Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Exp Med ; 217(2)2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31841125

RESUMO

Antibody-mediated autoimmune diseases are a major health burden. However, our understanding of how self-reactive B cells escape self-tolerance checkpoints to secrete pathogenic autoantibodies remains incomplete. Here, we demonstrate that patients with monogenic immune dysregulation caused by gain-of-function mutations in PIK3CD, encoding the p110δ catalytic subunit of phosphoinositide 3-kinase (PI3K), have highly penetrant secretion of autoreactive IgM antibodies. In mice with the corresponding heterozygous Pik3cd activating mutation, self-reactive B cells exhibit a cell-autonomous subversion of their response to self-antigen: instead of becoming tolerized and repressed from secreting autoantibody, Pik3cd gain-of-function B cells are activated by self-antigen to form plasmablasts that secrete high titers of germline-encoded IgM autoantibody and hypermutating germinal center B cells. However, within the germinal center, peripheral tolerance was still enforced, and there was selection against B cells with high affinity for self-antigen. These data show that the strength of PI3K signaling is a key regulator of pregerminal center B cell self-tolerance and thus represents a druggable pathway to treat antibody-mediated autoimmunity.

2.
Sci Immunol ; 4(41)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784499

RESUMO

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-ß-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-ß-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-ß. Furthermore, they displayed a transcriptional pattern in response to TGF-ß different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-ß-dependent homeostasis of connective tissues.

3.
Proc Natl Acad Sci U S A ; 116(33): 16463-16472, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31346092

RESUMO

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

4.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

6.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578351

RESUMO

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αß T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rß2-deficient than IL-12Rß1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.


Assuntos
Imunidade Inata/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium/imunologia , Humanos , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-23/deficiência , Interleucina-23/genética , Linhagem
7.
J Exp Med ; 215(8): 2073-2095, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018075

RESUMO

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa/genética , