graft survival may be greater, with considerable benefits on
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One-pot, mix-and-read peptide-MHC tetramers
DEFF Research Database (Denmark)
Leisner, Christian Valdemar Vinge; Loeth, Nina; Lamberth, Kasper
2008-01-01
BACKGROUND: Cytotoxic T Lymphocytes (CTL) recognize complexes of peptide ligands and Major Histocompatibility Complex (MHC) class I molecules presented at the surface of Antigen Presenting Cells (APC). Detection and isolation of CTL's are of importance for research on CTL immunity, and development...... molecules can be refolded in vitro, tetramerized with streptavidin, and used for specific T cell staining-all in a one-pot reaction without any intervening purification steps. CONCLUSIONS/SIGNIFICANCE: We have developed an efficient "one-pot, mix-and-read" strategy for peptide-MHC tetramer generation...
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DEFF Research Database (Denmark)
Morling, Niels; Andersen, V; Fugger, L
1992-01-01
. The frequencies of DNA fragments associated with the following HLA class II genes were increased in RA when compared to normal controls: DRB1*04 (DR4) (relative risk, RR = 7.4, P less than 10(-3), DRB4*0101 (DRw53) (RR = 9.6, P less than 10(-3), DQA1*0301 (RR = 9.6, P less than 10(-3), DQB1*0301 (DQw7) (RR = 2.......8, P less than 0.05, 'corrected' P greater than 0.05), and DQB1*0302 (DQw8) (RR = 4.5, P less than 10(-2). Negative associations were found between RA and DRB1*1501 (DR2/DRw15) (RR = 0.2, P less than 10(-2) and DQB1*0602 (DQw6) (RR = 0.2, P less than 10(-2), 'corrected' P greater than 0.......05). The frequencies in RA of other HLA class II associated DNA fragments including DPA and DPB and the antigens DPw1-w6 defined by primed lymphocyte stimulation, did not differ significantly from those in controls. In primary SS, the frequency of HLA-B8 was significantly increased (RR = 9.0, P less than 10...
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The evolution of immunity in relation to colonization and migration.
O'Connor, Emily A; Cornwallis, Charlie K; Hasselquist, Dennis; Nilsson, Jan-Åke; Westerdahl, Helena
2018-05-01
Colonization and migration have a crucial effect on patterns of biodiversity, with disease predicted to play an important role in these processes. However, evidence of the effect of pathogens on broad patterns of colonization and migration is limited. Here, using phylogenetic analyses of 1,311 species of Afro-Palaearctic songbirds, we show that colonization events from regions of high (sub-Saharan Africa) to low (the Palaearctic) pathogen diversity were up to 20 times more frequent than the reverse, and that migration has evolved 3 times more frequently from African- as opposed to Palaearctic-resident species. We also found that resident species that colonized the Palaearctic from Africa, as well as African species that evolved long-distance migration to breed in the Palaearctic, have reduced diversity of key immune genes associated with pathogen recognition (major histocompatibility complex class I). These results suggest that changes in the pathogen community that occur during colonization and migration shape the evolution of the immune system, potentially by adjusting the trade-off between the benefits of extensive pathogen recognition and the costs of immunopathology that result from high major histocompatibility complex class I diversity.
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Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE
DEFF Research Database (Denmark)
Liu, Yawei; Teige, Ingrid; Birnir, Bryndis
2006-01-01
Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflamma......Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS......) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in amplification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between...... neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4...
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International Nuclear Information System (INIS)
Vallera, D.A.; Soderling, C.C.; Carlson, G.J.; Kersey, J.H.
1982-01-01
Studies were undertaken to examine the role of T lymphocytes in engraftment of bone marrow (BM) in animals conditioned with total lymphoid irradiation (TLI) prior to transplantation across major histocompatibility barriers. Donor BM (added as a source of lymphohematopoietic stem cells) and spleen cells (added as a source of graft-versus-host disease (GVHD)-causing cells) were pretreated in vitro with monoclonal anti-Thy-1.2 plus complement (C). T cell-depleted grafts were then give to allogeneic mice conditioned with 900 rad of single dose TLI plus cyclophosphamide (CY). These mice did not engraft. Even in the absence of added spleen cells, elimination of the small T cell population from donor BM grafts prevented engraftment compared with animals that received the same conditioning regimen and untreated donor cells. These control animals demonstrated uniform evidence of engraftment about 1 month after transplantation. Similar findings were reported when recipients were conditioned with fractionated 17 x 200-rad TLI. In TLI plus CY-conditional recipients, we have also observed that increasing the donation of treated bone marrow cells still did not result in significant engraftment. Furthermore, graft failure in mice receiving normal dosages of anti-Thy-1.2 plus C-treated donor cells was not a strain-restricted phenomenon. Moreover, removal of bone marrow T cells with monoclonal anti-Lyt-1 plus complement also resulted in graft failure in TLI-conditioned recipients. In contrast to TLI conditioning, when Thy-1.2 plus C-treated donor cells were given to recipients conditioned with total body irradiation (TBI), a high percentage of engraftment was demonstrated by an H-2 microcytotoxicity assay. Plausible mechanisms for there findings are discussed
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Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.
Khong, Jwu Jin; Burdon, Kathryn P; Lu, Yi; Laurie, Kate; Leonardos, Lefta; Baird, Paul N; Sahebjada, Srujana; Walsh, John P; Gajdatsy, Adam; Ebeling, Peter R; Hamblin, Peter Shane; Wong, Rosemary; Forehan, Simon P; Fourlanos, Spiros; Roberts, Anthony P; Doogue, Matthew; Selva, Dinesh; Montgomery, Grant W; Macgregor, Stuart; Craig, Jamie E
2016-11-18
Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10 -8 ). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10 -4 . Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.
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The great diversity of major histocompatibility complex class II genes in Philippine native cattle
Takeshima, S.N.; Miyasaka, T.; Polat, M.; Kikuya, M.; Matsumoto, Y.; Mingala, C.N.; Villanueva, M.A.; Salces, A.J.; Onuma, M.; Aida, Y.
2014-01-01
Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle. PMID:25606401
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Dinah Singer, Ph.D., came to NCI in 1975 as a Postdoctoral Fellow in the Laboratory of Biochemistry, but soon created a career for herself in the Experimental Immunology Branch. Her interest in how genes are regulated to control biological function led her to focus on major histocompatibility complex class I genes (MHC Class I)—molecules critical to immune system function—as a
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Czech Academy of Sciences Publication Activity Database
Promerová, Marta; Vinkler, Michal; Bryja, Josef; Poláková, Radka; Schnitzer, J.; Munclinger, P.; Albrecht, Tomáš
2011-01-01
Roč. 42, č. 1 (2011), s. 5-10 ISSN 0908-8857 R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/06/0851; GA MŠk LC06073 Institutional research plan: CEZ:AV0Z60930519 Keywords : scarlet rosefinch * Major Histocompatibility Complex (MHC) * mate choice decisions * good genes * sexual selection Subject RIV: EG - Zoology Impact factor: 2.280, year: 2011
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Evidence for balancing selection at the DAB locus in the axolotl, Ambystoma mexicanum.
Richman, A D; Herrera, G; Reynoso, V H; Méndez, G; Zambrano, L
2007-12-01
The axolotl (Ambystoma mexicanum) has been characterized as immunodeficient, and the absence of major histocompatibility complex (MHC) class II polymorphism has been cited as a possible explanation. Here we present evidence for considerable allelic polymorphism at the MHC class II DAB locus for a sample of wild-caught axolotls. Evidence that these sequences are the product of balancing selection for disease resistance is discussed.
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Human leukocyte antigen-G polymorphism in relation to expression, function, and disease
DEFF Research Database (Denmark)
Larsen, Margit Hørup; Hviid, Thomas
2009-01-01
Human leukocyte antigen-G (HLA-G) is a nonclassical class Ib molecule belonging to the major histocompatibility complex. HLA-G appears to play a role in the suppression of immune responses and contribute to long-term immune escape or tolerance. The focus of this review is polymorphism in the HLA......-G gene and protein and its possible importance in expression, function, and disease associations....
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Czech Academy of Sciences Publication Activity Database
Migalska, M.; Sebastian, A.; Konczal, M.; Kotlík, Petr; Radwan, J.
2017-01-01
Roč. 118, č. 4 (2017), s. 348-357 ISSN 0018-067X R&D Projects: GA ČR GAP506/11/1872; GA ČR(CZ) GA16-03248S Institutional support: RVO:67985904 Keywords : bank vole * major histocompatibility complex * RNA-seq data Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Genetics and heredity (medical genetics to be 3) Impact factor: 3.961, year: 2016
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Czech Academy of Sciences Publication Activity Database
Loucká, Jiřina; Schlecht, G.; Vojtová, Jana; Leclerc, C.; Šebo, Peter
2002-01-01
Roč. 70, č. 2 (2002), s. 1002-1005 ISSN 0019-9567 R&D Projects: GA ČR GA310/01/0934; GA AV ČR IAA5020907; GA MŠk ME 167 Grant - others:QLK2-CT(US) 00556 Institutional research plan: CEZ:AV0Z5020903 Keywords : delivery * epitope * complex Subject RIV: EE - Microbiology, Virology Impact factor: 4.039, year: 2002
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Genetic factors and multiple sclerosis in the Moroccan population: a role for HLA class II.
Ouadghiri, S; El Alaoui Toussi, K; Brick, C; Ait Benhaddou, E H; Benseffaj, N; Benomar, A; El Yahyaoui, M; Essakalli, M
2013-12-01
Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system that mainly affects young adults. The association between susceptibility to MS and HLA class II genes, in particular the DRB1*15 allele, has been reported in diverse ethnic groups. The aim of our study was to investigate the distribution of HLA-DRB1* and -DQB1* alleles in Moroccan population and their implication in the susceptibility to the disease. Fifty-seven MS patients were compared to 172 healthy controls unrelated to one another and matched by age, sex and ethnic origin. HLA class II (DRB1* and DQB1*) typing was performed by PCR-SSP and/or Luminex (PCR-SSO). Allelic and haplotypic frequencies, P-values, odds ratio (OR) and 95% confidence interval (CI) were calculated using the software SPSS. A significant increase of DRB1*15 allele frequency (17.6% vs 8.4%, OR=2.67, 95% CI=1.36-5.23, P=0.004) and HLA-DRB1*15-DQB1*06 haplotype (8.8% vs 4.08%, OR=2.78, 95% CI=1.41-5.48, P=0.002) were observed in Moroccan MS patients. No association of the DR15 allele with sex or age at onset was appreciated. Concerning HLA-DQB1* alleles, no significant difference between patients and controls was found. Our results reveal a role for HLA-DRB1*15 allele molecules in the predisposition of Moroccan patients to MS. Although this study should be confirmed on a larger sample size, it analyzes for the first time the possible role of a genetic marker for susceptibility to MS in Moroccan population. Copyright © 2013 Elsevier Masson SAS. All rights reserved.
