... with agammaglobulinemia develop infections again and again. Common infections include ones that are due to bacteria such as Haemophilus influenzae , pneumococci ( Streptococcus pneumoniae ), and staphylococci. Common sites of infection ...
Barnes, S; Kotecha, S; Douglass, J A; Paul, E; Hore-Lacey, F; Stirling, R; Snell, G I; Westall, G P
X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency syndrome characterized by agammaglobulinemia, recurrent infections and bronchiectasis. Despite the association with end-stage bronchiectasis, the literature on XLA and lung transplantation is extremely limited. We report a series of 6 XLA patients with bronchiectasis who underwent lung transplantation. Short-term outcomes were excellent however long-term outcomes were disappointing with a high incidence of pulmonary sepsis and chronic lung allograft dysfunction (CLAD). PMID:25736826
Full Text Available Introduction. X-linked agammaglobulinemia (XLA is a primary immunodeficiency characterized by agammaglobulinemia requiring replacement treatment with immunoglobulin. The association of XLA and membranoproliferative glomerulonephritis (MPGN is unexpected and, to our knowledge, only one case was previously published. Case Report. The authors report the case of a 10-year-old boy with family history and prenatal diagnosis of XLA, treated from birth with intravenous immunoglobulin replacement therapy. He presented with pneumonia, macroscopic hematuria, nephrotic proteinuria, hypoalbuminemia, and hypercholesterolemia with normal renal function and serum complement levels. Renal histology showed immune complex mediated MPGN. He was started on high dose prednisolone and ramipril and switched to weekly subcutaneous immunoglobulin. After a 4-month treatment, hematuria and proteinuria significantly improved and prednisolone was gradually tapered without relapse. Conclusion. The pathogenic process underlying MPGN development in this patient is unknown but residual humoral immunity might play an important role. Thus, this case highlights the risk of autoimmune disorders among patients with XLA.
Allen, R.C.; Nachtman, R.G.; Belmont, J.W.; Rosenblatt, H.M.
Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19[sup +] peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated >95% skewing of X inactivation in peripheral blood CD19[sup +] cells but not in CD19[sup [minus
Bestas, Burcu; Moreno, Pedro M D; Blomberg, K Emelie M;
X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisens...... expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA....
Ramesh, Manish; Simchoni, Noa; Hamm, David; Cunningham-Rundles, Charlotte
To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V–J combinations, derived from both productive and nonproductive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cel...
Zhu, Zaihua; Kang, Yuli; Lin, Zhenlang; Huang, Yanjing; Lv, Huoyang; Li, Yasong
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disease caused by mutations in the Bruton's tyrosine kinase (BTK) gene. XLA can also present in combination with juvenile idiopathic arthritis (JIA), the major chronic rheumatologic disease in children. We report herein the first known case of a juvenile patient diagnosed with XLA combined with JIA that later developed into invasive Klebsiella pneumoniae polyarticular septic polyarthritis. An additional comprehensive review of XLA combined with JIA and invasive K. pneumoniae septic arthritis is also presented. XLA was identified by the detection of BTK mutations while the diagnosis of JIA was established by clinical and laboratory assessments. Septic arthritis caused by invasive K. pneumoniae was confirmed by culturing of the synovia and gene detection of the isolates. Invasive K. pneumoniae infections can not only result in liver abscesses but also septic arthritis, although this is rare. XLA combined with JIA may contribute to invasive K. pneumoniae infection.
Full Text Available Introduction. Coincidence of X-linked agammaglobulinemia (XLA and secondary hemophagocytic syndrome (sHS is atypical. Both diseases are rare and pathogenesis of the latter one is not clearly known. Case Presentation. A 5-year-old boy was diagnosed both with XLA and sHS. However, in his history, he did not have severe and recurrent infections. Bruton tyrosine kinase (BTK gene mutation was present (c.1581_1584delTTTG. To the best of the authors’ knowledge, coincidence of XLA and sHS had not been reported in the literature before. Conclusion. Patients with XLA are extremely vulnerable to recurrent bacterial infections. The diagnosis of XLA with sHS at any time of life is both an interesting and challenging situation without history of recurrent bacterial infections.
H. Halik Akar
Full Text Available Smith-Lemli-Opitz syndrome (SLO is a rare autosomal recessive (AR inherited genetic disorder characterized by multiple congenital anomalies, microcephaly, muscular hypotonia, and severe developmental delay. The deficiency of 7-dehydrocholesterol reductase enzyme leads to this syndrome. Patients with SLO display recurrent respiratory infections due to secondary muscular hypotonia which leads to decreased motility and respiratory effort. In this study, we report a 1-year-old boy with SLO presented with recurrent urinary infections and chronic diarrhea with Klebsiella pneumonia positivity in the rectal swabs. The patient had also markedly decreased immunoglobulin G (IgG between 50-100 g/dl. In follow-up of patient, markedly clinical improvement was observed with intravenous immunoglobulin (IVIG replacement. With this study, we would like to draw attention; recurrent infections may indicate primary immunodeficiencies such as agammaglobulinemia in patients with SLO.
Fernanda Aimée NOBRE
Full Text Available SUMMARY We describe the case of an eight-year-old boy with X-linked agammaglobulinemia who developed mild varicella despite regular intravenous immunoglobulin (IVIG therapy. He maintained protective antibody levels against varicella and the previous batches of IVIG that he received had adequate varicella-specific IgG levels. The case illustrates that IVIG may not prevent VZV infection.
Full Text Available Abstract Background X-linked agammaglobulinemia (XLA is a humoral immunodeficiency caused by disruption of the Bruton's tyrosine kinase (BTK gene. Typical XLA patients suffer recurrent and severe bacterial infections in childhood. Methods Flow cytometric analysis of the peripheral monocytes using the anti-BTK antibody was used to characterize a 27 year old male patient with mild hypogammaglobulinemia (IgG, 635 mg/dl; IgM, 11 mg/dl; IgA, Results Flow cytometric analysis of cytoplasmic BTK protein in peripheral monocytes indicated that the patient presents a rare case of adult-onset XLA and that his mother is an XLA carrier. Sequencing of the BTK gene revealed a deletion of AG in the codon for Glu605 (AGT, resulting in an aberrant stop codon that truncates the BTK protein in its kinase domain. Conclusions This case suggests that some XLA cases may remain undiagnosed because they only show mild hypogammaglobulinemia and they lack repeated infections in childhood. Flow cytometric analysis is a powerful method to screen these patients.
Full Text Available X-linked agammaglobulinemia (XLA is a primary immunodeficiency of the humoral compartment, due to a mutation in the Bruton tyrosine kinase (BTK gene, characterized by a severe defect of circulating B cells and serum immunoglobulins. Recurrent infections are the main clinical manifestations; although they are especially due to encapsulated bacteria, a specific association with Campylobacter species has been reported. Here, we report the case of a boy with XLA who presented with relapsing Campylobacter jejuni systemic infections. His clinical history supports the hypothesis of the persistence of C. jejuni in his intestinal tract. Indeed, as previously reported, XLA patients may become chronic intestinal carriers of Campylobacter, even in absence of symptoms, with an increased risk of relapsing bacteraemia. The humoral defect is considered to be crucial for this phenomenon, as well as the difficulties to eradicate the pathogen with an appropriate antibiotic therapy; drug resistance is raising in Campylobacter species, and the appropriate duration of treatment has not been established. C. jejuni should always be suspected in XLA patients with signs and symptoms of systemic infection, and treatment should be based on antibiogram to assure the eradication of the pathogen.
Schwaber, J; Payne, J.; Chen, R.
We report an unusual phenotype of B cells in a patient with X-linked agammaglobulinemia (XLA), and cellular evidence for Lyonization of B cells from his mother and sister. The patient has a failure of B cell maturation at the stage of early B lymphocytes, associated with production of D(mu delta) H chain. The phenotype of his B cells includes: (a) limitation to expression of the mu and delta H chain isotypes, (b) production of mu and delta H chains of reduced size and (c) delayed expression o...
Full Text Available X-linked agammaglobulinemia (XLA is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (Btk gene. In order to identify the mutations in Btk gene in Iranian patients with antibody deficiency, 13 male patients with an XLA phenotype from 11 unrelated families were enrolled as the subjects of investigation for Btk mutation analysis using PCR-SSCP followed by sequencing. Five different mutations were identified in 5 patients from 5 unrelated families. Three mutations had been reported previously including TTTG deletion in intron 15 (4 bps upstream of exon 16 boundary, nonsense point mutation (1896G>A that resulted in a premature stop codon (W588X in kinase domain, and nucleotide alteration in invariant splice donor site of exon12 (IVS12+1G>A. While 2 novel missense mutations (2084A>G, 1783T>C were identified leading to amino acid changes (I651T, Y551H. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier detection and prenatal diagnosis.
Liliana Aboultaif Aboultaif
Full Text Available Las inmunodeficiencias primarias (IDPs son un conjunto de enfermedades caracterizadas por defectos en el desarrollo y/o función del sistema inmune debido a anomalías genéticas en cualquiera de sus componentes. Las deficiencias de anticuerpos son las IDPs más comunes y dentro de estas la agammaglobulinemia congénita representa el 10%, siendo un 85% ligada al cromosoma X, existiendo también formas autosómicas recesivas. La agammaglobulinemia ligada a X (ALX consiste en la ausencia casi absoluta de linfocitos B, ocasionando incapacidad de sintetizar anticuerpos y una alta susceptibilidad a la adquisición de infecciones, con respuesta a vacunas disminuida o ausente. Se presenta el caso de un escolar masculino de 8 años de edad quien desde los 5 meses presentó infecciones a repetición principalmente por bacterias extracelulares encapsuladas. Estudios paraclínicos revelaron hipogammglobulinemia persistente con subpoblación de linfocitos B muy disminuida y conservación de linfocitos T en sangre periférica. El estudio molecular reportó la mutación R525X en el exón 16 del gen TirosinKinasa de Bruton (BTK en el paciente y su madre, más no en la abuela, lo que confirmó el diagnóstico de ALX y permitió concluir que se trataba de una mutación de novo en la madre. Actualmente recibe tratamiento con Inmunoglobulina por vía endovenosa, disminuyendo la frecuencia y severidad de episodios infecciosos. El diagnóstico precoz a través del reconocimiento de las señales de alarma de las IDPs, junto al tratamiento adecuado y vigilancia constante constituyen la mejor herramienta para el adecuado manejo de los pacientes con IDPs, logrando una disminución de los procesos infecciosos e inflamatorios y sus secuelas, así como también mejorar la calidad de vida y supervivencia. De novo mutation in BTK gene in X-linked agammaglobulinaemia. A case report in Mérida, Venezuela Abstract The Primary Immunodeficiencies (PIDs are a group of diseases
... Modell Foundation: National Primary Immunodeficiency Resource Center National Organization for Rare Disorders : ... V, Aiba Y, Shurtleff SA, Kurosaki T. A minimally hypomorphic mutation in Btk resulting in reduced B cell numbers but no clinical disease. Clin Exp Immunol. ...
Vorechovský, I; Luo, L; Hertz, Jens Michael;
in premature termination of the translation product. Mutations were detected in most BTK exons with a predominance of frameshift and nonsense mutations in the 5' end of the gene and missense mutations in its 3' part, corresponding to the catalytic domain of the enzyme. Nonsense and frameshift mutations were...... associated with diminished levels of BTK mRNA expression, except for a frameshift mutation in exon 17 and two nonsense mutations in exon 2, indicating that these cases are not confined to penultimate exons. One amino acid substitution (R28H) was found in the pleckstrin homology domain's residue, which...
李小琳; 付四毛; 刘玉玲; 张莉; 林国模; 潘晓芬
Objective To analyze the clinical features, diagnosis and treatment of X-Linked Agarnmaglobulinemia (XLA). Methods Clinical features, cellular and humoral immune functions, treatment and prognosis from 3 patients with XLA were retrospectively reviewed. Results The age of onset were from 11 months to 6 years in these 3 cases, however, the median age of diagnosis was 12 years. All patients showed multiple recurrent bacterial infections, arthritis involved large joints such as knee, ankle, elbow and hip. Laboratory examination revealed the decrease of serum gammmaglohulin and absence of B lymphocytes in the peripheral blood. All 3 patients were identiifed BTK mutations, which were frameshift mutation and nonsense mutation in exon 3, frameshift mutation in exon 10, missense mutation in exon 18. After XLA was diagnosed, the patients were managed by intravenous gammagloulin (IVIG) replacement. The non-steroidal anti-inflammatory drugs (NSAIDs) were administrated in patients combined arthritis. The small dose of hormones had been applied. All patients had a significantly improvement. Conclusions The clinical features of XLA have greater variability, with recurrent bacterial infections. Markedly decreased and absent tosils and lymph nodes, serum immunoglobulin may be one of the warning signs for early diagnosis of XLA. IVIG and NSAIDs can be jointly treatment of XLA with arthritis. The steroid and immunosuppressant agents should be used with caution.%目的：分析X-连锁无丙种球蛋白血症(XLA)的临床表现、诊断和治疗特点。方法回顾性分析3例XLA患儿的临床特点、细胞免疫、体液免疫指标及治疗和预后。结果3例XLA患儿的发病年龄自11个月至6岁，中位诊断年龄为12岁。患儿均表现为多发反复细菌感染；关节炎症累及膝、踝、肘和髋等大关节。实验室检查提示血清免疫球蛋白水平及循环B细胞明显降低。3例患儿均发现存在BTK基因突变，分别为外显子3的移码突变及无义突变，外显子10的移码突变，以及外显子18的错义突变。确诊为XLA后予静脉滴注丙种球蛋白(IVIG)替代治疗；合并关节炎加用非甾体类抗炎药物(NSAIDs)，酌情加用小剂量激素，病情得到明显改善。结论 XLA临床表现具有较大的变异性，反复不同部位的细菌感染，扁桃体、淋巴结发育不良及血清免疫球蛋白水平低下是早期诊断XLA的重要环节；XLA合并关节炎使用IVIG和NSAIDs联合治疗，谨慎使用激素或免疫抑制剂。
Immune Deficiency Disorders:; Severe Combined Immunodeficiency; Chronic Granulomatous Disease; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Hyper-IgM; DiGeorge Syndrome; Chediak-Higashi Syndrome; Common Variable Immune Deficiency; Immune Dysregulatory Disorder:; Hemophagocytic Lymphohistiocytosis; IPEX; Autoimmune Lymphoproliferative Syndrome; X-linked Lymphoproliferative Syndrome
Hügle, Boris; Hoffman, Hal; Bird, Lynne M; Gebauer, Corinna; Suchowerskyj, Philipp; Sack, Ulrich; Kohlhase, Jürgen; Schuster, Volker
Hypogammaglobulinemia or agammaglobulinemia are major features of specific syndromes, including X-linked agammaglobulinemia and common variable immunodeficiency. However, the combination of hypogammaglobulinemia with specific dysmorphic features is less common, with only a few reported cases. One such report was a sporadic case of humoral immunodeficiency, facial dysmorphism, and limb anomalies in a young girl, later referred to as Hoffman syndrome. We report on a 7-year-old girl with almost complete loss of B cells, facial dysmorphism, and malformation of the limbs and genitalia, whose mother shows similar dysmorphic features with an attenuated version of the B-cell deficiency. We believe that all three cases described above represent the same condition. The features of the three affected individuals with Hoffman syndrome are reviewed. Further investigations in this recently recognized B-cell immunodeficiency syndrome are warranted.
Primary antibody deficiency (common variable immunodeficiency, Hyper IgM, X-linked agammaglobulinemia and selective Ig A deficiency) is a group of heterogeneous diseases characterized by defective antibody production. In primary hypogammaglobulinemias, particularly in patients with common variable immunodeficiency there is an increased generation of reactive oxygen species from monocytes which may be important for both immunopathogenesis and clinical manifestations. The generation of toxic ox...
Chun, Jin-Kyong; Lee, Taek Jin; Song, Jae Woo; Linton, John A.; Kim, Dong Soo
Purpose X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene resulting in defective B cell differentiation. Because it is a relatively rare disorder, it is difficult for clinicians to have a comprehensive understanding of XLA due to a lack of exposure to the disease. Clinical presentations of patients with XLA were analyzed and discussed to improve care plans. Materials and Methods During a 20 year period, from J...
Renata Cristina de Angelo Calsaverini Leal; Érika Cristina Pavarino Bertelli; Zaida Aurora Sperli Geraldes Soler
Recurrent infections are a consequence of a series of genetic diseases characterized by deficiency in the immunological response. One of these diseases is the agammaglobulinemia, which is characterized by the basic defect in the maturation of lymphocytes B. The carrier of this kind of immunodeficiency, which is linked to the X (XLA) chromosome, has had primary pneumonias that have evolved into secondary pneumonias (chronic lungs with sequelae) after the third or fourth year of life. The clini...
Novero, Aileen; Ravella, Pavan M; Chen, Yamei; Dous, George; Liu, Delong
Research over the role of Bruton’s agammaglobulinemia tyrosine kinase (BTK) in B-lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site ...
Brown, Jennifer R
Ibrutinib is a potent covalent kinase inhibitor that targets BTK. BTK, or Bruton’s tyrosine kinase, is an obvious target for therapy of B cell diseases because inactivating mutations lead to B cell aplasia in humans and the disease X-linked agammaglobulinemia. Ibrutinib has modest cytotoxicity against CLL cells in vitro but also blocks trophic stimuli from the microenvironment. As with other inhibitors of the BCR pathway, ibrutinib causes rapid nodal reduction and response associated with rap...
M. Eric Gershwin; Arvind Kumar; Teuber, Suzanne S.
Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune man...
Román Jiménez, María Guadalupe; Yamazaki Nakashimada, Marco Antonio; Blancas Galicia, Lizbeth
Bruton's agammaglobulinemia is a primary immunodeficiency with a disease onset during the first months of age, when the maternal serum immunoglobulin levels decrease. It is characterized by recurrent infections and agammaglobulinemia. We report the case of a 6-year-old male patient with third-degree consanguinity, product of a third pregnancy and complete immunization scheme. He had a history of oral candidiasis at the age of 3 months, chicken pox at the age of 7 months, and two episodes of complicated bronchopneumonia at the age of 1 year and 6 years. He was admitted to the hospital because of fever and cough. Examination of the chest showed rales and right basilar hypoventilation, and a blood cell count revealed leukocytosis and neutrophilia. The diagnosis of pneumonia was made. He was treated with IV antibiotics. Serum immunoglobulins were reported to be low (IgM 55 mg/dL, IgA 0.9 mg/dL, and IgG 199 mg/dL). With these findings the clinical diagnosis of X-linked agammaglobulinemia (ALX) was concluded. A molecular test was performed fining a BTK gene confirming the diagnosis of Bruton's disease. Therapy with intravenous IgG was started every 21 days. During his evolution, he presented three episodes of rhinosinusitis, one of suppurative otitis media, and four events of pneumonia that required 37 days of hospitalization. After hospital discharge, the patient was free of infections and he returned to his daily activities. In cases of recurrent and severe respiratory infections in children, we must consider primary immunodeficiency disease in the differential diagnosis, mainly antibiotic deficiency. Early diagnosis and treatment improves the survival and quality of life in these patients. PMID:21854727
M. A. Gordukova
Full Text Available Primary immunodeficiencies (PID such as severe combined immunodeficiency (SCID and X-linked agammaglobulinemia are characterized by the lack of functional Tand B-cells, respectively. Without early diagnosis and prompt treatment children with PID suffer from severe infectious diseases, leading to their death or disability. Our purpose was developing of simple, inexpensive, high throughput technique based on the quantitative determination of TREC and KREC molecules by real-time PCR, and its validation in a group of children with a verified diagnosis of SCID and X-linked agammaglobulinemia.In this study, we developed and validated multiplex real-time PCR for the TREC’s and KREC’s quantitative analysis. We have shown that linear range of Ct changes depending on the concentrations of targets with a correlation coefficient R2 not worse than 0.98 was observed at concentrations from 109 to 5 × 104 copies per ml. The lowest amount of targets reliably detected in a reaction volume was 10 TREC’s copies, 5 KREC ‘s copies and 5 copies of internal control (IL17RA. We determined the age-depended reference values of TRECs and KRECs in whole blood in 29 boys and 27 girls with normal immunological parameters. The normal cut-offs for TRECs and KRECs were defined in dry blood spots depending on the method of extraction.The proposed method showed 100% diagnostic sensitivity and specificity in the studied group. The method can be proposed as a screening tool for the diagnosis of SCID and X-linked agammaglobulinemia both in whole blood and in the dry blood spots. The further investigation is required with larger number of samples.
MacGlashan, Donald; Honigberg, Lee; Smith, Ashley; Buggy, Joseph; Schroeder, John T.
The study of receptor-mediated signaling in human basophils is often limited by the availability of selective pharmacological agents. The early signaling reaction mediated by FcεRI aggregation is thought to require the activity of Bruton’s tyrosine kinase (btk), an enzyme that has been identified as important in B cells signaling because mutations lead to X-linked agammaglobulinemia. This study uses the btk selective irreversible inhibitor, PCI-32765, to explore the role of btk in a variety o...
Full Text Available D10223 Drug Ibrutinib (USAN); Imbruvica (TN) C25H24N6O2 440.1961 440.4971 D10223.gi...cell receptor signaling pathway USP drug classification [BR:br08302] Antineoplastics Molecular Target Inhibitors Ibrutin...r08310] Protein kinases Tyrosine protein kinases Tec family Bruton agammaglobulinemia tyrosine kinase [HSA:695] [KO:K07370] Ibrutin...ib D10223 Ibrutinib (USAN) CAS: 936563-96-1 PubChem: 163312254 ATOM 33 1 C8x C 18.410...ib D10223 Ibrutinib (USAN) Target-based classification of drugs [BR:b
Shaghaghi, Mohammadreza; Parvaneh, Nima; Ostad-Rahimi, Pouya; Fathi, Seyed Mohammad; Shahmahmoodi, Shohreh; Abolhassani, Hassan; Aghamohammadi, Asghar
Neurologic abnormalities compatible with vaccine-related poliovirus infection (VAPP) may be a first presentation of some primary immunodeficient patients. The risk of VAPP rises from 1 case per 750 000 in normal population to 1 per 7000 times higher, particularly for persons with agammaglobulinemia and hypogammaglobulinemia. However, there is no appropriate estimation for VAPP occurrence in patients with cellular immunity defects. Herein we report a case of combined immunodeficiency with paralytic complication due to oral polio vaccine and we present a literature review on this topic.
