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Ulrich Salzer - One of the best experts on this subject based on the ideXlab platform.
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heterozygous alterations of tnfrsf13b taci in tonsillar hypertrophy and sarcoidosis
Clinical & Developmental Immunology, 2013Co-Authors: Matthaios Speletas, Ulrich Salzer, Zoe Florou, Efthimia Petinaki, Zoe Daniil, Fotini Bardaka, Konstantinos I Gourgoulianis, Charalampos Skoulakis, Anastasios E GermenisAbstract:TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.
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sequence variants of the tnfrsf13b gene in czech cvid and igad patients in the context of other populations
Human Immunology, 2012Co-Authors: Tomas Freiberger, Ulrich Salzer, Barbora Ravcukova, Lucie Grodecka, Z Pikulova, Dagmar Stikarovska, Sava Pesak, Pavel Kuklinek, Jiři Jarkovský, Jiři LitzmanAbstract:Mutations in the TNFRSF13B gene, encoding TACI, have been found in common variable immunodefi- ciency (CVID) and selective IgA deficient (IgAD) patients, but only the association with CVID seems to be significant. In this study, Czech CVID, IgAD and primary hypo/dysgammaglobulinemic (HG/DG) patients were screened for all TNFRSF13B sequence variants. The TNFRSF13B gene was mutated in 4/70 CVID patients (5.7%), 9/161 IgAD patients (5.6%), 1/17 HG/DG patient (5.9%) and none of 195 controls. Eight different mutations were detected, including the most frequent p.C104R and p.A181E mutations as well as 1 novel missense mutation, p.R189K. A significant association of TNFRSF13B gene mutations was observed in both CVID (p = 0.01) and IgAD (p = 0.002) Czech patients. However, when combined with all published data, only the association with CVID remained significant compared with the controls (9.9% vs. 3.2%, p < 10^6), while statistical significance disappeared for IgAD (5.7% vs. 3.2%, p = 0.145). The silent mutation p.P97P was shown to be associated significantly with CVID compared with the controls in both Czech patients (allele frequency 4.3% vs. 0.2%, p = 0.01) and in connection with the published data (5.1% vs. 1.8%, p = 0.003). The relevance of some TNFRSF13B gene variants remains unclear and needs to be elu- cidated in future studies.
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the c76r transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and b cell homeostasis in heterozygous and homozygous mice
The Journal of Allergy and Clinical Immunology, 2011Co-Authors: Chiara Bacchelli, Ulrich Salzer, Sylvie Buckridge, Karen F Buckland, Pascal Schneider, Adrian J Thrasher, Bobby H GasparAbstract:Background Mutations in TNFRSF13B , the gene encoding transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), are found in 10% of patients with common variable immunodeficiency. However, the most commonly detected mutation is the heterozygous change C104R, which is also found in 0.5% to 1% of healthy subjects. The contribution of the C104R mutation to the B-cell defects observed in patients with common variable immunodeficiency therefore remains unclear. Objective We sought to define the functional consequences of the C104R mutation on B-cell function. Methods We performed in vitro studies of TACI C104R expression and signaling. A knock-in mouse with the equivalent mutation murine TACI (mTACI) C76R was generated as a physiologically relevant model of human disease. We examined homozygous and heterozygous C76R mutant mice alongside wild-type littermates and studied specific B-cell lineages and antibody responses to T cell–independent and T cell–dependent challenge. Results C104R expression and ligand binding are significantly diminished when the mutant protein is expressed in 293T cells or in patients' cell lines. This leads to defective nuclear factor κB activation, which is proportionally restored by reintroduction of wild-type TACI. Mice heterozygous and homozygous for mTACI C76R exhibit significant B-cell dysfunction with splenomegaly, marginal zone B-cell expansion, diminished immunoglobulin production and serological responses to T cell–independent antigen, and abnormal immunoglobulin synthesis. Conclusions These data show that the C104R mutation and its murine equivalent, C76R, can significantly disrupt TACI function, probably through haploinsufficiency. Furthermore, the heterozygous C76R mutation alone is sufficient to disturb B-cell function with lymphoproliferation and immunoglobulin production defects.