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Directory of Open Access Journals (Sweden)
Yasuaki Sadanaga
1998-01-01
Full Text Available We evaluated the incidence of the association of HLA class II phenotype and specific IgE responsiveness against house dust mite (HDM and/or Japanese cedar pollen (Jc in 176 patients with allergic rhinitis, with or without bronchial asthma, and 107 nonallergic subjects. Specific IgE antibody titration against the purified allergens Der f1 and Der f2 from HDM, and against Cry J1 and Cry J2 from Jc, was performed by using enzyme-linked immunosorbent assay (ELISA and radioimmunoassay (RIA in sera from all subjects. HLA class II oligotyping was performed by the polymerase chain reaction sequence specific oligonucleotide (PCR-SSO method on the DRB1*, DQA1*, DQB1* and DPB1* alleles using peripheral blood cells. The high IgE responders ≥ class 4 to the purified allergens were identified by using the IgE antibody reference concentration obtained by ELISA, RIA and routine IgE CAP RAST. Compared to the controls, the patients with both rhinitis and asthma showed significantly higher frequencies of DRB1* 0901, DQB1* 0303, and DPB1* 0401 alleles. High IgE responsiveness to HDM was associated with DRB1* 1101, 0901, DQB1* 0303, and DPB1*0401 alleles. The patients with anti-Der f1 IgE antibody concentration exceeding 72.2 ng/mL showed significantly elevated frequencies for DQB1*0401 and DPB1*0401 alleles, and those with anti Der f2 IgE antibody concentration exceeding 46.2 ng/mL showed significantly elevated frequencies for DPB1*0401 and 0901 alleles. High IgE responsiveness to Jc with Cry j1 and Cryj2was associated with the DRB1* 1201 alleles.
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Directory of Open Access Journals (Sweden)
Abdelhafidh Hajjej
Full Text Available In view of its distinct geographical location and relatively small area, Tunisia witnessed the presence of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Tunisian population. We investigated HLA class I and class II gene profiles in Tunisians, and compared this profile with those of Mediterranean and Sub-Sahara African populations. A total of 376 unrelated Tunisian individuals of both genders were genotyped for HLA class I (A, B and class II (DRB1, DQB1, using reverse dot-blot hybridization (PCR-SSO method. Statistical analysis was performed using Arlequin software. Phylogenetic trees were constructed by DISPAN software, and correspondence analysis was carried out by VISTA software. One hundred fifty-three HLA alleles were identified in the studied sample, which comprised 41, 50, 40 and 22 alleles at HLA-A,-B,-DRB1 and -DQB1 loci, respectively. The most frequent alleles were HLA-A*02:01 (16.76%, HLA-B*44:02/03 (17.82%, HLA-DRB1*07:01 (19.02%, and HLA-DQB1*03:01 (17.95%. Four-locus haplotype analysis identified HLA-A*02:01-B*50:01-DRB1*07:01-DQB1*02:02 (2.2% as the common haplotype in Tunisians. Compared to other nearby populations, Tunisians appear to be genetically related to Western Mediterranean population, in particular North Africans and Berbers. In conclusion, HLA genotype results indicate that Tunisians are related to present-day North Africans, Berbers and to Iberians, but not to Eastern Arabs (Palestinians, Jordanians and Lebanese. This suggests that the genetic contribution of Arab invasion of 7th-11th century A.D. had little impact of the North African gene pool.
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Toyo-Oka, L; Mahasirimongkol, S; Yanai, H; Mushiroda, T; Wattanapokayakit, S; Wichukchinda, N; Yamada, N; Smittipat, N; Juthayothin, T; Palittapongarnpim, P; Nedsuwan, S; Kantipong, P; Takahashi, A; Kubo, M; Sawanpanyalert, P; Tokunaga, K
2017-09-01
Tuberculosis (TB) occurs as a result of complex interactions between the host immune system and pathogen virulence factors. Human leukocyte antigen (HLA) class II molecules play an important role in the host immune system. However, no study has assessed the association between HLA class II genes and susceptibility to TB caused by specific strains. This study investigated the possible association of HLA class II genes with TB caused by modern and ancient Mycobacterium tuberculosis (MTB). The study included 682 patients with TB and 836 control subjects who were typed for HLA-DRB1 and HLA-DQB1 alleles. MTB strains were classified using a large sequence polymorphism typing method. Association analysis was performed using common HLA alleles and haplotypes in different MTB strains. HLA association analysis of patients infected with modern MTB strains showed significant association for HLA-DRB1*09:01 (odds ratio [OR] = 1.82; P-value = 9.88 × 10 -4 ) and HLA-DQB1*03:03 alleles (OR = 1.76; P-value = 1.31 × 10 -3 ) with susceptibility to TB. Haplotype analysis confirmed that these alleles were in strong linkage disequilibrium and did not exert an interactive effect. Thus, the results of this study showed an association between HLA class II genes and susceptibility to TB caused by modern MTB strains, suggesting the importance of strain-specific analysis to determine susceptibility genes associated with TB. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Nardo, Luca; Tosi, Giovanna; Bondani, Maria; Accolla, Roberto; Andreoni, Alessandra
2012-06-01
By tens-of-picosecond resolved fluorescence detection we study Förster resonance energy transfer between a donor and a black-hole-quencher bound at the 5'- and 3'-positions of an oligonucleotide probe matching the highly polymorphic region between codons 51 and 58 of the human leukocyte antigen DQB1 0201 allele, conferring susceptibility to type-1 diabetes. The probe is annealed with non-amplified genomic DNAs carrying either the 0201 sequence or other DQB1 allelic variants. We detect the longest-lived donor fluorescence in the case of hybridization with the 0201 allele and definitely faster and distinct decays for the other allelic variants, some of which are single-nucleotide polymorphic.
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Post-Traumatic Narcolepsy Associated with Thalamic/Hypothalamic Injury
Directory of Open Access Journals (Sweden)
Kikyoung Yi
2015-12-01
Full Text Available The hypothalamus is an important structure that regulates sleep via hypocretin neurotransmission. Central nervous system disorders such as tumors and vascular legions involving the hypothalamus can cause secondary narcolepsy. In addition, brain trauma can contribute to post-traumatic narcolepsy despite lack of any definite brain lesion. Here, we present a case of a 37-year-old man suffering from a hypothalamus-to-thalamus hemorrhage after a traffic accident. After this trauma, he suffered from excessive daytime sleepiness and was diagnosed with post-traumatic narcolepsy by polysomnography and multiple sleep latency tests. He was positive for human leukocyte antigen (HLA-DQB1*03:01 and HLA-DQB1*06:01 antigens.
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Directory of Open Access Journals (Sweden)
Kaossarath A. Fagbemi
2017-01-01
Full Text Available Background. Several studies have reported the implication of HLA-DR/DQ loci in the susceptibility to type 1 diabetes (T1D. Since no such study has yet been performed in Benin, this pilot one aimed at assessing HLA class II allele, haplotype, and genotype associations with T1D. Material and Methods. Class II HLA genotyping was performed in 51 patients with T1D and 51 healthy unrelated controls by means of the PCR-SSP method. The diagnosis of T1D was set up according to American Diabetes Association criteria. Odds ratio (OR and its 95% confidence interval (95% CI were calculated to assess the associations between T1D and HLA alleles, haplotypes, and genotypes. Results. Participants were aged 1–24 years. T1D was significantly associated with DR3, DQA1∗05:01, DQB1∗02:01, and DR3-DR4. No significant associations were observed with DR4, DQB1∗03:02, and DQB1∗06:02. Conclusion. Certain HLA class II alleles, haplotypes, and genotypes were related to T1D and may be used as genetic susceptibility markers to T1D in Benin.
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Class II HLA interactions modulate genetic risk for multiple sclerosis
Dilthey, Alexander T; Xifara, Dionysia K; Ban, Maria; Shah, Tejas S; Patsopoulos, Nikolaos A; Alfredsson, Lars; Anderson, Carl A; Attfield, Katherine E; Baranzini, Sergio E; Barrett, Jeffrey; Binder, Thomas M C; Booth, David; Buck, Dorothea; Celius, Elisabeth G; Cotsapas, Chris; D’Alfonso, Sandra; Dendrou, Calliope A; Donnelly, Peter; Dubois, Bénédicte; Fontaine, Bertrand; Fugger, Lars; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Hemmer, Bernhard; Hillert, Jan; Kockum, Ingrid; Leslie, Stephen; Lill, Christina M; Martinelli-Boneschi, Filippo; Oksenberg, Jorge R; Olsson, Tomas; Oturai, Annette; Saarela, Janna; Søndergaard, Helle Bach; Spurkland, Anne; Taylor, Bruce; Winkelmann, Juliane; Zipp, Frauke; Haines, Jonathan L; Pericak-Vance, Margaret A; Spencer, Chris C A; Stewart, Graeme; Hafler, David A; Ivinson, Adrian J; Harbo, Hanne F; Hauser, Stephen L; De Jager, Philip L; Compston, Alastair; McCauley, Jacob L; Sawcer, Stephen; McVean, Gil
2016-01-01
Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles. PMID:26343388
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Mothé, Bianca R.; Southwood, Scott; Sidney, John; English, A. Michelle; Wriston, Amanda; Hoof, Ilka; Shabanowitz, Jeffrey; Hunt, Donald F.; Sette, Alessandro
2013-01-01
Chinese rhesus macaques are of particular interest in SIV/HIV research as these animals have prolonged kinetics of disease progression to AIDS, compared to their Indian counterparts, suggesting that they may be a better model for HIV. Nevertheless, the specific mechanism(s) accounting for these kinetics remains unclear. The study of Major Histocompatibility Complex (MHC) molecules, including their MHC:peptide binding motifs, provides valuable information for measuring cellular immune response...
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HLA associations reveal genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype.
LENUS (Irish Health Repository)
Winchester, Robert
2012-04-01
Rigorously ascertained cases of psoriatic arthritis in subjects presenting to a rheumatology unit were compared with cases of psoriasis in subjects presenting to a dermatology unit, where subjects with musculoskeletal features were excluded, to address 1) the extent to which the contribution of the major histocompatibility complex (MHC) to psoriatic arthritis susceptibility resembles that in psoriasis, and 2) whether MHC genes determine quantitative traits within the psoriatic arthritis phenotype.
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DEFF Research Database (Denmark)
Hviid, Thomas Vauvert F
2005-01-01
The non-classical human leukocyte antigen (HLA) class Ib genes, HLA-E, -G and -F, are located on chromosome 6 in the human major histocompatibility complex (MHC). HLA class Ib antigens resemble the HLA class Ia antigens in many ways, but several major differences have been described. This review ...... transplantation and in inflammatory or autoimmune disease, and of HLA-G in an evolutionary context, are also briefly examined....
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Impact of HLA Diversity on Donor Selection in Organ and Stem Cell Transplantation
Tiercy Jean-Marie; Claas Frans
2013-01-01
The human major histocompatibility complex is a multigene system encoding polymorphic human leucocyte antigens (HLA) that present peptides derived from pathogens to the immune system. The high diversity of HLA alleles and haplotypes in the worldwide populations represents a major barrier to organ and allogeneic hematopoietic stem cell transplantation because HLA incompatibilities are efficiently recognized by T and B lymphocytes. In organ transplantation pre transplant anti HLA antibodies nee...
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The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation
Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I.W.; Walker, Bruce D.; Jia, Xiaoming; McLaren, Paul J.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Telenti, Amalio; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.
2010-01-01
Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. W...
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Directory of Open Access Journals (Sweden)
Amit Kumar
Full Text Available Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.
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Pig but not Human Interferon-γ Initiates Human Cell-Mediated Rejection of Pig Tissue in vivo
Sultan, Parvez; Murray, Allan G.; McNiff, Jennifer M.; Lorber, Marc I.; Askenase, Philip W.; Bothwell, Alfred L. M.; Pober, Jordan S.