Kumar, Arvind; Teuber, Suzanne S.; Gershwin, M. Eric
Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis. PMID:17162365
Full Text Available Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis.
Tachdjian, Raffi; Keller, Janet J; Pfeffer, Michael
Good's syndrome is a relatively rare immunodeficiency condition that presents in the fourth or fifth decade of life and is defined by hypogammaglobulinemia in the setting of a thymoma. The humoral defect may be severe enough to cause an absence in B cells, with a consequent recurrence of sinopulmonary disease, chronic non-infectious diarrhea and opportunistic infections. The prognosis in patients with Good's syndrome appears to be worse than in those with X-linked agammaglobulinemia (XLA) and common variable immune deficiency (CVID). There have only been three cases of Good's syndrome associated with mycobacterium, and only one case with a cavitary lesion in the lungs. We present here a unique case of Good's syndrome with a non-mycobacterial cavitary lesion.
Full Text Available Primary immunodeficiency disorders are a heterogeneous group of genetic disorders, with different modes of inheritance, consisting of more than 100 different types. We constructed the DNA banking of primary immunodeficiency disorders for the first time in Iran. The DNA of 31 immunodeficient patients and their families (total of 92 samples were collected, as the first step for construction of DNA banking. DNA was isolated from whole blood by salting out method. Among our patients, Common variable immunodeficiency was the most common disorder, followed by X-linked agammaglobulinemia, Ataxia-telangiectasia, Chronic granulomatous disease, Severe combined immunodeficiency, Hyper IgM syndromes, and Leukocyte adhesion defects. DNA banking is a useful method for further detection of mutation in immunodeficient patients and prenatal diagnosis for presence or absence of the disorder in the fetus which can be confirmed by molecular genetics testing.
Taneichi, Hiromichi; Miyawaki, Toshio
Intravenous immunoglobulin treatment was introduced as replacement therapy for patients with congenital agammaglobulinemia. For the last three decades, high-dose intravenous immunoglobulin (HD-IVIg) has been used for autoimmune diseases and systemic inflammatory diseases, such as idiopathic thrombocytopenic purpura, Kawasaki disease, myasthenia gravis and Guillain-Barré/syndrome. Although the immunomodulatory mechanisms of HD-IVIg remains unclear. Its use in many other diseases have been expected. Acute encephalitis/encephalopathy is a complex neurological syndrome associated with significant morbidity and mortality. The pathogenicity of brain dysfunction is still unknown. This review provides an overview and discussion of mechanisms that may be responsible for HD-IVIg effects in acute encephalitis/encephalopathy. PMID:21400848
Latysheva, T V; Latysheva, E A; Martynova, I A; Aminova, G E
Primary immunodeficiencies (PIDs) are a group of congenital diseases of the immune system, which numbers more than 230 nosological entities associated with lost, decreased, or wrong function of its one or several components. Due to the common misconception that these are extremely rare diseases that occur only in children and lead to their death at an early age, PIDs are frequently ruled out by physicians of related specialties from the range of differential diagnosis. The most common forms of PIDs, such as humoral immunity defects, common variable immune deficiency, X-linked agammaglobulinemia, selective IgA deficiency, etc., are milder than other forms of PID, enabling patients to attain their adult age, and may even manifest in adulthood. Bronchopulmonary involvements are the most common manifestations of the disease in patients with a defect in humoral immunity. Thus, a therapist and a pulmonologist are mostly the first doctors who begin to treat these patients and play a key role in their fate, since only timely diagnosis and initiation of adequate therapy can preserve not only the patient's life, but also its quality, avoiding irreversible complications. Chest computed tomography changes play a large role in diagnosis. These are not specific for PID; however, there are a number of characteristic signs that permit this diagnosis to be presumed. PMID:27636936
Detre, Cynthia; Keszei, Marton; Garrido-Mesa, Natividad; Kis-Toth, Katalin; Castro, Wilson; Agyemang, Amma F; Veerapen, Natacha; Besra, Gurdyal S; Carroll, Michael C; Tsokos, George C; Wang, Ninghai; Leadbetter, Elizabeth A; Terhorst, Cox
One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-).B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-).BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.
Intravenous immunoglobulins (IVIGs) are currently used in many fields of medicine for replacement and immunomodulation. This review focuses on the milestones in the history of human immunoglobulins since the initial observation by Ogden C. Bruton who described replacement therapy in a boy with agammaglobulinemia. Since then, the preparations used for treatment have been markedly improved with respect to tolerability, clinical efficacy, and pathogen safety. Preparations and appropriate pumps for subcutaneous administration of IgG have been developed and offer an alternative mode of treatment for immunodeficient patients. Appropriate replacement today allows patients with humoral immunodeficiencies to reach adulthood and normal or near-normal quality of life. In 1981 a second fundamental discovery was made. Paul Imbach and coauthors in children with idiopathic thrombocytopenic purpura (ITP) showed that IVIG has immunomodulatory potential, offering a chance for affected children to receive effective treatment with little or no side effects compared to systemic corticosteroids. This new principle of treatment encouraged many researchers worldwide to exploit the potential of IVIG in many other immunopathological situations. As an example, Rhesus hemolytic disease in newborn babies is discussed. PMID:27312172
Full Text Available Long-term intravenous immunoglobulin (IVIG infusion is an effective treatment for children with humoral immunodeficiencies, already be complicated by systemic ad¬verse effects. In order to determine the adverse effects of intravenous immunoglobulin inpatients with antibody deficiency, 45 immunodeficientpatients receiving intravenous immunoglobulin were studied during a 36-month period at Children's Medical Center. The investigated group included 25 patients with common variable immunodeficiency, 14 patients with X-linked agammaglobulinemia and 6 patients with IgG subclass defi¬ciency. A total of fifty adverse effects occurred through 955 infusions (5.2%. The most frequent immediate adverse effects were mild (40 infusions out of 955 in 22 cases, including: chills, flushing, fever, nausea and headache. Three patients experienced mod¬erate effects (10 infusions out of 955 such as rash, severe headache, joint pain and chest tightness. None of the effects was anaphylactic type. It can be concluded that intravenous immunoglobulin is generally a well-tolerated medical agent for patients with antibody deficiency, but all patients should be monitored by a physician who is familiar with its indications, risks, adverse effects and their appropriate management.
Corneth, Odilia B J; Klein Wolterink, Roel G J; Hendriks, Rudi W
Since the original identification of Bruton's tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.
Cerbone, Manuela; Wang, Jun; Van der Maarel, Silvère M.; d’Amico, Alessandra; d’Agostino, Antonio; Romano, Alfonso; Brunetti-Pierri, Nicola
The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agammaglobulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases. PMID:22786748
Chinen, Javier; Shearer, William T.
Progress in immunology continues to grow exponentially every year. New applications of this knowledge are being developed for a broad range of clinical conditions. Conversely, the study of primary and secondary immunodeficiencies is helping to elucidate the intricate mechanisms of the immune system. We have selected a few of the most significant contributions to the fields of basic and clinical immunology published between October 2001 and October 2002. Our choice of topics in basic immunology included the description of T-bet as a determinant factor for T(H)1 differentiation, the role of the activation-induced cytosine deaminase gene in B-cell development, the characterization of CD4(+)CD25(+) regulatory T cells, and the use of dynamic imaging to study MHC class II transport and T-cell and dendritic cell membrane interactions. Articles related to clinical immunology that were selected for review include the description of immunodeficiency caused by caspase 8 deficiency; a case series report on X-linked agammaglobulinemia; the mechanism of action, efficacy, and complications of intravenous immunoglobulin; mechanisms of autoimmunity diseases; and advances in HIV pathogenesis and vaccine development. We also reviewed two articles that explore the possible alterations of the immune system caused by spaceflights, a new field with increasing importance as human space expeditions become a reality in the 21st century.