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novel mutations in taci tnfrsf13b causing common variable immunodeficiency
Journal of Clinical Immunology, 2009Co-Authors: Javad Mohammadi, Ulrich Salzer, Qiang Panhammarstrom, Astrid Bergbreiter, Chonghai Liu, Asghar Aghamohammadi, Nima Rezaei, Ali Akbar Amirzargar, Mostafa Moin, Lennart HammarstromAbstract:Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production. The disorder is also characterized by co-occurrence of autoimmune, lymphoproliferative, and granulomatous diseases. Mutations in the gene encoding TACI (Transmembrane Activator and CAML Interactor, TNFRSF13B) were previously found to be associated with CVID. We therefore sequenced TNFRSF13B gene in a cohort of 48 Iranian CVID patients. Expression of TACI and binding of A proliferation-inducing ligand (APRIL) were tested by FACS. We identified one patient with a homozygous G to T substitution in the TNFRSF13B gene at the splice site of intron 1 (c.61+1G>T), which abolished expression of the TACI molecule and binding capacity of APRIL. This represents the second CVID patient in the world with a complete absence of TACI expression. B cell lines from family members carrying the same mutation in a heterozygous form showed a reduced level of TACI expression and APRIL-binding capacity, suggesting a gene dosage effect. In addition, we found the previously recognized C104R and C172Y mutations in a heterozygous form in two patients with CVID and one, novel, heterozygous P42T mutation. TACI mutations were observed in Iran CVID patients in a similar frequency as in other Caucasian populations. The novel mutations identified in this study support the notion of a crucial role for TACI in B cell differentiation.
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relevance of biallelic versus monoallelic tnfrsf13b mutations in distinguishing disease causing from risk increasing tnfrsf13b variants in antibody deficiency syndromes
Blood, 2009Co-Authors: Ulrich Salzer, Chiara Bacchelli, Sylvie Buckridge, Qiang Panhammarstrom, Stephanie Jennings, Vassilis Lougaris, Astrid Bergbreiter, Tina Hagena, Jennifer Birmelin, Alessandro PlebaniAbstract:TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD−CD27+ B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
Anastasios E Germenis - One of the best experts on this subject based on the ideXlab platform.
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TNFRSF13C baffr p21r and h159y polymorphisms in multiple sclerosis
Multiple sclerosis and related disorders, 2020Co-Authors: Panagiotis Ntellas, Anastasios E Germenis, Efthimios Dardiotis, Eirini Sevdali, Vasileios Siokas, Athinamaria Aloizou, Gerasimina Tsinti, Georgios M Hadjigeorgiou, Hermann Eibel, Matthaios SpeletasAbstract:Recent studies implicate B cells in multiple sclerosis (MS) pathogenesis, and consequently, several molecules participating in B cell survival and proliferation, including B-cell activating factor (BAFF), have recently been analyzed in MS patients. BAFF mediates its function through binding to three receptors; among them, its interaction with the BAFF receptor (BAFFR) is crucial in mediating its survival function. Interestingly, two common polymorphisms of the TNFRSF13C gene, encoding BAFFR, P21R (rs77874543) and H159Y (rs61756766), have been reported to affect BAFFR assembly and signaling. In order to evaluate the possible contribution of BAFFR in MS pathogenesis and/or phenotype, we analyzed both TNFRSF13C/BAFFR polymorphisms in 486 MS patients in relation to their disease severity, their disability status and the age of disease onset and duration. As control group, we used allele frequencies extracted from the Exome Aggregation Consortium (ExAC) Browser. Interestingly, we found a higher prevalence of the H159Y polymorphism in MS patients, suggesting that enhanced BAFFR-signaling might contribute to the disease pathogenesis.
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heterozygous alterations of tnfrsf13b taci in tonsillar hypertrophy and sarcoidosis
Clinical & Developmental Immunology, 2013Co-Authors: Matthaios Speletas, Ulrich Salzer, Zoe Florou, Efthimia Petinaki, Zoe Daniil, Fotini Bardaka, Konstantinos I Gourgoulianis, Charalampos Skoulakis, Anastasios E GermenisAbstract:TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies.