1997-08-01
Split-thickness pig skin was transplanted on severe combined immunodeficient mice so that pig dermal microvessels spontaneously inosculated with mouse microvessels and functioned to perfuse the grafts. Pig endothelial cells in the healed grafts constitutively expressed class I and class II major histocompatibility complex molecules. Major histocompatibility complex molecule expression could be further increased by intradermal injection of pig interferon-γ (IFN-γ ) but not human IFN-γ or tumor necrosis factor. Grafts injected with pig IFN-γ also developed a sparse infiltrate of mouse neutrophils and eosinophils without evidence of injury. Introduction of human peripheral blood mononuclear cells into the animals by intraperitoneal inoculation resulted in sparse perivascular mononuclear cell infiltrates in the grafts confined to the pig dermis. Injection of pig skin grafts on mice that received human peripheral blood mononuclear cells with pig IFN-γ (but not human IFN-γ or heat-inactivated pig IFN-γ ) induced human CD4+ and CD8+ T cells and macrophages to more extensively infiltrate the pig skin grafts and injure pig dermal microvessels. These findings suggest that human T cell-mediated rejection of xenotransplanted pig organs may be prevented if cellular sources of pig interferon (e.g., passenger lymphocytes) are eliminated from the graft.
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Betz, Regina C; Petukhova, Lynn; Ripke, Stephan; Huang, Hailiang; Menelaou, Androniki; Redler, Silke; Becker, Tim; Heilmann, Stefanie; Yamany, Tarek; Duvic, Madeliene; Hordinsky, Maria; Norris, David; Price, Vera H; Mackay-Wiggan, Julian; de Jong, Annemieke; DeStefano, Gina M; Moebus, Susanne; Böhm, Markus; Blume-Peytavi, Ulrike; Wolff, Hans; Lutz, Gerhard; Kruse, Roland; Bian, Li; Amos, Christopher I; Lee, Annette; Gregersen, Peter K; Blaumeiser, Bettina; Altshuler, David; Clynes, Raphael; de Bakker, Paul I W; Nöthen, Markus M; Daly, Mark J; Christiano, Angela M
2015-01-22
Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.
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Grimholt, Unni
2016-01-01
Major histocompatibility complex (MHC) molecules are key players in initiating immune responses towards invading pathogens. Both MHC class I and class II genes are present in teleosts, and, using phylogenetic clustering, sequences from both classes have been classified into various lineages. The polymorphic and classical MHC class I and class II gene sequences belong to the U and A lineages, respectively. The remaining class I and class II lineages contain nonclassical gene sequences that, de...
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Sallaberry?Pincheira, Nicole; Gonz?lez?Acu?a, Daniel; Padilla, Pamela; Dantas, Gisele P. M.; Luna?Jorquera, Guillermo; Frere, Esteban; Vald?s?Vel?squez, Armando; Vianna, Juliana A.
2016-01-01
Abstract The evolutionary and adaptive potential of populations or species facing an emerging infectious disease depends on their genetic diversity in genes, such as the major histocompatibility complex (MHC). In birds, MHC class I deals predominantly with intracellular infections (e.g., viruses) and MHC class II with extracellular infections (e.g., bacteria). Therefore, patterns of MHC I and II diversity may differ between species and across populations of species depending on the relative e...
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Ghosh, Arnab; Koestner, Wolfgang; Hapke, Martin; Schlaphoff, Verena; Länger, Florian; Baumann, Rolf; Koenecke, Christian; Cornberg, Markus; Welte, Karl; Blazar, Bruce R.; Sauer, Martin G.
2009-01-01
Antigen-presenting cells (APCs) of host origin drive graft-versus-leukemia (GVL) effects but can also trigger life-threatening graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) across major histocompatibility complex (MHC) barriers. We show that in vitro priming of donor lymphocytes can circumvent the need of recipient-derived APCs in vivo for mediating robust GVL effects and significantly diminishes the risk of severe GVHD. In vitro, generated and expanded T cel...
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Sibling rivalry: competition between MHC class II family members inhibits immunity.
Denzin, Lisa K; Cresswell, Peter
2013-01-01
Peptide loading of major histocompatibility complex (MHC) class II molecules in the endosomes and lysosomes of antigen-presenting cells is catalyzed by human leukocyte antigen-DM (HLA-DM) and modulated by HLA-DO. In a structural study in this issue, Guce et al. show that HLA-DO is an MHC class II mimic and functions as a competitive and essentially irreversible inhibitor of HLA-DM activity, thereby inhibiting MHC class II antigen presentation.
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Hedgehog Signalling in the Embryonic Mouse Thymus
Directory of Open Access Journals (Sweden)
Alessandro Barbarulo
2016-07-01
Full Text Available T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC development, and thymocyte–TEC cross-talk in the embryonic mouse thymus during the last week of gestation.
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International Nuclear Information System (INIS)
DeMars, R.; Chang, C.C.; Rudersdorf, R.A.
1983-01-01
Twenty-six human lymphoblastoid cell mutants that had lost expressions of HLA-DR were created with a two-step procedure: (i) A mutant from which one entire haplotype had been physically deleted by gamma-rays was isolated by means of immunoselection against cells expressing a specific HLA-B antigen. (ii) This heterozygous deletion mutant was irradiated with gamma-rays or treated with ICR 191, a frameshift mutagen, and mutants that no longer expressed the remaining DR1 antigen were selected with a monoclonal antibody directed against a monomorphic DR determinant. Monoclonal antibody GENOX 3.53 was used to show that four of the gamma-ray induced DR-null mutants did not express the cis-linked MB1/MT1 locus. Since MB1/MT1 was still expressed in the other 16 gamm-ray induced and 6 ICR 191-induced DR-null mutants, the separate loss of expression of MB1/MT1 and DR1 is strong evidence that the DR1 and MB1/MT1 alloantigens are under separate genetic control in the cells we used. Since DR-null mutants bound SB2-specific monoclonal antibody ILR1, whether or not they expressed MB1/MT1, the results mean that gamma-rays resolved the genetic determinants for DR1, MB1/MT1, and SB2. Additional complexity of determinants encoded by D-region genes is indicated by the following results. The amount of MB1/MT1 antigen that was detected with ELISA tests for binding of GENOX 3.53 antibody to cells varied inversely with the number of expressed copies of DR or of a locus near DR. This could result from an increased amount of MB1/MT1 antigen or from increased binding accessibility of GENOZ 3.53-reactive antigen in DR-null mutants. Monoclonal antibodies CC 11.23 and CC 6.4 displayed patterns of binding to parental and diverse mutant cells that differed from that of GENOX 3.53, suggesting the existence of at least one additional D-region antigen that is neither SB, DR, nor MB/MT
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Histocompatibility antigen test
... Updated by: Frank A. Greco, MD, PhD, Director, Biophysical Laboratory, Edith Nourse Rogers Memorial Hospital, Bedford, MA. ... any medical emergency or for the diagnosis or treatment of any medical condition. A licensed physician should ...
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Czech Academy of Sciences Publication Activity Database
Winternitz, Jamie Caroline; Abbate, J. L.
2015-01-01
Roč. 6, 13 May (2015), s. 73-88 ISSN 1179-7274 R&D Projects: GA MŠk(CZ) EE2.3.30.0048 Institutional support: RVO:67985939 Keywords : secual selection * olfaction * facial attraction * inbreeding avoidance * parasite resistance Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Genetics and heredity (medical genetics to be 3)
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International Nuclear Information System (INIS)
Hunt, J.M.; Desai, P.A.; Chakraborty, S.
1986-01-01
Altered expression of Class I MHC alloantigens has been reported for murine tumors, and may be associated with the tumorigenic phenotype of tumor cells. To characterize MHC Class I alloantigen expression on a chemically-induced transplantable rat hepatoma cell line, 17X, derived from a (WF x F344) F 1 rat, polyvalent anti-F344 and anti-WF rat alloantisera were first used to immunoprecipitate the rat RT1.A Class I MHC alloantigens expressed on primary (WF x F344) F 1 hepatocyptes in short-term monolayer cultures. Two-dimensional isoelectric focusing and SDS-PAGE of immunoprecipitates from 35 S-methionine-labeled (WF x F344) F 1 hepatocytes clearly resolved the RT1.A/sup u/ (WF) and RT1.A/sup LvI/ (F344) parental alloantigens. Identical radiolabeling and immunoprecipitation failed to detect either parental alloantigen on the 17X hepatoma cells. However, indirect immunofluorescence and immunoblot analyses demonstrated the presence of parental alloantigens on the 17X cells. Immunization of F344 rats but not of WF rats with 17X cells resulted in antibodies cytotoxic for normal (WF X F344) F 1 spleen cells in the presence of complement. These findings indicate that a combination of detection techniques will be necessary to characterize altered alloantigen expression on rat hepatoma cells
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Functional recombinant MHC class II molecules and high-throughput peptide-binding assays
DEFF Research Database (Denmark)
Justesen, Sune; Harndahl, Mikkel; Lamberth, Kasper
2009-01-01
BACKGROUND: Molecules of the class II major histocompability complex (MHC-II) specifically bind and present exogenously derived peptide epitopes to CD4+ T helper cells. The extreme polymorphism of the MHC-II hampers the complete analysis of peptide binding. It is also a significant hurdle......-II molecules and accompanying HTS peptide-binding assay were successfully developed for nine different MHC-II molecules including the DPA1*0103/DPB1*0401 (DP401) and DQA1*0501/DQB1*0201, where both alpha and beta chains are polymorphic, illustrating the advantages of producing the two chains separately....... CONCLUSION: We have successfully developed versatile MHC-II resources, which may assist in the generation of MHC class II -wide reagents, data, and tools....
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Effects of the genome on immune regulation in type 1 diabetes
DEFF Research Database (Denmark)
Pociot, Flemming; Kaur, Simranjeet; Nielsen, Lotte B
2016-01-01
Type 1 diabetes (T1DM) is a complex disease, arising through the interaction of an incompletely defined combination of genetic susceptibility and environmental factors. It is well accepted that T1DM results from selective immune-mediated destruction of the insulin-producing β cells in the islets...... CCL2 and CCL4 in recent onset T1DM patients. Finally, we report that genetic variants predict autoantibody positivity in T1DM cases....... into a limited number of DRB1 and DQB1 amino acid residues that account for most of the HLA-risk. Second, we use the Immunochip data to look for functional significance by correlation to circulating levels of chemokines and demonstrate that genetic variation at chromosome 2, 3, and 6 correlates with circulating...
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Directory of Open Access Journals (Sweden)
Junfeng Zhang
2013-01-01
Full Text Available In traditional Chinese medicine (TCM, correct syndrome differentiation is the most important principle guiding the prescription of Chinese herbal formulae for the treatment of gastric cancer (GC. We aimed to reveal the genetic mechanisms underlying GC syndrome differentiation (ZHENG in a population of 387 GC patients. Twenty-nine single nucleotide polymorphisms (SNPs in EGF, TGFA, and EGFR were investigated. Two SNPs, rs11466285 in TGFA and rs884225 in EGFR, were significantly associated with the distribution of ZHENG (P<0.05. The rs11466285 TT genotype increased the risk of damp heat with toxin (DHT and deficiency of both Qi and yin (DQY compared with obstruction of blood stasis (OBS. The rs884225 AA genotype could increase the risk of DQY and deficiency of both Qi and blood (DQB compared with yin deficiency due to stomach heat (YDSH. Parallel comparison among the SNPs and syndrome types revealed that DQB was distinct from YDSH, disharmony between the liver and stomach, stagnation of phlegm muddiness (SPM, OBS, and other syndromes at several SNP loci (P<0.05. The rs11466285 TT and rs884225 AA genotypes exhibit increased risk of DQB compared with OBS and SPM (P<0.05, respectively. In conclusion, the formation of GC ZHENG was related to EGF, TGFA, and EGFR gene polymorphisms.
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Epidemiology of human leukocyte antigens among omani population.
Al Salmi, Issa; Metry, Abdul Massiah; Al Ismaili, Faisal; Hola, Alan; Shaheen, Faissal; Fakhoury, Hana; Hannawi, Suad
2017-01-01
Oman is located on the Southeastern coast of the Arabian Peninsula, and its population has high levels of consanguinity. Human leukocytic antigen (HLA) typing analysis in human population holds unexploited potential for elucidating the genetic causes of human disease and possibly leads to personalized medicine. This is a retrospective, descriptive study evaluating HLA frequencies of Omani individuals who underwent workup for kidney transplantation at the Royal Hospital (RH) from 2005 to 2016. Data on 870 subjects were collected from the Oman kidney transplant registry at RH as well from electronic medical record system. The mean age (standard deviation) years for the cohort were 33.2 (13.0). Males constituted 56.3% (490) while females constituted 43.7% (380). Seven HLA-A alleles accounted for more than 70% of the total alleles. Of which, HLA-A2 contributed the highest frequency (24%), followed by HLA A11 (9.4%), and A32 (8.1%). Ten alleles accounted for 70% of HLA-B alleles. Of which, HLA-B51 was the most common (18.9%), followed by HLA-B-35 (13.6%), and HLA-B8 (7.9%). Seven HLA-DRB1 alleles accounted for more than 70% of the total HLA DRB1 alleles, of which HLA- DRB1*16 contributed the highest frequency (29.56%). This was followed by HLA-DRB1*03 (14.57%) and HLA-DRB1*11 (9.48%). While three alleles accounted for more than 75% of the total HLA DQB1alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%). This was followed by allele HLA-DQB1*02 (26.48%) and HLA-DQB1*03 (17.18%). This study showed considerable heterogeneity in both HLA Class I and Class II antigens, which reflects admixture of our population with rest of old world countries. Despite the high levels of consanguinity, this population is genetically highly heterogeneous. These findings may be useful for transplantation programs, noncommunicable diseases, epidemiology of HLA linked diseases, pharmacogenomics, and anthropology.
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Epidemiology of human leukocyte antigens among omani population
Directory of Open Access Journals (Sweden)
Issa Al Salmi
2017-01-01
Full Text Available Oman is located on the Southeastern coast of the Arabian Peninsula, and its population has high levels of consanguinity. Human leukocytic antigen (HLA typing analysis in human population holds unexploited potential for elucidating the genetic causes of human disease and possibly leads to personalized medicine. This is a retrospective, descriptive study evaluating HLA frequencies of Omani individuals who underwent workup for kidney transplantation at the Royal Hospital (RH from 2005 to 2016. Data on 870 subjects were collected from the Oman kidney transplant registry at RH as well from electronic medical record system. The mean age (standard deviation years for the cohort were 33.2 (13.0. Males constituted 56.3% (490 while females constituted 43.7% (380. Seven HLA-A alleles accounted for more than 70% of the total alleles. Of which, HLA-A2 contributed the highest frequency (24%, followed by HLA A11 (9.4%, and A32 (8.1%. Ten alleles accounted for 70% of HLA-B alleles. Of which, HLA-B51 was the most common (18.9%, followed by HLA-B-35 (13.6%, and HLA-B8 (7.9%. Seven HLA-DRB1 alleles accounted for more than 70% of the total HLA DRB1 alleles, of which HLA- DRB1*16 contributed the highest frequency (29.56%. This was followed by HLA-DRB1*03 (14.57% and HLA-DRB1*11 (9.48%. While three alleles accounted for more than 75% of the total HLA DQB1alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%. This was followed by allele HLA-DQB1*02 (26.48% and HLA-DQB1*03 (17.18%. This study showed considerable heterogeneity in both HLA Class I and Class II antigens, which reflects admixture of our population with rest of old world countries. Despite the high levels of consanguinity, this population is genetically highly heterogeneous. These findings may be useful for transplantation programs, noncommunicable diseases, epidemiology of HLA linked diseases, pharmacogenomics, and anthropology.
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Signatures of natural selection among lineages and habitats in Oncorhynchus mykiss
DEFF Research Database (Denmark)
Limborg, Morten; Blankenship, S.; Young, S.
2012-01-01
lineage. Overall patterns of variation affirmed clear distinctions between lineages and in most instances, isolation by distance within them. Evidence for divergent selection at eight candidate loci included significant landscape correlations, particularly with temperature. High diversity of two...... nonsynonymous mutations within the peptide-binding region of the major histocompatibility complex (MHC) class II (DAB) gene provided signatures of balancing selection. Weak signals for potential selection between sympatric resident and anadromous populations were revealed from genome scans and allele frequency...
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Improved methods for predicting peptide binding affinity to MHC class II molecules
DEFF Research Database (Denmark)
Jensen, Kamilla Kjærgaard; Andreatta, Massimo; Marcatili, Paolo
2018-01-01
Major histocompatibility complex class II (MHC-II) molecules are expressed on the surface of professional antigen presenting cells where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. Understanding which peptides will be presented b...... are publicly available at www.cbs.dtu.dk/services/NetMHCII-2.3 and www.cbs.dtu.dk/services/NetMHCIIpan-3.2. This article is protected by copyright. All rights reserved....
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The Intensity of Human Body Odors and the MHC: Should We Expect a Link?
Claus Wedekind; Thomas Seebeck; Florence Bettens; Alexander J. Paepke
2006-01-01
It is now well established that genes within the major histocompatibility complex (MHC) somehow affect the production of body odors in several vertebrates, including humans. Here we discuss whether variation in the intensity of body odors may be influenced by the MHC. In order to examine this question, we have to control for MHC-linked odor perception on the smeller's side. Such a control is necessary because the perception of pleasantness and intensity seem to be confounded, a...
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Yi-Guang Chen; Clayton E. Mathews; John P. Driver
2018-01-01
For more than 35 years, the NOD mouse has been the primary animal model for studying autoimmune diabetes. During this time, striking similarities to the human disease have been uncovered. In both species, unusual polymorphisms in a major histocompatibility complex (MHC) class II molecule confer the most disease risk, disease is caused by perturbations by the same genes or different genes in the same biological pathways and that diabetes onset is preceded by the presence of circulating autorea...
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Jurtz, Vanessa; Paul, Sinu; Andreatta, Massimo; Marcatili, Paolo; Peters, Bjoern; Nielsen, Morten
2017-01-01
Cytotoxic T cells are of central importance in the immune systems response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC (major histocompatibility complex) class I molecules. Peptide binding to MHC molecules is the single most selective step in the antigen presentation pathway. On the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has therefore attracted large attention. In the past, predictors of peptide-...
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Krause, A.
2011-01-01
Genetic diversity is a prerequisite for evolution. The genes of the Major Histocompatibility Complex (MHC) show genetic variation. They are polygenic and contain highly polymorphic loci. MHC molecules are an important part of the adaptive immune system due to their ability to bind and present different antigens to the T-lymphocytes. But this high specificity also implies a risk: the higher the number of recognized antigens, the more likely the similarity of foreign and auto antigens. This can...
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DEFF Research Database (Denmark)
Maehlen, J; Nennesmo, I; Olsson, A B
1989-01-01
After a peripheral nerve lesion (rat facial and sciatic) an induction of major histocompatibility complex (MHC) antigens class I was detected immunohistochemically in skeletal muscle fibers and motor neurons. This MHC expression was transient after a nerve crush, when regeneration occurred......, but persisted after a nerve cut, when regeneration was prevented. Since the time course of MHC class I expression correlates to that of regeneration a role for this cell surface molecule in regeneration may be considered....
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Non-MHC Antigenic Targets of the Humoral Immune Response in Transplantation
Zhang, Qiuheng; Reed, Elaine F.
2010-01-01
There is a growing body of data supporting a role for non-HLA antibodies in acute and chronic rejection of solid organ transplants. While many of these non-HLA antigens remain poorly defined, the principle antigenic targets are expressed on cells of the allograft including endothelium and epithelium. These non-HLA antigens are classified as either alloantigens, such as the major histocompatibility complex class I chain-related gene A (MICA) or MICB, or tissue-specific autoantigens such as vim...
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Czech Academy of Sciences Publication Activity Database
Mucksová, J.; Plachý, Jiří; Staněk, Ondřej; Hejnar, Jiří; Kalina, J.; Benešová, B.; Trefil, P.
2017-01-01
Roč. 48, č. 18 (2017), č. článku 18. ISSN 0928-4249 R&D Projects: GA MZe QJ1210041 Institutional support: RVO:61388971 ; RVO:68378050 Keywords : major histocompatibility complex * natural-killer-cells * rous-sarcoma-virus * class-i molecule * c-type lectin * induced tumors * inbred lines * b-nk * mycobacterium-tuberculosis * receptor dec-205 Subject RIV: EB - Genetics ; Molecular Biology; EE - Microbiology, Virology (MBU-M) OBOR OECD: Microbiology; Microbiology (MBU-M) Impact factor: 2.798, year: 2016
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Werneck, Lineu Cesar; Lorenzoni, Paulo José; Arndt, Raquel Cristina; Kay, Cláudia Suemi Kamoi; Scola, Rosana Herminia
2016-08-01
To study the HLA of class 1and 2 in a multiple sclerosis (MS) population to verify the susceptibility for the disease in the Southern Brazil. We analyzed patients with MS and controls, by direct sequencing of the genes related to HLA DRB1, DQB1, DPB1, A, B and C alleles with high resolution techniques. We found a lower frequency of all HLA alleles class 1 and 2 in MS and controls comparing to the European population. Several alleles had statistical correlation, but after Bonferroni correction, the only allele with significance was the HLA-DQB1*02:03, which has a positive association with MS. Our data have different frequency of HLA-alleles than the previous published papers in the Southeast Brazil and European population, possible due to several ethnic backgrounds.
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Communication complexity and information complexity
Pankratov, Denis
Information complexity enables the use of information-theoretic tools in communication complexity theory. Prior to the results presented in this thesis, information complexity was mainly used for proving lower bounds and direct-sum theorems in the setting of communication complexity. We present three results that demonstrate new connections between information complexity and communication complexity. In the first contribution we thoroughly study the information complexity of the smallest nontrivial two-party function: the AND function. While computing the communication complexity of AND is trivial, computing its exact information complexity presents a major technical challenge. In overcoming this challenge, we reveal that information complexity gives rise to rich geometrical structures. Our analysis of information complexity relies on new analytic techniques and new characterizations of communication protocols. We also uncover a connection of information complexity to the theory of elliptic partial differential equations. Once we compute the exact information complexity of AND, we can compute exact communication complexity of several related functions on n-bit inputs with some additional technical work. Previous combinatorial and algebraic techniques could only prove bounds of the form theta( n). Interestingly, this level of precision is typical in the area of information theory, so our result demonstrates that this meta-property of precise bounds carries over to information complexity and in certain cases even to communication complexity. Our result does not only strengthen the lower bound on communication complexity of disjointness by making it more exact, but it also shows that information complexity provides the exact upper bound on communication complexity. In fact, this result is more general and applies to a whole class of communication problems. In the second contribution, we use self-reduction methods to prove strong lower bounds on the information
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HLA class II linkage disequilibrium and haplotype evolution in the Cayapa Indians of Ecuador
Energy Technology Data Exchange (ETDEWEB)
Trachtenberg, E.A.; Erlich, H.A. [Roche Molecular Systems, Alameda, CA (United States); Klitz, W. [Univ. of California, Berkeley, CA (United States)] [and others
1995-08-01
DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals several lines of evidence that selection has operated to maintain and to diversify the existing level of polymorphism in the class II region. As has been noticed for other Native American groups, the overall level of polymorphism at the DRB1, DQA1, DQB1, and DPB1 loci is reduced relative to that found in other human populations. Nonetheless, the relative eveness in the distribution of allele frequencies at each of the four loci points to the role of balancing selection in the maintenance of the polymorphism. The DQA1 and DQB1 loci, in particular, have near-maximum departures from the neutrality model, which suggests that balancing selection has been especially strong in these cases. Several novel DQA1-DQB1 haplotypes and the discovery of a new DRB1 allele demonstrate an evolutionary tendency favoring the diversification of class II alleles and haplotypes. The recombination interval between the centromeric DPB1 locus and the other class II loci will, in the absence of other forces such as selection, reduce disequilibrium across this region. However, nearly all common alleles were found to be part of DR-DP haplotypes in strong disequilibrium, consistent with the recent action of selection acting on these haplotypes in the Cayapa. 50 refs., 3 figs., 3 tabs.
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Lau, Quintin; Griffith, Joanna E.; Higgins, Damien P.
2014-01-01
Chlamydiosis, the most common infectious disease in koalas, can cause chronic urogenital tract fibrosis and infertility. High titres of serum immunoglobulin G against 10 kDa and 60 kDa chlamydial heat-shock proteins (c-hsp10 and c-hsp60) are associated with fibrous occlusion of the koala uterus and uterine tube. Murine and human studies have identified associations between specific major histocompatibility complex class II (MHCII) alleles or genotypes, and higher c-hsp 60 antibody levels or c...
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Energy Technology Data Exchange (ETDEWEB)
Wynn, Katherine K.; Fulton, Zara; Cooper, Leanne; Silins, Sharon L.; Gras, Stephanie; Archbold, Julia K.; Tynan, Fleur E.; Miles, John J.; McCluskey, James; Burrows, Scott R.; Rossjohn, Jamie; Khanna, Rajiv (Monash); (Queensland Inst. of Med. Rsrch.); (Melbourne)
2008-04-29
CD8{sup +} T-cell responses to persistent viral infections are characterized by the accumulation of an oligoclonal T-cell repertoire and a reduction in the naive T-cell pool. However, the precise mechanism for this phenomenon remains elusive. Here we show that human cytomegalovirus (HCMV)-specific CD8{sup +} T cells recognizing distinct epitopes from the pp65 protein and restricted through an identical HLA class I allele (HLA B*3508) exhibited either a highly conserved public T-cell repertoire or a private, diverse T-cell response, which was uniquely altered in each donor following in vitro antigen exposure. Selection of a public T-cell receptor (TCR) was coincident with an atypical major histocompatibility complex (MHC)-peptide structure, in that the epitope adopted a helical conformation that bulged from the peptide-binding groove, while a diverse TCR profile was observed in response to the epitope that formed a flatter, more 'featureless' landscape. Clonotypes with biased TCR usage demonstrated more efficient recognition of virus-infected cells, a greater CD8 dependency, and were more terminally differentiated in their phenotype when compared with the T cells expressing diverse TCR. These findings provide new insights into our understanding on how the biology of antigen presentation in addition to the structural features of the pMHC-I might shape the T-cell repertoire and its phenotype.
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Arlehamn, Cecilia S Lindestam; Copin, Richard; Leary, Shay; Mack, Steven J; Phillips, Elizabeth; Mallal, Simon; Sette, Alessandro; Blatner, Gretta; Siefers, Heather; Ernst, Joel D
2017-04-01
One hundred healthy infants enrolled as controls in a tuberculosis vaccine study in Nyanza Province, Kenya provided anonymized samples for DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-B, -C, -DRB1, -DPB1, -DQA1 and -DQB1 loci. A minor deviation was detected at the HLA-A locus due to an excess of HLA-A*02:02, 29:02, 30:02, and 68:02 homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3393. Copyright © 2017. Published by Elsevier Inc.
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Directory of Open Access Journals (Sweden)
Rajendra Kumar Singh
2009-12-01
Full Text Available The down-regulation of the major histocompatibility complex class I (MHC-I from the surface of infected cells by the Nef proteins of primate immunodeficiency viruses likely contributes to pathogenesis by providing evasion of cell-mediated immunity. HIV-1 Nef-induced down-regulation involves endosomal trafficking and a cooperative interaction between the cytoplasmic domain (CD of MHC-I, Nef, and the clathrin adaptor protein complex-1 (AP-1. The CD of MHC-I contains a key tyrosine within the sequence YSQA that is required for down-regulation by Nef, but this sequence does not conform to the canonical AP-binding tyrosine-based motif Yxxphi, which mediates binding to the medium (micro subunits of AP complexes. We previously proposed that Nef allows the MHC-I CD to bind the mu subunit of AP-1 (micro1 as if it contained a Yxxphimotif.Here, we show that a direct interaction between the MHC-I CD/Nef and micro1 plays a primary role in the down-regulation of MHC-I: GST pulldown assays using recombinant proteins indicated that most of the MHC-I CD and Nef residues that are required for the down-regulation in human cells contribute to direct interactions with a truncated version of micro1. Specifically, the tyrosine residue of the YSQA sequence in the MHC-I CD as well as Nef residues E62-65 and P78 each contributed to the interaction between MHC-I CD/Nef and micro1 in vitro, whereas Nef M20 had little to no role. Conversely, residues F172/D174 and V392/L395 of the binding pocket on micro1 for Yxxphi motifs were required for a robust interaction.These data indicate that the MHC-I cytoplasmic domain, Nef, and the C-terminal two thirds of the mu subunit of AP-1 are sufficient to constitute a biologically relevant interaction. The data also reveal an unexpected role for a hydrophobic pocket in micro1 for interaction with MHC-I CD/Nef.
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Czech Academy of Sciences Publication Activity Database
Bryja, Josef; Charbonnel, N.; Berthier, K.; Galan, M.; Cosson, J.-F.
2007-01-01
Roč. 16, č. 23 (2007), s. 5084-5097 ISSN 0962-1083 R&D Projects: GA AV ČR IAA600930608 EU Projects: European Commission(XE) 10284 - EDEN Institutional research plan: CEZ:AV0Z60930519 Source of funding: R - rámcový projekt EK Keywords : Arvicola terrestris * balancing selection * local adaptation * MHC * population cycles Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.169, year: 2007
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Gul, Ahmet; Erman, Burak
2018-03-01
Prediction of peptide binding on specific human leukocyte antigens (HLA) has long been studied with successful results. We herein describe the effects of entropy and dynamics by investigating the binding stabilities of 10 nanopeptides on various HLA Class I alleles using a theoretical model based on molecular dynamics simulations. The fluctuational entropies of the peptides are estimated over a temperature range of 310-460 K. The estimated entropies correlate well with experimental binding affinities of the peptides: peptides that have higher binding affinities have lower entropies compared to non-binders, which have significantly larger entropies. The computation of the entropies is based on a simple model that requires short molecular dynamics trajectories and allows for approximate but rapid determination. The paper draws attention to the long neglected dynamic aspects of peptide binding, and provides a fast computation scheme that allows for rapid scanning of large numbers of peptides on selected HLA antigens, which may be useful in defining the right peptides for personal immunotherapy.
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International Nuclear Information System (INIS)
Alexander, A.J.; Bailey, E.; Woodward, J.G.
1986-01-01
Fourteen standard bred horses were serotyped as homozygous for 1 of 6 Equine Leukocyte Antigen (ELA) specificities. DNA was purified from peripheral leukocytes and digested with Hind III or Pvu II. Southern blot hybridization analysis was carried out using a 32 P-labeled mouse cDNA probe (PH2IIa) specific for class I MHC genes. Both enzymes generated blots that contained a large number of bands (23 to 30) per horse. Significant polymorphism existed among most fragment sizes, while a dozen highly conserved band sizes suggested the presence of Qa/tla - like genes. Only 2 animals (both W6's) showed identical band patterns. Polymorphism was greatest between horses of different serotypes and was significantly decreased within serotypes. Unique bands were present on both blots for both W1's and W6's and may account for the serologic specificity seen in ELA W1 and W6 horses. This study is consistent with the findings in other higher vertebrates and implies that the MHC of the horse includes a highly polymorphic class I multigene family
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Volanakis, J E; Zhu, Z B; Schaffer, F M; Macon, K J; Palermos, J; Barger, B O; Go, R; Campbell, R D; Schroeder, H W; Cooper, M D
1992-01-01
We have proposed that significant subsets of individuals with IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) may represent polar ends of a clinical spectrum reflecting a single underlying genetic defect. This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles. Here we present our analysis of the MHC haplotypes of 12 IgA-D and 19 CVID individuals from 21 families...
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International Nuclear Information System (INIS)
Cho, Kyung Ja; Jang, Ja June; Kim, Yong Dae; Ha, Chang Won; Koh, Jae Soo
1993-01-01
Consecutive 50 cases of squamous cell carcinomas of the uterine cervix diagnosed in 1992 were subjected to immunohistochemical study for ras oncogene product (p21) and MHC class II (DR) antigen using a microprobe immunostainer. Activated ras and aberrant DR expression were noted in 26 cases (52%) and 11 cases (22%) of cervical squamous cell carcinomas, respectively, without difference among histologic types. The reaction was mainly intracytoplasmic, with granular staining pattern and diffuse distribution. No direct histologic correlation between ras and DR expression was found. Four cases with HPV 16/18 DNA in superficial koilocytotic cells, revealed by in situ hybridization, showed various expression of ras and DR, and these 3 factors histologically did not seem to be affected one another. (Author)
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A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis.
Directory of Open Access Journals (Sweden)
Judith Field
2010-10-01
Full Text Available We conducted an association study across the human leukocyte antigen (HLA complex to identify loci associated with multiple sclerosis (MS. Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6. All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001 and were highly significant in the combined dataset (P ≤ 6 x 10(-8. The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9, replication set P = 7 x 10(-4, combined P = 2 x 10(-10. HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.
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Steger, Brigitte; Milosevic, Slavoljub; Doessinger, Georg; Reuther, Susanne; Liepert, Anja; Braeu, Marion; Schick, Julia; Vogt, Valentin; Schuster, Friedhelm; Kroell, Tanja; Busch, Dirk H; Borkhardt, Arndt; Kolb, Hans-Jochem; Tischer, Johanna; Buhmann, Raymund; Schmetzer, Helga
2014-04-01
T-cells play an important role in the remission-maintenance in AML-patients (pts) after SCT, however the role of LAA- (WT1, PR1, PRAME) or minor-histocompatibility (mHag, HA1) antigen-specific CD4(+) and CD8(+)T-cells is not defined. A LAA/HA1-peptide/protein stimulation, cloning and monitoring strategy for specific CD8(+)/CD4(+)T-cells in AML-pts after SCT is given. Our results show that (1) LAA-peptide-specific CD8+T-cells are detectable in every AML-pt after SCT. CD8(+)T-cells, recognizing two different antigens detectable in 5 of 7 cases correlate with long-lasting remissions. Clonal TCR-Vβ-restriction exemplarily proven by spectratyping in PRAME-specific CD8(+)T-cells; high PRAME-peptide-reactivity was CD4(+)-associated, as shown by IFN-γ-release. (2) Two types of antigen-presenting cells (APCs) were tested for presentation of LAA/HA1-proteins to CD4(+)T-cells: miniEBV-transduced lymphoblastoid cells (B-cell-source) and CD4-depleted MNC (source for B-cell/monocyte/DC). We provide a refined cloning-system for proliferating, CD40L(+)CD4(+)T-cells after LAA/HA1-stimulation. CD4(+)T-cells produced cytokines (GM-CSF, IFN-γ) upon exposure to LAA/HA1-stimulation until after at least 7 restimulations and demonstrated cytotoxic activity against naive blasts, but not fibroblasts. Antileukemic activity of unstimulated, stimulated or cloned CD4(+)T-cells correlated with defined T-cell-subtypes and the clinical course of the disease. In conclusion we provide immunological tools to enrich and monitor LAA/HA1-CD4(+)- and CD8(+)T-cells in AML-pts after SCT and generate data with relevant prognostic value. We were able to demonstrate the presence of LAA-peptide-specific CD8(+)T-cell clones in AML-pts after SCT. In addition, we were also able to enrich specific antileukemic reactive CD4(+)T-cells without GvH-reactivity upon repeated LAA/HA1-protein stimulation and limiting dilution cloning. Copyright © 2013 Elsevier GmbH. All rights reserved.
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The Immune Epitope Database 2.0
DEFF Research Database (Denmark)
Hoof, Ilka; Vita, R; Zarebski, L
2010-01-01
The Immune Epitope Database (IEDB, www.iedb.org) provides a catalog of experimentally characterized B and T cell epitopes, as well as data on Major Histocompatibility Complex (MHC) binding and MHC ligand elution experiments. The database represents the molecular structures recognized by adaptive...... immune receptors and the experimental contexts in which these molecules were determined to be immune epitopes. Epitopes recognized in humans, nonhuman primates, rodents, pigs, cats and all other tested species are included. Both positive and negative experimental results are captured. Over the course...
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NLRC5: a newly discovered MHC class I transactivator (CITA)
Meissner, Torsten B.; Li, Amy; Kobayashi, Koichi S.
2011-01-01
Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator), is a master regulator of MHC class II gene expression as well as of some of the genes involved in MHC class II antigen presentation. It has recently been discovered that another member of the NLR protein family, NLRC5, transcriptionally activates MHC class I genes, and thus acts as “CITA” (MHC class I transactivator)...
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Selection of unrelated donors for bone marrow transplantation studied in rhesus monkeys
International Nuclear Information System (INIS)
Wagemaker, G.; Bekkum, D.W. van
Graft versus Host disease (GvHD) remains to be a severe limitation to a more general application of bone marrow transplantation. Clinically acceptable results are restricted to those potential recipients for which a major histocompatibility complex (MHC) identical sibling donor is available. At an average family size of 2 to 3 siblings, the frequency of such donors is not more than approximately 30%. This pre-clinical study in rhesus monkeys is directed at the selection of donors for recipients which lack an MHC identical sibling. (Auth.)
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Masoudi, Sanita; Ploen, Daniela; Kunz, Katharina; Hildt, Eberhard
2014-05-23
After the H1N1 swine flu vaccination campaign an increased number of narcolepsy cases in children and adolescents was observed in Scandinavian and later in further European countries that correlated with the vaccination by an AS03-adjuvanted influenza vaccine (Pandemrix). Narcolepsy is a chronic sleep disorder characterized by the loss of hypocretin in the cerebrospinal fluid due to selective destruction of hypocretin-producing neurons in the perifornical hypothalamus. In >99% of the cases narcolepsy is associated with the HLA-subtype DQB1*602 giving the link to an autoimmune process. In contrast to other squalene-based adjuvants, for which no association with narcolepsy was reported so far, ASO3 contains in addition α-tocopherol. It could be observed recently that α-tocopherol activates the transcription factor Nrf2. Nrf2 triggers the expression of cytoprotective genes, i.e. the catalytic active subunits of the constitutive proteasome, by binding to the antioxidant response element (ARE). It was hypothesized that α-tocopherol via activation of Nrf2 affects expression and turnover of hypocretin, leading to an increased amount of hypocretinα-specific fragments that bind to DQB1*602. α-Tocopherol activates Nrf2 in neuronal cells in vitro. Promoter analysis revealed an ARE sequence in the hypocretin promoter. Indeed, α-tocopherol increases by activation of Nrf2 the expression of hypocretin. In parallel, α-tocopherol -dependent induction of Nrf2 augments expression of catalytic subunits of the proteasome leading to increased degradation of hypocretin. Moreover, elevated activation of Nrf2 is associated with a decreased activity of NF-κB that results in an increased sensitivity to apoptotic stimuli. In case of a genetic predisposition (DQB1*602) α-tocopherol could confer to development of narcolepsy by activation of Nrf2 that finally leads to an elevated formation of longer hypocretin-derived fragments that can be presented by HLA-subtype DQB1*602. These cells
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The use of HPLC-MS in T-cell epitope identification.
Lemmel, Claudia; Stevanović, Stefan
2003-03-01
The hunt for T-cell epitopes is going on because hopes are set on such peptide sequences for diagnosis and vaccine development in the fight against infectious and tumor diseases. In addition to a variety of other techniques used in T-cell epitope identification, mass spectrometers coupled to microcapillary liquid chromatography have now become an important and sensitive tool in separation, detection, and sequence analysis of highly complex natural major histocompatibility complex (MHC) ligand mixtures. In this article, we review the basics of mass spectrometric techniques and their on-line coupling to microcapillary liquid chromatography (microcap-LC). Furthermore, we introduce current strategies for the identification of new T-cell epitopes using microcapillary liquid chromatography-mass spectrometry (microcap-LC-MS).
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DEFF Research Database (Denmark)
Knudsen, S; Mikkelsen, J D; Bang, B
2010-01-01
Narcolepsy with cataplexy (NC) is caused by substantial loss of hypocretin neurons. NC patients carry the HLA-DQB1*0602 allele suggesting that hypocretin neuron loss is due to an autoimmune attack. We tested intravenous immunoglobulin (IVIG) treatment in early onset NC....
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Czech Academy of Sciences Publication Activity Database
Stejskalová, K.; Bayerova, Z.; Futas, J.; Hrazdilová, K.; Klumplerova, M.; Oppelt, J.; Šplíchalová, P.; Di Guardo, G.; Mazzariol, S.; Di Francesco, C. E.; Di Francesco, G.; Terracciano, G.; Paiu, R.M.; Ursache, T. D.; Modrý, David; Horin, P.
2017-01-01
Roč. 90, č. 6 (2017), s. 343-353 ISSN 2059-2302 Institutional support: RVO:60077344 Keywords : Cetacea * haplotype * immunity * innate * mhc-dqb * Phocoena phocoena * polymorphism * single nucleotide * Stenella coeruleoalba Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology
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Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.
Goris, An; Pauwels, Ine; Gustavsen, Marte W; van Son, Brechtje; Hilven, Kelly; Bos, Steffan D; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål; Aarseth, Jan; Myhr, Kjell-Morten; D'Alfonso, Sandra; Barizzone, Nadia; Leone, Maurizio A; Martinelli Boneschi, Filippo; Sorosina, Melissa; Liberatore, Giuseppe; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan; Alfredsson, Lars; Bedri, Sahl Khalid; Hemmer, Bernhard; Buck, Dorothea; Berthele, Achim; Knier, Benjamin; Biberacher, Viola; van Pesch, Vincent; Sindic, Christian; Bang Oturai, Annette; Søndergaard, Helle Bach; Sellebjerg, Finn; Jensen, Poul Erik H; Comabella, Manuel; Montalban, Xavier; Pérez-Boza, Jennifer; Malhotra, Sunny; Lechner-Scott, Jeannette; Broadley, Simon; Slee, Mark; Taylor, Bruce; Kermode, Allan G; Gourraud, Pierre-Antoine; Sawcer, Stephen J; Andreassen, Bettina Kullle; Dubois, Bénédicte; Harbo, Hanne F
2015-03-01
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such
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Genetic variants are major determinants of CSF antibody levels in multiple sclerosis
Pauwels, Ine; Gustavsen, Marte W.; van Son, Brechtje; Hilven, Kelly; Bos, Steffan D.; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål; Aarseth, Jan; Myhr, Kjell-Morten; D’Alfonso, Sandra; Barizzone, Nadia; Leone, Maurizio A.; Martinelli Boneschi, Filippo; Sorosina, Melissa; Liberatore, Giuseppe; Kockum, Ingrid; Olsson, Tomas; Hillert, Jan; Alfredsson, Lars; Bedri, Sahl Khalid; Hemmer, Bernhard; Buck, Dorothea; Berthele, Achim; Knier, Benjamin; Biberacher, Viola; van Pesch, Vincent; Sindic, Christian; Bang Oturai, Annette; Søndergaard, Helle Bach; Sellebjerg, Finn; Jensen, Poul Erik H.; Comabella, Manuel; Montalban, Xavier; Pérez-Boza, Jennifer; Malhotra, Sunny; Lechner-Scott, Jeannette; Broadley, Simon; Slee, Mark; Taylor, Bruce; Kermode, Allan G.; Gourraud, Pierre-Antoine; Sawcer, Stephen J.; Andreassen, Bettina Kullle; Dubois, Bénédicte; Harbo, Hanne F.
2015-01-01
Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such
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Genetic affinities of north and northeastern populations of India: inference from HLA-based study.
Agrawal, S; Srivastava, S K; Borkar, M; Chaudhuri, T K
2008-08-01
India is like a microcosm of the world in terms of its diversity; religion, climate and ethnicity which leads to genetic variations in the populations. As a highly polymorphic marker, the human leukocyte antigen (HLA) system plays an important role in the genetic differentiation studies. To assess the genetic diversity of HLA class II loci, we studied a total of 1336 individuals from north India using DNA-based techniques. The study included four endogamous castes (Kayastha, Mathurs, Rastogies and Vaishyas), two inbreeding Muslim populations (Shias and Sunnis) from north India and three northeast Indian populations (Lachung, Mech and Rajbanshi). A total of 36 alleles were observed at DRB1 locus in both Hindu castes and Muslims from north, while 21 alleles were seen in northeast Indians. At the DQA1 locus, the number of alleles ranged from 11 to 17 in the studied populations. The total number of alleles at DQB1 was 19, 12 and 20 in the studied castes, Muslims and northeastern populations, respectively. The most frequent haplotypes observed in all the studied populations were DRB1*0701-DQA1*0201-DQB1*0201 and DRB1*1501-DQA1*0103-DQB1*0601. Upon comparing our results with other world populations, we observed the presence of Caucasoid element in north Indian population. However, differential admixturing among Sunnis and Shias with the other north Indians was evident. Northeastern populations showed genetic affinity with Mongoloids from southeast Asia. When genetic distances were calculated, we found the north Indians and northeastern populations to be markedly unrelated.
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Selective changes in expression of HLA class I polymorphic determinants in human solid tumors
International Nuclear Information System (INIS)
Natali, P.G.; Nicotra, M.R.; Bigotti, A.; Venturo, I.; Giacomini, P.; Marcenaro, L.; Russo, C.
1989-01-01
Analysis of surgical biopsies with monoclonal antibodies (mAbs) to framework determinants of major histocompatibility complex class I antigens has shown that malignant transformation is frequently associated with a marked loss of these cell surface molecules. The present study sought to determine whether more selective losses of major histocompatibility complex class I expression occur. Multiple specimens from 13 different types of primary and metastatic tumors were tested utilizing mAb BB7.2, which recognizes a polymorphic HLA-A2 epitope. In each case, expression of HLA-A,B,C molecules was determined by testing with mAb W6/32 directed to a framework HLA class I determinant. The authors have found that in HLA-A2-positive patients, HLA-A2 products are not detectable or are reduced in their expression in 70-80% of endometrial, colorectal, mammary, and renal tumors; in 40-60% of soft-tissue, skin, ovary, urinary bladder, prostate, and stomach tumors; and in 25-30% of melanomas and lung carcinomas tested. All tumors expressed the framework HLA-A,B.C determinant. The HLA-A2 epitope recognized by mAb BB7.2 is located in a portion of the HLA-A2 molecule postulated to react with the T-cell receptor. The selective loss of an HLA class I polymorphic epitope shown in this study may explain the mechanism by which tumor cells escape both T-cell recognition and natural killer cell surveillance
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The role of gamma delta T cells in haematopoietic stem cell transplantation
DEFF Research Database (Denmark)
Minculescu, L; Sengeløv, H
2015-01-01
transplantation modalities increasingly focuses on selective cell depletion and graft engineering with the aim of retaining beneficial immune donor cells for the graft-versus-leukaemia (GVL) effect. In this context, the adoptive and especially innate effector functions of γδ T cells together with clinical studies...... recognition independent from the major histocompatibility complex (MHC) allows for the theoretical possibility of mediating GVL without an allogeneic response in terms of GVHD. Early studies on the impact of γδ T cells in HSCT have reported conflicting results. Recent studies, however, do suggest an overall...
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Interaction between a "processed" ovalbumin peptide and Ia molecules
DEFF Research Database (Denmark)
Buus, S; Colon, S; Smith, C
1986-01-01
The binding of 125I-labeled immunogenic peptides to purified Ia molecules in detergent solution was examined by equilibrium dialysis. We used the chicken ovalbumin peptide ovalbumin-(323-339)-Tyr, which is immunogenic in the BALB/c mouse and restricted to I-Ad. 125I-labeled ovalbumin-(323-339)-Tyr......-Ak but not to I-Ek, I-Ad, or I-Ed. Thus, a specific interaction between Ia and antigen that correlates with the major histocompatibility complex restriction was demonstrated, strongly arguing in favor of a determinant selection hypothesis for such restriction....
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DEFF Research Database (Denmark)
Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot
2015-01-01
high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA......Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including...
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MHC Class II epitope predictive algorithms
DEFF Research Database (Denmark)
Nielsen, Morten; Lund, Ole; Buus, S
2010-01-01
Major histocompatibility complex class II (MHC-II) molecules sample peptides from the extracellular space, allowing the immune system to detect the presence of foreign microbes from this compartment. To be able to predict the immune response to given pathogens, a number of methods have been...... developed to predict peptide-MHC binding. However, few methods other than the pioneering TEPITOPE/ProPred method have been developed for MHC-II. Despite recent progress in method development, the predictive performance for MHC-II remains significantly lower than what can be obtained for MHC-I. One reason...
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MHCcluster, a method for functional clustering of MHC molecules
DEFF Research Database (Denmark)
Thomsen, Martin Christen Frølund; Lundegaard, Claus; Buus, Søren
2013-01-01
The identification of peptides binding to major histocompatibility complexes (MHC) is a critical step in the understanding of T cell immune responses. The human MHC genomic region (HLA) is extremely polymorphic comprising several thousand alleles, many encoding a distinct molecule. The potentially...... binding specificity. The method has a flexible web interface that allows the user to include any MHC of interest in the analysis. The output consists of a static heat map and graphical tree-based visualizations of the functional relationship between MHC variants and a dynamic TreeViewer interface where...
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Axotomy induces MHC class I antigen expression on rat nerve cells
DEFF Research Database (Denmark)
Maehlen, J; Schröder, H D; Klareskog, L
1988-01-01
Immunomorphological staining demonstrates that class I major histocompatibility complex (MHC)-coded antigen expression can be selectively induced on otherwise class I-negative rat nerve cells by peripheral axotomy. Induction of class I as well as class II antigen expression was simultaneously seen...... on non-neural cells in the immediate vicinity of the injured nerve cells. As nerve regeneration after axotomy includes growth of new nerve cell processes and formation of new nerve cell contacts, the present findings raise the question of a role for MHC-coded molecules in cell-cell interactions during...... nerve cell growth....
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DEFF Research Database (Denmark)
Bentzen, Amalie Kai; Marquard, Andrea Marion; Lyngaa, Rikke Birgitte
2016-01-01
-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer-restricted antigens. When analyzing T-cell recognition of shared melanoma antigens before and after adoptive...... cell therapy in melanoma patients, we observe a greater number of melanoma-specific T-cell populations compared with cytometry-based approaches. Furthermore, we detect neoepitope-specific T cells in tumor-infiltrating lymphocytes and peripheral blood from patients with non-small cell lung cancer...
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[Immunological mechanisms of graft versus tumor effect].
Ine, Shoji; Yamada, Minami; Miyamura, Koichi; Sasaki, Takeshi
2003-09-01
Lesson from hematopoietic stem cell transplantation demonstrated that donor immuno-surveillance system can eradicate tumor cells. This is so-call graft versus tumor(GVT) effect. Antigen presenting cells show peptide from minor antigen rather leukemic specific antigen in the context of major histocompatibility complex. The effector cells composed of CD8 T lymphocyte, CD4 T lymphocyte, natural killer cell and natural killer T cell. Death signal was transmitted from effector cells via granzyme/perforin system and FasL/Fas system, and recently TRAIL system seems most important for GVT effect.
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DEFF Research Database (Denmark)
Langerhuus, S. N.; Tønnesen, E. K.; Jensen, K. H.
2010-01-01
Aortic vascular prosthetic graft infection (AVPGI) with Staphylococcus aureus is a feared post-operative complication. This study was conducted to evaluate the clinical signs and potential biomarkers of infection in a porcine AVPGI model. The biomarkers evaluated were: C-reactive protein (CRP......), fibrinogen, white blood cells (WBC), major histocompatibility complex II (MHC II) density, lymphocyte CD4:CD8 ratio and tumour necrosis factor-alpha (TNF-α) in vitro responsiveness. Sixteen pigs were included in the study, and randomly assigned into four groups (n = 4): “SHAM” pigs had their infra...
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DEFF Research Database (Denmark)
Juncker, Agnieszka; Larsen, Mette Voldby; Weinhold, Nils
2009-01-01
Background: Presentation of peptides on Major Histocompatibility Complex (MHC) molecules is the cornerstone in immune system activation and increased knowledge of the characteristics of MHC ligands and their source proteins is highly desirable. Methodology/Principal Finding: In the present large......-scale study, we used a large data set of proteins containing experimentally identified MHC class I or II ligands and examined the proteins according to their expression profiles at the mRNA level and their Gene Ontology (GO) classification within the cellular component ontology. Proteins encoded by highly...
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DEFF Research Database (Denmark)
Karosiene, Edita; Rasmussen, Michael; Blicher, Thomas
2013-01-01
Major histocompatibility complex class II (MHCII) molecules play an important role in cell-mediated immunity. They present specific peptides derived from endosomal proteins for recognition by T helper cells. The identification of peptides that bind to MHCII molecules is therefore of great importa......MHCIIpan-3.0 method is the first pan-specific predictor covering all HLA class II molecules with known sequences including HLA-DR, HLA-DP, and HLA-DQ. The NetMHCpan-3.0 method is available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0....
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DEFF Research Database (Denmark)
Pouget, Jennie G; Gonçalves, Vanessa F; Spain, Sarah L
2016-01-01
There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been...... 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...
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DEFF Research Database (Denmark)
Pedersen, Lasse Eggers; Breum, Solvej Østergaard; Riber, Ulla
2014-01-01
Background: Major histocompatibility complex (MHC) class I peptide binding and presentation are essential for antigen-specific activation of cytotoxic T lymphocytes (CTLs) and swine MHC class I molecules, also termed swine leukocyte antigens (SLA), thus play a crucial role in the process that leads...... to elimination of viruses such as swine influenza virus (SwIV). This study describes the identification of SLA-presented peptide epitopes that are targets for a swine CTL response, and further analyses multiple specificities expressed by SwIV activated CTL subsets. Findings: Four SwIV derived peptides were...
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Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach
DEFF Research Database (Denmark)
Nielsen, Morten; Lundegaard, Claus; Worning, Peder
2004-01-01
Prediction of which peptides will bind a specific major histocompatibility complex (MHC) constitutes an important step in identifying potential T-cell epitopes suitable as vaccine candidates. MHC class II binding peptides have a broad length distribution complicating such predictions. Thus......, identifying the correct alignment is a crucial part of identifying the core of an MHC class II binding motif. In this context, we wish to describe a novel Gibbs motif sampler method ideally suited for recognizing such weak sequence motifs. The method is based on the Gibbs sampling method, and it incorporates...
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Mathew, Mohit P; Donaldson, Julie G
2018-05-11
Clathrin-independent endocytosis (CIE) is a form of endocytosis that lacks a defined cytoplasmic machinery. Here, we asked whether glycan interactions, acting from the outside, could be a part of that endocytic machinery. We show that the perturbation of global cellular patterns of protein glycosylation by modulation of metabolic flux affects CIE. Interestingly, these changes in glycosylation had cargo-specific effects. For example, in HeLa cells, GlcNAc treatment, which increases glycan branching, increased major histocompatibility complex class I (MHCI) internalization but inhibited CIE of the glycoprotein CD59 molecule (CD59). The effects of knocking down the expression of galectin 3, a carbohydrate-binding protein and an important player in galectin-glycan interactions, were also cargo-specific and stimulated CD59 uptake. By contrast, inhibition of all galectin-glycan interactions by lactose inhibited CIE of both MHCI and CD59. None of these treatments affected clathrin-mediated endocytosis, implying that glycosylation changes specifically affect CIE. We also found that the galectin lattice tailors membrane fluidity and cell spreading. Furthermore, changes in membrane dynamics mediated by the galectin lattice affected macropinocytosis, an altered form of CIE, in HT1080 cells. Our results suggest that glycans play an important and nuanced role in CIE, with each cargo being affected uniquely by alterations in galectin and glycan profiles and their interactions. We conclude that galectin-driven effects exist on a continuum from stimulatory to inhibitory, with distinct CIE cargo proteins having unique response landscapes and with different cell types starting at different positions on these conceptual landscapes.
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Yang, K L; Lee, S K; Lin, P Y
2013-08-01
We detected a rare HLA-B locus allele, B*39:77, in a Taiwanese unrelated marrow stem cell donor in our routine HLA sequence-based typing (SBT) exercise for a possible haematopoietic stem cell donation. In exons 2, 3 and 4, the DNA sequence of B*39:77 is identical to the sequence of B*39:01:01:01 except one nucleotide at nucleotide position 733 (G->A) in exon 4. The nucleotide variation caused one amino acid alteration at residue 221 (Gly->Ser). B*39:77 was probably derived from a nucleotide substitution event involving B*39:01:01:01. The probable HLA-A, -B, -C, -DRB1 and -DQB1 haplotype in association with B*39:77 may be deduced as A*02:01-B*39:77-C*07:02-DRB1*08:03-DQB1*06:01. Our discovery of B*39:77 in Taiwanese adds further polymorphism of B*39 variants in Taiwanese population. © 2013 John Wiley & Sons Ltd.
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Molecular typing of HLA class II antigens in a São Paulo population
Directory of Open Access Journals (Sweden)
Goldberg A.C.
1998-01-01
Full Text Available In the present paper we show data obtained from a normal population with a racially mixed profile typical of the city of São Paulo, State of São Paulo. Data were generated with polymerase chain reaction using sequence specific primers (PCR-SSP for HLA-DRB and polymerase chain reaction followed by hybridization with sequence specific oligonucleotide probes (PCR-SSO for HLA-DQA1 and HLA-DQB1 loci. HLA-DRB, DQA1, DQB1 and haplotype frequencies as well as common linkage disequilibria were found. This population was also shown to be in genetic equilibrium according to the Hardy-Weinberg law. HLA-DR typing of a normal sample from the city of Porto Velho, State of Rondonia, highlighted the importance of different sets of HLA profiles found in other regions of the country. This database provides essential information for screening studies of disease associations, forensic analyses and transplants.
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Gluten sensitivity and neurological manifestations
Directory of Open Access Journals (Sweden)
Agostino Berio
2015-12-01
Full Text Available The authors report on six cases of gluten-sensitivity, also defined non-celiac gluten sensitivity, characterized by abdominal features (diarrhea, bloating, pain, genetic positivity for predisposition to celiac disease (DQB1* 02 in all cases; DQA1*05 in three; DQA1*02 in two, DQB1*03 in two, negative anti-t-Transglutaminase antibodies, normal mucosa on biopsy in four cases, type 1 of Marsh in one case. The subjects presented frequent central nervous system (CNS symptoms: headache in three patients, somnolence in one, electroencephalogram aspecific alterations in three (in two of them with previous seizures, leptomeningeal cyst in one, intracranial calcification in one, cerebral gliosis in two. After a gluten-free diet, all intestinal and clinical CNS features remitted, but re-appeared after gluten reintroduction. On the basis of the neurological signs, the authors stress the relevance of immune innate system in the pathogenesis of these cases with possible subsequent evolution on immune adaptive system involvement.
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Kiryluk, Krzysztof; Li, Yifu; Scolari, Francesco; Sanna-Cherchi, Simone; Choi, Murim; Verbitsky, Miguel; Fasel, David; Lata, Sneh; Prakash, Sindhuri; Shapiro, Samantha; Fischman, Clara; Snyder, Holly J.; Appel, Gerald; Izzi, Claudia; Viola, Battista Fabio; Dallera, Nadia; Vecchio, Lucia Del; Barlassina, Cristina; Salvi, Erika; Bertinetto, Francesca Eleonora; Amoroso, Antonio; Savoldi, Silvana; Rocchietti, Marcella; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Salvadori, Maurizio; Ravani, Pietro; Magistroni, Riccardo; Ghiggeri, Gian Marco; Caridi, Gianluca; Bodria, Monica; Lugani, Francesca; Allegri, Landino; Delsante, Marco; Maiorana, Mariarosa; Magnano, Andrea; Frasca, Giovanni; Boer, Emanuela; Boscutti, Giuliano; Ponticelli, Claudio; Mignani, Renzo; Marcantoni, Carmelita; Di Landro, Domenico; Santoro, Domenico; Pani, Antonello; Polci, Rosaria; Feriozzi, Sandro; Chicca, Silvana; Galliani, Marco; Gigante, Maddalena; Gesualdo, Loreto; Zamboli, Pasquale; Maixnerová, Dita; Tesar, Vladimir; Eitner, Frank; Rauen, Thomas; Floege, Jürgen; Kovacs, Tibor; Nagy, Judit; Mucha, Krzysztof; Pączek, Leszek; Zaniew, Marcin; Mizerska-Wasiak, Małgorzata; Roszkowska-Blaim, Maria; Pawlaczyk, Krzysztof; Gale, Daniel; Barratt, Jonathan; Thibaudin, Lise; Berthoux, Francois; Canaud, Guillaume; Boland, Anne; Metzger, Marie; Panzer, Ulf; Suzuki, Hitoshi; Goto, Shin; Narita, Ichiei; Caliskan, Yasar; Xie, Jingyuan; Hou, Ping; Chen, Nan; Zhang, Hong; Wyatt, Robert J.; Novak, Jan; Julian, Bruce A.; Feehally, John; Stengel, Benedicte; Cusi, Daniele; Lifton, Richard P.; Gharavi, Ali G.
2014-01-01
We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN. PMID:25305756
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Distinct HLA associations of LGI1 and CASPR2-antibody diseases.
Binks, Sophie; Varley, James; Lee, Wanseon; Makuch, Mateusz; Elliott, Katherine; Gelfand, Jeffrey M; Jacob, Saiju; Leite, M Isabel; Maddison, Paul; Chen, Mian; Geschwind, Michael D; Grant, Eleanor; Sen, Arjune; Waters, Patrick; McCormack, Mark; Cavalleri, Gianpiero L; Barnardo, Martin; Knight, Julian C; Irani, Sarosh R
2018-05-18
The recent biochemical distinction between antibodies against leucine-rich, glioma-inactivated-1 (LGI1), contactin-associated protein-2 (CASPR2) and intracellular epitopes of voltage-gated potassium-channels (VGKCs) demands aetiological explanations. Given established associations between human leucocyte antigen (HLA) alleles and adverse drug reactions, and our clinical observation of frequent adverse drugs reactions in patients with LGI1 antibodies, we compared HLA alleles between healthy controls (n = 5553) and 111 Caucasian patients with VGKC-complex autoantibodies. In patients with LGI1 antibodies (n = 68), HLA-DRB1*07:01 was strongly represented [odds ratio = 27.6 (95% confidence interval 12.9-72.2), P = 4.1 × 10-26]. In contrast, patients with CASPR2 antibodies (n = 31) showed over-representation of HLA-DRB1*11:01 [odds ratio = 9.4 (95% confidence interval 4.6-19.3), P = 5.7 × 10-6]. Other allelic associations for patients with LGI1 antibodies reflected linkage, and significant haplotypic associations included HLA-DRB1*07:01-DQA1*02:01-DQB1*02:02, by comparison to DRB1*11:01-DQA1*05:01-DQB1*03:01 in CASPR2-antibody patients. Conditional analysis in LGI1-antibody patients resolved further independent class I and II associations. By comparison, patients with both LGI1 and CASPR2 antibodies (n = 3) carried yet another complement of HLA variants, and patients with intracellular VGKC antibodies (n = 9) lacked significant HLA associations. Within LGI1- or CASPR2-antibody patients, HLA associations did not correlate with clinical features. In silico predictions identified unique CASPR2- and LGI1-derived peptides potentially presented by the respective over-represented HLA molecules. These highly significant HLA associations dichotomize the underlying immunology in patients with LGI1 or CASPR2 antibodies, and inform T cell specificities and cellular interactions at disease initiation.
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Directory of Open Access Journals (Sweden)
Florence Bettens
2016-12-01
Full Text Available HLA-C locus mismatches are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C mismatches we have developed a one-way in vitro mixed lymphocyte reaction (MLR assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid mismatches in the α1/α2 domains (peptide binding region. Because of the high rate of HLA-DPB1 incompatibilities in HLA-A, B, C, DRB1 and DQB1 matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs, representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 mismatch did not induce any positive alloresponse in 5 MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic mismatch. A difference of at least 10 amino acid residues known to impact peptide/TCR binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p=0.021. The same HLA-C mismatch, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by10 or more amino acids in the peptide/TCR binding
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DEFF Research Database (Denmark)
Bentzen, Amalie Kai; Marquard, Andrea Marion; Lyngaa, Rikke Birgitte
2016-01-01
diversity of T cell recognition in humans. Consequently it has been impossible to comprehensively analyze T cell responsiveness in cancer, infectious and autoimmune diseases. We present and validate a novel technology that enables parallel detection of numerous different peptide-MHC responsive T cells...... with combinatorial encoding of fluorescent-labeled MHC multimers. Finally, we have demonstrated that this technology can be applied for multiplex T cell detection both in limited biological samples, such as uncultured tumor material, and for simultaneous assessment of target recognition and functional capability...... of T cells. This technology enables true high-throughput detection of antigen-responsive T cells and will advance our understanding of immune recognition from model antigens to genomewide immune assessments on a personalized basis....
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Benedictus, L.; Luteijn, Rutger D.; Otten, H.; Lebbink, Robert Jan; Kooten, van P.J.S.; Wiertz, E.J.H.J.; Rutten, Victor P.M.G.; Koets, A.P.
2015-01-01
Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens
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Czech Academy of Sciences Publication Activity Database
Čížková, Dagmar; Goüy de Bellocq, J.; Baird, S. J. E.; Piálek, Jaroslav; Bryja, Josef
2011-01-01
Roč. 106, č. 5 (2011), s. 727-740 ISSN 0018-067X R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/08/0640 Institutional research plan: CEZ:AV0Z60930519 Keywords : MHC * house mouse * selection * population structure * trans-species polymorphism Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.597, year: 2011
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Czech Academy of Sciences Publication Activity Database
Rymešová, D.; Králová, Tereza; Promerová, Marta; Bryja, Josef; Tomášek, Oldřich; Svobodová, J.; Šmilauer, P.; Šálek, M.; Albrecht, Tomáš
2017-01-01
Roč. 14, č. 1 (2017), č. článku 9. ISSN 1742-9994 R&D Projects: GA ČR GA206/08/1281 Institutional support: RVO:68081766 Keywords : Grey partridge * Mate choice * MHC genes * Ornaments * Sexual selection * Social monogamy * Inbreeding avoidance Subject RIV: EG - Zoology OBOR OECD: Zoology Impact factor: 2.781, year: 2016
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International Nuclear Information System (INIS)
Vermeer, B.J.; Santerse, B.; Van De Kerckhove, B.A.; Schothorst, A.A.; Claas, F.H.
1988-01-01
The influence of ultraviolet (UVB) irradiation on the survival of H-2 class II-disparate skin grafts was studied in congenic mouse strains. Isolated skin was UVB irradiated in vitro at a dose of 40 mJ/cm 2 from both sides to remove Ia immunogenicity. Immediately after irradiation the skin was transplanted onto the flank of allogeneic mice. When B10.AQR grafts were transplanted onto B10.T(6R) recipients, a significant prolongation of the survival time was observed, while 50% of the UVB-treated grafts were not rejected at all. However, in the opposite direction--i.e., B10.T(6R) grafts onto B10.AQR recipients, no significant prolongation of the survival was observed. To test whether this effect was due to a difference in susceptibility of the donor skin to UVB irradiation or to a different immune response in the recipients, (B10.T(6R) x B10.AQR) grafts were transplanted onto the parent strains. Similar results were obtained, in that UVB-treated grafts did not show a prolonged survival in B10.AQR recipients, whereas a significant prolongation (50% of the grafts survived more than 100 days) was observed in B10.T(6R) recipients. UVB-treated (B10.T(6R) x B10.AQR)F1 grafts were also transplanted onto (B10.T(6R) x C57B1/10)F1, (B10.AQR x C57B1/10)F1, (B10.T(6R) x Balb/c)F1 and (B10.AQR x Balb/c)F1 recipients--but in none of these combinations was a prolonged survival time observed. These data suggest that, in contrast to all in vitro experiments, the abrogation of the immune response by UVB treatment of the stimulator cells is, in vivo, not a general phenomenon. The genetic constitution of the responder mice seems to play an important role in determining whether or not an immune response takes place
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DEFF Research Database (Denmark)
Buus, S; Sette, A; Colon, S M
1987-01-01
The capacity of purified I-Ad, I-Ed, I-Ak, and I-Ek to bind to protein derived peptides that have been previously reported to be T cell immunogens has been examined. For each of the 12 peptides studied strong binding to the relevant Ia restriction element was observed. All the peptides bound more...... than one Ia molecule; however, for 11 of 12 peptides, the dominant binding was to the restriction element, whereas in one instance the dominant binding was to a nonrestriction element. When the peptides were used to inhibit the presentation of antigen by prefixed accessory cells to T cells......, an excellent correlation was found between the capacity of a peptide to inhibit the binding of an antigen to purified Ia and the capacity of the peptide to inhibit accessory cell presentation of the antigen. Thus, the binding of peptide to purified Ia is immunologically relevant, and Ia seems to be the only...