Central nervous system infections represents a group of life-threatening diseases that present a formidable challenge to physicians. Despite the development of effective antimicrobial agents and modern surgical techniques, significant mortality and morbidity with CNS infections persist. Since the introduction of computed tomography, there is evidence of a marked decrease in mortality among patients with brain abscesses, although the morbidity has not changed significantly. CT correlation with pathology of the various CNS infections may aid in earlier diagnosis and bring about further disease in morbidity and mortality. Infections reach the brain or meninges mainly by two routes: (1) hematogenous dissemination from a distant infective focus to the meninges, corticomedullary junction, and choroid plexus; (2) direct extension by bony erosion for an adjacent focus of suppuration (otitis, mastoidits, sinusitis), by transmission along anaostomotic veins from the face, scalp, and orbits, and by transmission along cranial nerves following neurosurgery or traumatic craniocerebral wounds. Certain external factors serve to enhance the risk of intracranial infections, such as radiation; immunosuppressive or steroid therapy; cyanotic congenital heart disease; systemic illness such as diabetes mellitus, alcoholism, or cirrhosis; leukemia, lymphoma, or agammaglobulinemia; severe body stress; midline bony fusion defects; surgical or traumatic craniocerebral injury; and pulmonary or other systemic infections
Bonnie K Harrington
Full Text Available Acalabrutinib (ACP-196 is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL. First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR was 25% (5/20 with a median progression free survival (PFS of 22.5 days. Clinical benefit was observed in 30% (6/20 of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL.
Full Text Available The main clinical presentation of patients with primary antibody deficiency (PAD incorporates upper respiratory tract infections comprising otitis media, sinusitis and pneumonia. This study was designed to investigate clinical and paraclinical otological complications in major types of PAD. A cross sectional study was conducted on 55 PAD patients with diagnosis of selective IgA deficiency, common variable immunodeficiency (CVID, X-linked agammaglobulinemia (XLA, and hyper IgM syndrome. All patients underwent otological examinations, audiometry, and auditory brain stem response. Otological complications were detected in 54.5% of PAD patients. Conductive hearing loss was the main finding amongst PID patients (73.3% followed by sensorineural hearing loss which was present in 8 cases. Otitis media with effusion (21.8%, chronic otitis media (27.2%, tympanosclerosis with intact tympanic membrane (5.4% and auditory neuropathy (3.6% were most important found complications. CVID and XLA patients with prophylactic usage of antibiotics had lower rate of audiological complications (p=0.04 and otitis media with effusion (p=0.027. As our results showed, asymptomatic otological findings were not rare in PAD patients; therefore, a systematic otological investigation is recommended as an integral part of the management and follow-up of these patients.
Rita R Barbosa
Full Text Available IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17 share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID, defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21(lowCD38(low. Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.
Full Text Available Primary immunodeficiencies (PID are congenital disorders of immune competence, which are mainly characterized by a pathological susceptibility to infection. More than 240 PID disease entities have been defined so far, accounting for a broad spectrum of clinical symptoms and severity. Severe PID are increasingly becoming appreciated as a relevant health problem, and diagnostic procedures and screening profiles to allow earliest possible diagnosis on a population scale have already been developed in the USA and few European countries. The most severe PID are characterized by significant mortality in the first years of life, as well as serious morbidity with irreversible organ damage. This applies in particular to PID that are defined by the absence or functional anergy of T-lymphocytes (severe combined immunodeficiency; SCID or B-lymphocytes (e.g., X-linked agammaglobulinemia; XLA. A strategy to improve the outcome of severe PID by prompt diagnosis and immediate adequate treatment is screening newborns for the presence of T and B cells.
Harrington, Bonnie K; Gardner, Heather L; Izumi, Raquel; Hamdy, Ahmed; Rothbaum, Wayne; Coombes, Kevin R; Covey, Todd; Kaptein, Allard; Gulrajani, Michael; Van Lith, Bart; Krejsa, Cecile; Coss, Christopher C; Russell, Duncan S; Zhang, Xiaoli; Urie, Bridget K; London, Cheryl A; Byrd, John C; Johnson, Amy J; Kisseberth, William C
Acalabrutinib (ACP-196) is a second-generation inhibitor of Bruton agammaglobulinemia tyrosine kinase (BTK) with increased target selectivity and potency compared to ibrutinib. In this study, we evaluated acalabrutinib in spontaneously occurring canine lymphoma, a model of B-cell malignancy similar to human diffuse large B-cell lymphoma (DLBCL). First, we demonstrated that acalabrutinib potently inhibited BTK activity and downstream effectors in CLBL1, a canine B-cell lymphoma cell line, and primary canine lymphoma cells. Acalabrutinib also inhibited proliferation in CLBL1 cells. Twenty dogs were enrolled in the clinical trial and treated with acalabrutinib at dosages of 2.5 to 20mg/kg every 12 or 24 hours. Acalabrutinib was generally well tolerated, with adverse events consisting primarily of grade 1 or 2 anorexia, weight loss, vomiting, diarrhea and lethargy. Overall response rate (ORR) was 25% (5/20) with a median progression free survival (PFS) of 22.5 days. Clinical benefit was observed in 30% (6/20) of dogs. These findings suggest that acalabrutinib is safe and exhibits activity in canine B-cell lymphoma patients and support the use of canine lymphoma as a relevant model for human non-Hodgkin lymphoma (NHL). PMID:27434128
Full Text Available Epidemiological studies have shown wide geographical and racial variation in the prevalence and patterns of immunodeficiency disorders. To determine the frequency of primary immunodeficiencies (PID in Iran, the Iranian primary Immunodeficiencies Registry (IPIDR was organized in 1999. the diagnosis of immunodeficiency in our patients was based on standard criteria. The patient’s data were extracted, by using a uniform questionnaire from their hospital records. Three hundred and twenty eight patients with PID have been registered in our registry till 2000. Among these patients, the following frequencies were found: predominantly antibody deficiency in 48.48% of patients (n=159, T-cell disorders in 25.91% (n=85, phagocytic disorders in 24.7% (n=81, and complement deficiencies in 0.91% (n=3. Common variable immunodeficiency was the most frequent disorder (n=73, followe by chronic granulomatous disease (n=55, ataxia telangiectasia (n=39, x-linked agammaglobulinemia (n=35, selective IgA deficiency (n=34. This study reveals that antibody deficiencies are the most frequent diagnosed primary immunodeficiency disorder in our patients, which is similar to that observed in other registries. A comparative study shows some differences between our results and other registries
This paper reviews the chest radiographs and high-resolution CT (HRCT) scans in patients with immunodeficiency disorders and define the role of HRCT. Thirty-three cases were retrospectively graded according to the consensus of two radiologists. Patients with HIV seropositivity and asthma were excluded. HRCT was performed in 12 cases with standard techniques. Diagnoses included common variable hypogammaglobulinemia (n = 19), X-linked agammaglobulinemia (n = 4), chronic mucocutaneous candidiasis (n = 4), and selective immunoglobulin g deficiencies (n = 2). Chest radiographs showed bronchiectasis in 11 of 33 cases with a predominant lower lobe distribution (82%). Nodules were present in six cases and mucus plugs in four cases. HRCT showed bronchiectasis in nine of 12 cases; in five of these nine cases, bronchiectasis was not apparent on chest radiographs. Other HRCT findings included segmental air trapping (four of 12), mucus plugs (three of 12), hazy consolidation (four of 12), nodules (five of 12), and bronchiolectasis (two of 12). Therapy was altered in seven of 12 cases in which HRCT was performed. Most pertinent to clinical management were the presence of a thymoma (n = 1) and severe focal of diffuse bronchiectasis
Full Text Available Primary Humoral Immunodeficiencies (PHID are currently increasingly being recognized. Patients with PHID frequently show respiratory complications.The objectives of the study is to determine the clinical spectrum of respiratory diseases in patients with PHID."We extracted data from the clinical files of patients with PHID, diagnosed according to WHO criteria. We encountered 125 patients (84 males, with the diagnosis of primary antibody deficiency including common-variable immunodeficiency (64 pts, x-linked agammaglobulinemia (29 pts, IgA deficiency (20 pts, IgG-subc!ass deficiency (8 pts, and hyper-IgM syndrome (4 pts. The mean age of the patients at the time of study was 11 years. In the evolution of their disease, 92 cases (73.6% developed upper respiratory tract infections, among which acute otitis media (68 pts, 54.4%, sinusitis (61 pts, 48.8%, and pharyngitis (12 pts, 10.4% were found to be the most frequent. Among the lower respiratory tract infections, pneumonia was the most common occurance (91 pts, 72.8%. The other lower respiratory tract complications were: bronchiectasis (22 pts, 17.6%, bronchitis (8 pts, tuberculosis (6 pts, lung abscess (4 pts, and Pneumocystis carinii pneumonia (2 pts.Respiratory infections constitute the most common presenting symptom of patients with primary humoral immunodeficiency. There may be some differences in the type and frequency of infections in each of these disorders.
Full Text Available Primary antibody deficiency (common variable immunodeficiency, Hyper IgM, X-linked agammaglobulinemia and selective Ig A deficiency is a group of heterogeneous diseases characterized by defective antibody production. In primary hypogammaglobulinemias, particularly in patients with common variable immunodeficiency there is an increased generation of reactive oxygen species from monocytes which may be important for both immunopathogenesis and clinical manifestations. The generation of toxic oxygen metabolites may contribute to inflammation and tissue damage associated with phagocytic infiltration, and play role in the pathogenesis of malignancies, autoimmune disorders, acute and chronic pulmonary diseases seen in these patients. In primary immunodeficiencies and functional antibody deficiencies, IVIG act as replacement therapy and several mechanisms of IVIG action have been postulated. In vitro studies with human granulocytes showed stimulation of respiratory burst and promotion of bacterial killing by IVIG. In adult patients with primary humoral immunodeficiency, treated with IVIG showed that IVIG does not affect superoxide generation. We investigated superoxide generation from PMNL in 35 children with hyper IgM syndrome, XLA, CVID and IgA deficiency and 13 healthy children. We also explored the effect of IVIG administration on superoxide generation from granulocytes, white cell count, absolute neutrophil count, absolute lymphocyte count and quantitative CRP levels. There was a substantial increase in superoxide generation from PMNL in patients with XLA, CVID and IgA deficiency. Comparison of the superoxide generation before, 24 hours and one week after IVIG treatment showed no difference. In patients with CVID, quantitative CRP levels before and 24 hours after IVIG revealed significant difference. Other parameters were not changed. It can be concluded that enhanced superoxide generation in patients with XLA, CVID, Ig A deficiency may result from
Full Text Available Bruton's tyrosine kinase (Btk is a Tec family non-receptor tyrosine kinase that plays a critical role in immune signaling and is associated with the immunological disorder X-linked agammaglobulinemia (XLA. Our previous findings showed that the Tec kinases are allosterically activated by the adjacent N-terminal linker. A single tryptophan residue in the N-terminal 17-residue linker mediates allosteric activation, and its mutation to alanine leads to the complete loss of activity. Guided by hydrogen/deuterium exchange mass spectrometry results, we have employed Molecular Dynamics simulations, Principal Component Analysis, Community Analysis and measures of node centrality to understand the details of how a single tryptophan mediates allostery in Btk. A specific tryptophan side chain rotamer promotes the functional dynamic allostery by inducing coordinated motions that spread across the kinase domain. Either a shift in the rotamer population, or a loss of the tryptophan side chain by mutation, drastically changes the coordinated motions and dynamically isolates catalytically important regions of the kinase domain. This work also identifies a new set of residues in the Btk kinase domain with high node centrality values indicating their importance in transmission of dynamics essential for kinase activation. Structurally, these node residues appear in both lobes of the kinase domain. In the N-lobe, high centrality residues wrap around the ATP binding pocket connecting previously described Catalytic-spine residues. In the C-lobe, two high centrality node residues connect the base of the R- and C-spines on the αF-helix. We suggest that the bridging residues that connect the catalytic and regulatory architecture within the kinase domain may be a crucial element in transmitting information about regulatory spine assembly to the catalytic machinery of the catalytic spine and active site.
Mohammad, Dara K; Nore, Beston F; Hussain, Alamdar; Gustafsson, Manuela O; Mohamed, Abdalla J; Smith, C I Edvard
Bruton's tyrosine kinase (Btk) is crucial for B-lymphocyte activation and development. Mutations in the Btk gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Using tandem mass spectrometry, 14-3-3ζ was identified as a new binding partner and negative regulator of Btk in both B-cell lines and primary B lymphocytes. The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3ζ binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. The double-alanine, S51A/T495A, replacement mutant failed to bind 14-3-3ζ, while phosphomimetic aspartate substitutions, S51D/T495D, caused enhanced interaction. The phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 abrogated S51/T495 phosphorylation and binding. A newly characterized 14-3-3 inhibitor, BV02, reduced binding, as did the Btk inhibitor PCI-32765 (ibrutinib). Interestingly, in the presence of BV02, phosphorylation of Btk, phospholipase Cγ2, and NF-κB increased strongly, suggesting that 14-3-3 also regulates B-cell receptor (BCR)-mediated tonic signaling. Furthermore, downregulation of 14-3-3ζ elevated nuclear translocation of Btk. The loss-of-function mutant S51A/T495A showed reduced tyrosine phosphorylation and ubiquitination. Conversely, the gain-of-function mutant S51D/T495D exhibited intense tyrosine phosphorylation, associated with Btk ubiquitination and degradation, likely contributing to the termination of BCR signaling. Collectively, this suggests that Btk could become an important new candidate for the general study of 14-3-3-mediated regulation.
Diego S. Fernández Romero
Full Text Available Las inmunodeficiencias humorales (IDH comprenden a un grupo de enfermedades caracterizadas por la imposibilidad de desarrollar una respuesta inmune efectiva mediada por anticuerpos. Estos pacientes presentan infecciones, principalmente por bacterias extracelulares capsuladas, del tracto respiratorio. El objetivo de nuestro estudio fue describir las características clínicas de una población de 128 pacientes derivados con sospecha o diagnóstico de IDH a tres centros para inmunodeficiencias de adultos, asistidos entre junio de 2004 y diciembre de 2009. Tres (2.3% consultaron por infecciones recurrentes en una sola oportunidad sin datos suficientes para su adecuada clasificación y fueron excluidos del estudio. De los 125 pacientes restantes, en 21 (16.8% se descartó IDH, en 8 (6.4% se diagnosticó inmunodeficiencia humoral secundaria (IDHS y en 96 (76.8% inmunodeficiencia humoral primaria (IDHP. Las causas de IDHS fueron: en un caso enfermedad renal, en uno uso de fenitoína, dos casos: gammapatía monoclonal y en 4 linfoma B. Las causas de las 96 IDHP fueron: 57 inmunodeficiencia común variable, 12 agammaglobulinemia ligada al cromosoma X, 10 deficiencia selectiva de IgA, 7 deficiencia de IgG1, 3 síndrome hiper-IgM, 3 deficiencia de IgM, 2 síndrome linfoproliferativo ligado al cromosoma X, un síndrome de Good y una deficiencia funcional de anticuerpos. Sesenta y siete pacientes estaban en seguimiento en el momento de la finalización del estudio, 25 de ellos estaban en seguimiento al iniciarse el estudio. De los 58 pacientes en seguimiento con indicación de tratamiento sustitutivo con gammaglobulina, 54 se encontraban en tratamiento al finalizar el estudio. En cuatro pacientes no se pudo confirmar el diagnóstico de IDHP.