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tnfrsf13b taci alterations in greek patients with antibody deficiencies
Journal of Clinical Immunology, 2011Co-Authors: Matthaios Speletas, Fotini Bardaka, Antigoni Mamara, Efimia Papadopouloualataki, George Iordanakis, Kyriaki Liadaki, Maria Kanariou, Anastasios E GermenisAbstract:TNFRSF13B/TACI defects have recently been associated with common variable immunodeficiency (CVID) pathogenesis. Considering that TNFRSF13B/TACI is very polymorphic and the frequency of its alterations may be different in various ethnic groups, we analyzed their prevalence in 47 Greek patients with antibody deficiencies, including CVID (16 patients), IgAD (16 patients), selective IgG4D (11 patients), and transient hypogammaglobulinemia of infancy (4 patients). A rather high frequency of TNFRSF13B/TACI defects was identified in patients with selective IgG4D (18.18%). Moreover, a patient with CVID was heterozygous in the common C104R mutation (6.25%). Both his children and a further healthy individual carried the same mutation, albeit without recurrent infections and/or hypogammaglobulinemia. The common polymorphisms V220A and P251L were identified in all disease subgroups, in an almost similar frequency with that observed in 259 healthy controls. Our data provide further evidence that TNFRSF13B/TACI alterations are not causative of CVID. Possibly, they predispose to humoral deficiencies and/or contribute to their phenotype when combined with other immune gene alterations.
Raif S Geha - One of the best experts on this subject based on the ideXlab platform.
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tnfrsf13b genotypes control immune mediated pathology by regulating the functions of innate b cells
JCI insight, 2021Co-Authors: Mayara Garcia De Mattos Barbosa, Richard J Bram, Raif S Geha, Daniel Huynh, Adam R Lefferts, Hui Liu, Yu Zhang, Jenna Barnes, Milagros Samaniego, Ariella ShikanovAbstract:Host genes define the severity of inflammation and immunity but specific loci doing so are unknown. Here we show that TNFRSF13B variants which enhance defense against certain pathogens, also control immune-mediated injury of transplants, by regulating innate B cells' functions. Analysis of TNFRSF13B in human kidney transplant recipients revealed that 33% of the subjects with antibody-mediated rejection (AMR) but less than 6% of those with stable graft function had TNFRSF13B missense mutations. To explore mechanisms underlying aggressive immune responses we investigated allo-immunity and rejection in mice. Cardiac allografts in Tnfrsf13b-mutant mice underwent early and severe AMR. The dominance and precocity of AMR in Tnfrsf13b-deficient mice was not caused by increased alloantibodies. Rather, Tnfrsf13b mutations decreased "natural" IgM and compromised complement regulation leading to complement deposition in allografted hearts and autogenous kidneys. Thus, wild type TNFRSF13B and Tnfrsf13b support innate B cell functions that limit complement-associated inflammation; in contrast, common variants of these genes, intensify inflammatory responses that help clear microbial infections but allow inadvertent tissue injury to ensue. The wide variation in inflammatory reactions associated with TNFRSF13B diversity suggests polymorphisms could underlie variation in host defense and explosive inflammatory responses that sometimes enhances morbidity associated with immune responses.
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tnfrsf13b polymorphisms counteract microbial adaptation to natural iga
JCI insight, 2021Co-Authors: Jeffrey L Platt, Daniel Huynh, Adam R Lefferts, J Katta, C Kharas, Peter L Freddolino, Christine M Bassis, Christiane E Wobus, Mayara Garcia De Mattos Barbosa, Raif S GehaAbstract:TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.
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natural iga and tnfrsf13b polymorphism a double edged sword fueling balancing selection
bioRxiv, 2021Co-Authors: Jeffrey L Platt, Raif S Geha, Daniel Huynh, Adam R Lefferts, J Katta, C Kharas, Peter L Freddolino, Christine M Bassis, Christiane E Wobus, Richard J BramAbstract:TNFRSF13B encodes the "transmembrane-activator and CAML-interactor" (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we asked whether and how a common human dominant negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono-allelic or bi-allelic A144E variants of tnrsf13B, corresponding to A181E exhibited striking resistance to pathogenicity and transmission of C. rodentium, a murine pathogen that models enterohemorrhagic E. coli, and resistance was principally owed to deficiency of natural IgA in the intestine. In wild type mice with gut IgA and in mutant mice fed IgA, binding of Ig induces expression of LEE encoded virulence genes, which confer pathogenicity and transmission. C. rodentium and probably some other enteric organisms thus appropriated binding of otherwise protective antibodies to signal induction of the virulence program and the high prevalence of TNFRSF13B dominant negative variants thus reflects balancing selection.
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the c104r mutant impairs the function of transmembrane activator and calcium modulator and cyclophilin ligand interactor taci through haploinsufficiency
The Journal of Allergy and Clinical Immunology, 2010Co-Authors: John Lee, Ingrid Rauter, Tatyana Sannikova, Stacey R. Dillon, Haifa Jabara, Lilit Garibyan, Richard J Bram, Raif S GehaAbstract:Background TNFRSF13B , which encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), is mutated in 10% of patients with common variable immunodeficiency. One of the 2 most common TACI mutations in common variable immunodeficiency, C104R, abolishes ligand binding and is found predominantly in the heterozygous state. The murine TACI mutant C76R is the equivalent of the human TACI mutant C104R. Objective We sought to define the consequence of the C76R mutation on TACI function in mice that express both wild-type TACI and the murine C76R mutant. Methods Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI +/− B6/129 background (C76R/TACI +/− mice) were constructed. Serum immunoglobulins and antibody responses to the type II T-independent antigen trinitrophenylated (TNP)-Ficoll were determined by means of ELISA. B-cell proliferation in response to a proliferation-inducing ligand was determined based on tritiated thymidine incorporation into DNA. IgG1 secretion by B cells in response to a proliferation-inducing ligand plus IL-4 was determined by means of ELISA. Results C76R/TACI +/− mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI +/+ B6/129 control animals, and their B cells were impaired in their capacity to proliferate and secrete IgG1 in response to TACI ligation. Unexpectedly, TACI +/− mice had similarly impaired B-cell function as C76R/TACI +/− littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI +/− mice on the C57BL/6 background. Conclusion These results suggest that the human TACI mutant C104R might impair TACI function in heterozygotes through haploinsufficiency.
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taci is mutant in common variable immunodeficiency and iga deficiency
Nature Genetics, 2005Co-Authors: Emanuela Castigli, Lilit Garibyan, Rima Rachid, Stephen A Wilson, Francisco A Bonilla, Lynda C Schneider, Raif S GehaAbstract:The tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in B cells. We found that 4 of 19 unrelated individuals with common variable immunodeficiency (CVID) and 1 of 16 individuals with IgA deficiency (IgAD) had a missense mutation in one allele of TNFRSF13B (encoding TACI). One of the four individuals with CVID had a single nucleotide insertion in the other TNFRSF13B allele. None of these mutations were present in 50 healthy subjects. TNFRSF13B mutations cosegregated with the phenotype of CVID or IgAD in family members of four index individuals that we studied. B cells from individuals with TACI mutations expressed TACI but did not produce IgG and IgA in response to the TACI ligand APRIL, probably reflecting impaired isotype switching. These results suggest that TACI mutations can result in CVID and IgAD.
Necil Kutukculer - One of the best experts on this subject based on the ideXlab platform.
