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1.
J Allergy Clin Immunol ; 145(1): 46-69, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31568798

RESUMO

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

2.
J Allergy Clin Immunol ; 144(6): 1660-1673, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

3.
Ann Allergy Asthma Immunol ; 123(5): 461-467, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31382019

RESUMO

OBJECTIVE: To update the reader on recently proposed common variable immune deficiency (CVID) diagnostic criteria, newly uncovered CVID pathobiology, freshly identified CVID-related genes, and novel CVID therapies. DATA SOURCES: PubMed Central. STUDY SELECTIONS: We selected 60 clinical and translational research articles that have shaped CVID diagnostic criteria, introduced personalized therapies, and advanced our understanding of CVID biology and genetics. We have incorporated recent articles and older published work that are foundational to the modern understanding of this protean disease. RESULTS: CVID has proven to be a heterogenous group of antibody deficiency diseases driven by defects in diverse biologic processes, including B-cell development, activation, tolerance, class-switch recombination, somatic hypermutation, and lymphoproliferation. Recent genetic advances have enabled identification of several CVID-related gene defects that may contribute to patients' infectious and noninfectious symptoms. CONCLUSION: Improved understanding of the aberrant biologic processes that drive CVID and the disease's genetic basis may be useful in directing therapeutic decisions, especially in cases complicated by autoimmune, lymphoproliferative, and inflammatory features.

4.
Sci Immunol ; 4(34)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979797

RESUMO

Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naïve B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naïve B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (Tregs) that lacked common TCRß clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naïve B cells recognizing peripheral self-antigens.

5.
J Allergy Clin Immunol ; 143(4): 1660, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30773289
6.
J Virol ; 93(2)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30355686

RESUMO

Clearance of HIV-infected germinal center (GC) CD4+ follicular helper T cells (Tfh) after combination antiretroviral therapy (ART) is essential to an HIV cure. Blocking B cell lymphoma 6 (BCL6; the master transcription factor for Tfh cells) represses HIV infection of tonsillar CD4+ Tfh ex vivo, reduces GC formation, and limits immune activation in vivo We assessed the anti-HIV activity of a novel BCL6 inhibitor, FX1, in Tfh/non-Tfh CD4+ T cells and its impact on T cell activation and SAMHD1 phosphorylation (Thr592). FX1 repressed HIV-1 infection of peripheral CD4+ T cells and tonsillar Tfh/non-Tfh CD4+ T cells (P < 0.05) and total elongated and multispliced HIV-1 RNA production during the first round of viral life cycle (P < 0.01). Using purified circulating CD4+ T cells from uninfected donors, we demonstrate that FX1 treatment resulted in downregulation pSAMHD1 expression (P < 0.05) and T cell activation (HLA-DR, CD25, and Ki67; P < 0.01) ex vivo corresponding with inhibition of HIV-1 and HIV-2 replication. Ex vivo HIV-1 reactivation using purified peripheral CD4+ T cells from HIV-infected ART-suppressed donors was also blocked by FX1 treatment (P < 0.01). Our results indicate that BCL6 function contributes to Tfh/non-Tfh CD4+ T cell activation and cellular susceptibility to HIV infection. BCL6 inhibition represents a novel therapeutic strategy to potentiate HIV suppression in Tfh/non-Tfh CD4+ T cells without reactivation of latent virus.IMPORTANCE The expansion and accumulation of HIV-infected BCL6+ Tfh CD4+ T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4+ T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8+ T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4+ T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/metabolismo , Indóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Tiazolidinedionas/farmacologia , Adulto , Regulação para Baixo , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , HIV-2/efeitos dos fármacos , HIV-2/fisiologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Pessoa de Meia-Idade , Fosforilação , Replicação Viral/efeitos dos fármacos , Adulto Jovem
7.
J Allergy Clin Immunol ; 143(1): 258-265, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29935219

RESUMO

BACKGROUND: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy. OBJECTIVE: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC). METHODS: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID. RESULTS: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria. CONCLUSIONS: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens.


Assuntos
Autoanticorpos/imunologia , Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/patologia , Biópsia , Criança , Imunodeficiência de Variável Comum/patologia , Feminino , Centro Germinativo/patologia , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia
8.
J Allergy Clin Immunol ; 143(4): 1482-1495, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

9.
Front Immunol ; 9: 1715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30087679

RESUMO

Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.

10.
Nature ; 559(7714): 405-409, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29995861

RESUMO

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.


Assuntos
Reprogramação Celular/genética , Edição de Genes , Genoma Humano/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Autoimunidade/genética , Sistemas CRISPR-Cas/genética , Células Cultivadas , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Masculino , Camundongos , Transplante de Neoplasias , Engenharia de Proteínas , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/citologia
14.
Curr Opin Allergy Clin Immunol ; 17(6): 398-404, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28957823

RESUMO

PURPOSE OF REVIEW: The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies. RECENT FINDINGS: Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and antiinterferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases. SUMMARY: The NLRC4 inflammasomopathies constitute a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.