Renata Cristina de Angelo Calsaverini Leal
Full Text Available Recurrent infections are a consequence of a series of genetic diseases characterized by deficiency in the immunological response. One of these diseases is the agammaglobulinemia, which is characterized by the basic defect in the maturation of lymphocytes B. The carrier of this kind of immunodeficiency, which is linked to the X (XLA chromosome, has had primary pneumonias that have evolved into secondary pneumonias (chronic lungs with sequelae after the third or fourth year of life. The clinical and rehabilitative quest for prophylaxis against the XLA immunodeficiency is accomplished in order to avoid the evolution of the bacterial infection into sequelae and loss of pulmonary function, which propitiates the recurrence of the disease and deteriorates the life quality of the patient. Forty cases of recurrent respiratory infections were studied. Some of them were associated with primary respiratory diseases without investigation of serum immunoglobulins and some were not. Casuistics was performed according to data from medical records with pertinent treatments collected from January 1997 to September 2004 at the Specialized Physiotherapy Center. Age average was 2.7 years of life. It is statistically impossible to precise results concerning only the immunosuppressed patients due to the lack of specific diagnosis. That is explained by the fact that recurrent XLA pneumonias may be attributed to the gastroesophageal reflux disease or to bronchial asthma. However, the improved results showed by the pulmonary function as preventive strategy were attributed to the respiratory physiotherapy, since intravenous immunoglobulin replacement therapies were not performed. Respiratory physiotherapy acts as a supportive factor in the healing process and occupies a fundamental role in the prophylaxis against recurrent respiratory clinical features, especially those of obstructive and secretionary characteristics.
Witte Owen N
Full Text Available Abstract Background Bruton's tyrosine kinase (Btk is essential for B cell development and function. Mutations of Btk elicit X-linked agammaglobulinemia in humans and X-linked immunodeficiency in the mouse. Btk has been proposed to participate in B cell antigen receptor-induced signaling events leading to activation of phospholipase C-γ2 (PLCγ2 and calcium mobilization. However it is unclear whether Btk activation is alone sufficient for these signaling events, and whether Btk can activate additional pathways that do not involve PLCγ2. To address such issues we have generated Btk:ER, a conditionally active form of the kinase, and expressed it in the PLCγ2-deficient DT40 B cell line. Results Activation of Btk:ER was sufficient to induce multiple B cell signaling pathways in PLCγ2-sufficient DT40 cells. These included tyrosine phosphorylation of PLCγ2, mobilization of intracellular calcium, activation of extracellular signal-regulated kinase (ERK and c-Jun NH2-terminal kinase (JNK mitogen-activated protein kinase (MAPK pathways, and apoptosis. In DT40 B cells deficient for PLCγ2, Btk:ER activation failed to induce the signaling events described above with the consequence that the cells failed to undergo apoptosis. Conclusions These data suggest that Btk:ER regulates downstream signaling pathways primarily via PLCγ2 in B cells. While it is not known whether activated Btk:ER precisely mimics activated Btk, this conditional system will likely facilitate the dissection of the role of Btk and its family members in a variety of biological processes in many different cell types.
Full Text Available Primary antibody deficiencies (PAD are a group of immune system disorders, associated with decreased levels of secretory and protective immunoglobulins. Because of the important role of immunoglobulins in the protection of oral cavity, patients with PADs are more susceptible to dental caries or oral manifestations.This study was performed to investigate the oral and dental manifestations of PADs patients. In this study, 33 patients with PADs (21 common variable immunodeficiency, 8 X- linked agammaglobulinemia and 4 hyper IgM syndrome and 66 controls were examined; the number of decayed, missed and filled teeth (DMFT were investigated.Aphthous was the most frequent manifestation in PADs patients (38.7%, which wassignificantly16.7% higher than the controls (p=0.03. The patients with PADs showed significantly higher presentation of other oral and dental manifestations, including herpes sores, candidiasis tonsillitis, gingivitis, calculus, enamel hypoplasia and other ulcerations. The mean DMFT scores were 6.15±3.6 and 1.93±0.4 in PADs patients and controls, respectively (p<0.001. Although the patients with common variable immunodeficiency had higher means of DMFT in comparison with other groups of PADs, this difference was not statistically significant.This study showed significantly higher frequency of oral and dental manifestations in the patients with PADs compared to controls. Therefore, regular examination of oral cavity could be suggested in this group of immunodeficient patients.
Full Text Available Drosophila Btk29A is the ortholog of mammalian Btk, a Tec family nonreceptor tyrosine kinase whose deficit causes X-linked agammaglobulinemia in humans. The Btk29AficP mutation induces multiple abnormalities in oogenesis, including the growth arrest of ring canals, large intercellular bridges that allow the flow of cytoplasm carrying maternal products essential for embryonic development from the nurse cells to the oocyte during oogenesis. In this study, inactivation of Parcas, a negative regulator of Btk29A, was found to promote Btk29A accumulation on ring canals with a concomitant increase in the ring canal diameter, counteracting the Btk29AficP mutation. This mutation markedly reduced the accumulation of phosphotyrosine on ring canals and in the regions of cell-cell contact, where adhesion-supporting proteins such as DE-cadherin and β-catenin ortholog Armadillo (Arm are located. Our previous in vitro and in vivo analyses revealed that Btk29A directly phosphorylates Arm, leading to its release from DE-cadherin. In the present experiments, immunohistological analysis revealed that phosphorylation at tyrosine 150 (Y150 and Y667 of Arm was diminished in Btk29AficP mutant ring canals. Overexpression of an Arm mutant with unphosphorylatable Y150 inhibited ring canal growth. Thus Btk29A-induced Y150 phosphorylation is necessary for the normal growth of ring canals. We suggest that the dissociation of tyrosine-phosphorylated Arm from DE-cadherin allows dynamic actin to reorganize, leading to ring canal expansion and cell shape changes during the course of oogenesis.
Hamada-Kawaguchi, Noriko; Nishida, Yasuyoshi; Yamamoto, Daisuke
Drosophila Btk29A is the ortholog of mammalian Btk, a Tec family nonreceptor tyrosine kinase whose deficit causes X-linked agammaglobulinemia in humans. The Btk29AficP mutation induces multiple abnormalities in oogenesis, including the growth arrest of ring canals, large intercellular bridges that allow the flow of cytoplasm carrying maternal products essential for embryonic development from the nurse cells to the oocyte during oogenesis. In this study, inactivation of Parcas, a negative regulator of Btk29A, was found to promote Btk29A accumulation on ring canals with a concomitant increase in the ring canal diameter, counteracting the Btk29AficP mutation. This mutation markedly reduced the accumulation of phosphotyrosine on ring canals and in the regions of cell-cell contact, where adhesion-supporting proteins such as DE-cadherin and β-catenin ortholog Armadillo (Arm) are located. Our previous in vitro and in vivo analyses revealed that Btk29A directly phosphorylates Arm, leading to its release from DE-cadherin. In the present experiments, immunohistological analysis revealed that phosphorylation at tyrosine 150 (Y150) and Y667 of Arm was diminished in Btk29AficP mutant ring canals. Overexpression of an Arm mutant with unphosphorylatable Y150 inhibited ring canal growth. Thus Btk29A-induced Y150 phosphorylation is necessary for the normal growth of ring canals. We suggest that the dissociation of tyrosine-phosphorylated Arm from DE-cadherin allows dynamic actin to reorganize, leading to ring canal expansion and cell shape changes during the course of oogenesis.
Gaschignard, Jean; Levy, Corinne; Chrabieh, Maya; Boisson, Bertrand; Bost-Bru, Cécile; Dauger, Stéphane; Dubos, François; Durand, Philippe; Gaudelus, Joël; Gendrel, Dominique; Gras Le Guen, Christèle; Grimprel, Emmanuel; Guyon, Gaël; Jeudy, Catherine; Jeziorski, Eric; Leclerc, Francis; Léger, Pierre-Louis; Lesage, Fabrice; Lorrot, Mathie; Pellier, Isabelle; Pinquier, Didier; de Pontual, Loïc; Sachs, Philippe; Thomas, Caroline; Tissières, Pierre; Valla, Frédéric V.; Desprez, Philippe; Frémeaux-Bacchi, Véronique; Varon, Emmanuelle; Bossuyt, Xavier; Cohen, Robert; Abel, Laurent; Casanova, Jean-Laurent; Puel, Anne; Picard, Capucine
Background. About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD. Methods. We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines. Results. We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X-linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P 2 years, as PIDs may be discovered in up to 26% of cases. PMID:24759830
Lanyi, A; Li, B; Li, S; Talmadge, C B; Brichacek, B; Davis, J R; Kozel, B A; Trask, B; van den Engh, G; Uzvolgyi, E; Stanbridge, E J; Nelson, D L; Chinault, C; Heslop, H; Gross, T G; Seemayer, T A; Klein, G; Purtilo, D T; Sumegi, J
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family, 43. In this study we estimated the deletion in XLP patient 43-004 by dual-laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mb of DNA sequence. From a human chromosome Xq25-specific yeast artificial chromosome (YAC) sublibrary, five YACs containing DNA sequences deleted in patient 43-004 have been isolated. Sequence-tagged sites (STSs) from these YACs have been used to identify interstitial deletions in unrelated XLP patients. Three more families with interstitial deletions were found. Two of the patients (63-003 and 73-032) carried an interstitial deletion of 3.0 Mb overlapping the 43-004 deletion. In one XLP patient (30-011) who exhibited the characteristic postinfectious mononucleosis phenotype of XLP with hypogammaglobulinemia and malignant lymphoma, a deletion of approximately 250 kb was detected overlapping the deletion detected in patients 43-004, 63-003, and 73-032. A YAC contig of 2.2 Mb spanning the XLP critical region, whose orientation on chromosome X was determined by double-color fluorescence in situ hybridization and which consists of 15 overlapping YAC clones, has been constructed. A detailed restriction enzyme map of the region has been constructed. YAC insert sizes were determined by counter-clamped homogenous electric field gel electrophoresis. Chimerism of YACs was determined by FISH and restriction mapping. On the basis of lambda subclones, YAC end-derived plasmids, and STSs with an average spacing of 100 kb, a long-range physical map was constructed using 5 rare-cutter restriction
Full Text Available Primary infection with varicella zoster virus (VZV results in varicella (more commonly known as chickenpox after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles, a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax and herpes zoster (Zostavax are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have
Inmunodeficiencias humorales: Un estudio en tres Centros de Inmunología Clínica de adultos en la Ciudad de Buenos Aires Antibody deficiencies: A survey from three Clinical Immunology Centers for adults in Buenos Aires City
Diego S. Fernández Romero
Full Text Available Las inmunodeficiencias humorales (IDH comprenden a un grupo de enfermedades caracterizadas por la imposibilidad de desarrollar una respuesta inmune efectiva mediada por anticuerpos. Estos pacientes presentan infecciones, principalmente por bacterias extracelulares capsuladas, del tracto respiratorio. El objetivo de nuestro estudio fue describir las características clínicas de una población de 128 pacientes derivados con sospecha o diagnóstico de IDH a tres centros para inmunodeficiencias de adultos, asistidos entre junio de 2004 y diciembre de 2009. Tres (2.3% consultaron por infecciones recurrentes en una sola oportunidad sin datos suficientes para su adecuada clasificación y fueron excluidos del estudio. De los 125 pacientes restantes, en 21 (16.8% se descartó IDH, en 8 (6.4% se diagnosticó inmunodeficiencia humoral secundaria (IDHS y en 96 (76.8% inmunodeficiencia humoral primaria (IDHP. Las causas de IDHS fueron: en un caso enfermedad renal, en uno uso de fenitoína, dos casos: gammapatía monoclonal y en 4 linfoma B. Las causas de las 96 IDHP fueron: 57 inmunodeficiencia común variable, 12 agammaglobulinemia ligada al cromosoma X, 10 deficiencia selectiva de IgA, 7 deficiencia de IgG1, 3 síndrome hiper-IgM, 3 deficiencia de IgM, 2 síndrome linfoproliferativo ligado al cromosoma X, un síndrome de Good y una deficiencia funcional de anticuerpos. Sesenta y siete pacientes estaban en seguimiento en el momento de la finalización del estudio, 25 de ellos estaban en seguimiento al iniciarse el estudio. De los 58 pacientes en seguimiento con indicación de tratamiento sustitutivo con gammaglobulina, 54 se encontraban en tratamiento al finalizar el estudio. En cuatro pacientes no se pudo confirmar el diagnóstico de IDHP.Antibody deficiency (AD comprises a group of diseases characterized by the inability to develop an effective antibody mediated immune response. These patients suffer mainly of encapsulated extracellular bacterial
刘珺; 王荃; 曾健生; 李峥; 钱素云
Objective To study the clinical features of invasive pneumococcus disease (IPD) with resistance to antimicrobial agents in children,and to improve the diagnosis and treatment of this disease.Methods The clinical data from 21 IPD patients younger than 13 years old were collected from January 2008 through December 2010 in Pediatric Intensive Care Unit in Beijing Children's Hospital for retrospective analysis. Specimens of blood,pleural effusion,cerebrospinal fluid and soft tissue aspirated were collected from these children,and 23 strains of streptococcus pneumonia (SP) were cultured,isolated and confirmed,and the antibiotics susceptibility to penicillin and other antibiotics of these strains were assayed.Results Among the 21 IPD children,the ratio of male to female was 0.9∶1,and the age was 5 months to 13 years,with 61.9％ of them under 2 years.Of them,12 patients (57.1％ ) had purulent pleurisy,and 1 (4.8％ )patient had an underlying disease diagnosed to be X - linked agammaglobulinemia (XLA).There was no seasonal difference in the occurrence rate of this disease. Eight (38.1％) patients were cured,11(52.4％ ) were improved,while 2 (9.5％ ) patients not improved without death.There was no statistically significant difference in the annual detection rate of invasive SP (x2 =3.711,P =0.156).The incidences of penicillin-intermediate susceptibility SP (PISP) and penicillin-resistant SP (PRSP) were 47.8％ and 26.1％ respectively.The rate of resistance to multiple antibiotics was 91.3％.Conclusions Children aged less than 5 years,especially younger than 2 years,are prone to IPD,and purulent pleurisy and septicemia are often seen in this disease. Some patients had the underlying diseases.The complications included hemophagocytic syndrome,acute respiratory distress syndrome,septic shock,bronchial pleural fistula and so on.The multidrug resistance rate was 91.3％.It is important to put great emphasis on the monitoring antibiotics resistance to invasive