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tnfrsf13b taci alterations in turkish patients with common variable immunodeficiency and iga deficiency
Avicenna journal of medical biotechnology, 2018Co-Authors: Neslihan Edeer Karaca, Guzide Aksu, Ezgi Ulusoy Severcan, Burcu Guven, Elif Azarsiz, Necil KutukculerAbstract:Background The Transmembrane Activator and Calcium modulator ligand Interactor (TACI), encoded by TNFRSF13B/TACI gene, is mutated in some patients with Common Variable Immunodeficiency (CVID) and IgA Deficiency (IgAD). The purpose of the study was to investigate for the first time in Turkish patients the prevalence of TNFRSF13B alterations in CVID, selective and partial IgAD patients. Methods Forty two CVID, 36 selective IgAD, 34 partial IgAD and 25 healthy controls were included. All patients were examined for TNFRSF13B gene mutations by PCR. Results The percentages of TNFRSF13B mutations in CVID, selective and partial IgAD patients were 7.1, 2.7 and 2.9%, respectively. No disease causing TNFRSF13B mutation in healthy controls was found. Patients with TACI mutations had recurrent respiratory tract infections. None of them experienced autoimmunity, bronchiectasis or granulomatous disease. In conclusion, TNFRSF13B mutations were present not only in CVID patients, but also in IgAD cases. Conclusion Modifier genes as well as their combination with other genetic or environmental factors may play an important role in the development of the immunodeficiency phenotype.
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Three Different Classifications, B Lymphocyte Subpopulations, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) Gene Mutations, CTLA-4 and ICOS Gene Polymorphisms in Turkish Patients with Common Variable Immunodeficiency
Journal of clinical immunology, 2012Co-Authors: Necil Kutukculer, Nesrin Gulez, Neslihan Edeer Karaca, Guzide Aksu, Afig BerdeliAbstract:B lymphocyte subpopulations, previously defined classification schemes (Freiburg, Paris, EuroClass), TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF13 (APRIL) gene mutations, CTLA-4 and ICOS gene polymorphisms were analyzed in 25 common variable immunodeficiency (CVID) patients and 25 healthy controls. Patients were also divided into two subgroups due to some disease severity criteria. SG (severe disease group) (n:11) included patients who have splenomegaly and/or granulomatous diseases and/or bronchiectasis and/or lower baseline IgG values ( G changes in exon 1 of CTLA-4 gene: GG and AG genotypes increase the risk of CVID development 1.32 and 2.18 fold, respectively. 1564 T > C polymorphisms on 3′UTR region in exon 2 of ICOS gene was not found to be significantly different in CVID patients. CVID classifications were not helpful in determining the genetic etiology of CVID.
Alessandro Plebani - One of the best experts on this subject based on the ideXlab platform.
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relevance of biallelic versus monoallelic tnfrsf13b mutations in distinguishing disease causing from risk increasing tnfrsf13b variants in antibody deficiency syndromes
Blood, 2009Co-Authors: Ulrich Salzer, Chiara Bacchelli, Sylvie Buckridge, Qiang Panhammarstrom, Stephanie Jennings, Vassilis Lougaris, Astrid Bergbreiter, Tina Hagena, Jennifer Birmelin, Alessandro PlebaniAbstract:TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD−CD27+ B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
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mutational analysis of human baff receptor TNFRSF13C baff r in patients with common variable immunodeficiency
Journal of Clinical Immunology, 2005Co-Authors: Claretta Gioia Losi, Simona Ferrari, Antonietta Silini, Claudia Fiorini, Annarosa Soresina, A Meini, Luigi D Notarangelo, Vassilios Lougaris, Alessandro PlebaniAbstract:BAFF receptor (BAFF-R/BR3/TNFRSF13C) is a recently identified molecule that specifically binds BLyS, a protein belonging to the tumor necrosis factor (TNF) family, and is involved in survival and maturation of B cells. Recent studies have demonstrated that mice defective in BAFF-R gene exhibit an altered profile of the B cell pool, a phenotype observed in BLyS knockout mice as well. These features suggest that mutations in this gene may result in humoral immunodeficiency. To test this hypothesis, we sequenced the BAFF-R gene in 48 patients with common variable immunodeficiency (CVID) along with 57 healthy controls. We have identified three novel variants present at the heterozygous state leading to amino acid substitutions, and have also confirmed the existence of a previously reported intronic variant. The hereby described novel variants were also present in healthy controls and in the healthy patients’ parents. These variants do not affect the expression of BAFF-R neither at the mRNA nor at the protein level, suggesting that these variants represent novel polymorphic variants of the BAFF-R gene.