Assuntos
Doenças Autoimunes/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Inflamassomos/metabolismo , Mutação/genética , Urticária/genética , Animais , Doenças Autoimunes/imunologia , Biomarcadores Tumorais/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Humanos , Inflamação , Interleucina-18/metabolismo , Urticária/imunologia
15.
Nat Genet ; 49(8): 1192-1201, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628108

RESUMO

Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Dermatite Atópica/genética , Mutação em Linhagem Germinativa , Guanilato Ciclase/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Estudos de Coortes , Análise Mutacional de DNA , Dermatite Atópica/imunologia , Feminino , Genes Dominantes , Glutamina/metabolismo , Humanos , Células Jurkat , Ativação Linfocitária , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina , Antígenos de Histocompatibilidade Menor/metabolismo , Complexos Multiproteicos/metabolismo , NF-kappa B/metabolismo , Linhagem , Linfócitos T/imunologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo
17.
J Allergy Clin Immunol Pract ; 5(5): 1344-1350.e3, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28286158

RESUMO

BACKGROUND: Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder associated with recurrent otitis. Most SMS cases result from heterozygous interstitial chromosome 17p11.2 deletions that encompass not only the intellectual disability gene retinoic acid-induced 1 but also other genes associated with immunodeficiency, autoimmunity, and/or malignancy. OBJECTIVES: The goals of this study were to describe the immunological consequence of 17p11.2 deletions by determining the prevalence of immunological diseases in subjects with SMS and by assessing their immune systems via laboratory methods. METHODS: We assessed clinical histories of 76 subjects with SMS with heterozygous 17p11.2 deletions and performed in-depth immunological testing on 25 representative cohort members. Laboratory testing included determination of serum antibody concentrations, vaccine titers, and lymphocyte subset frequencies. Detailed reactivity profiles of SMS serum antibodies were performed using custom-made antigen microarrays. RESULTS: Of 76 subjects with SMS, 74 reported recurrent infections including otitis (88%), pneumonia (47%), sinusitis (42%), and gastroenteritis (34%). Infections were associated with worsening SMS-related neurobehavioral symptoms. The prevalence of autoimmune and atopic diseases was not increased. Malignancy was not reported. Laboratory evaluation revealed most subjects with SMS to be deficient of isotype-switched memory B cells and many to lack protective antipneumococcal antibodies. SMS antibodies were not more reactive than control antibodies to self-antigens. CONCLUSIONS: Patients with SMS with heterozygous 17p.11.2 deletions display an increased susceptibility to sinopulmonary infections, but not to autoimmune, allergic, or malignant diseases. SMS sera display an antibody reactivity profile favoring neither recognition of pathogen-associated antigens nor self-antigens. Prophylactic strategies to prevent infections may also provide neurobehavioral benefits to selected patients with SMS.


Assuntos
Linfócitos B/imunologia , Síndromes de Imunodeficiência/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Proteína DEAD-box 58/genética , Feminino , Humanos , Switching de Imunoglobulina , Memória Imunológica , Lactente , Deficiência Intelectual , Masculino , Mutação/genética , Otite , Pneumonia , Prevalência , Sinusite , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/imunologia , Adulto Jovem
19.
J Clin Invest ; 125(10): 3941-51, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26368308

RESUMO

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and high susceptibility to developing tumors and autoimmunity. Recent evidence suggests that B cells may be key players in the pathogenesis of autoimmunity in WAS. Here, we assessed whether WAS protein deficiency (WASp deficiency) affects the establishment of B cell tolerance by testing the reactivity of recombinant antibodies isolated from single B cells from 4 WAS patients before and after gene therapy (GT). We found that pre-GT WASp-deficient B cells were hyperreactive to B cell receptor stimulation (BCR stimulation). This hyperreactivity correlated with decreased frequency of autoreactive new emigrant/transitional B cells exiting the BM, indicating that the BCR signaling threshold plays a major role in the regulation of central B cell tolerance. In contrast, mature naive B cells from WAS patients were enriched in self-reactive clones, revealing that peripheral B cell tolerance checkpoint dysfunction is associated with impaired suppressive function of WAS regulatory T cells. The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. We conclude that WASp plays an important role in the establishment and maintenance of B cell tolerance in humans and that restoration of WASp by GT is able to restore B cell tolerance in WAS patients.


Assuntos
Linfócitos B/imunologia , Terapia Genética , Vetores Genéticos/uso terapêutico , Tolerância Imunológica , Proteína da Síndrome de Wiskott-Aldrich/uso terapêutico , Síndrome de Wiskott-Aldrich/terapia , Adulto , Sequência de Aminoácidos , Medula Óssea/patologia , Criança , Pré-Escolar , Deleção Clonal , Células Clonais/imunologia , Humanos , Lentivirus/genética , Masculino , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos B/imunologia , Proteínas Recombinantes de Fusão , Linfócitos T Reguladores/imunologia , Síndrome de Wiskott-Aldrich/imunologia , Proteína da Síndrome de Wiskott-Aldrich/deficiência , Proteína da Síndrome de Wiskott-Aldrich/genética
20.
J Allergy Clin Immunol ; 136(5): 1315-25, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26100089

RESUMO

BACKGROUND: Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION: TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Síndrome de Smith-Magenis/imunologia , Linfócitos T Reguladores/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Formação de Anticorpos/genética , Autoimunidade , Criança , Feminino , Haploinsuficiência , Hemizigoto , Humanos , Memória Imunológica , Ativação Linfocitária/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Adulto Jovem
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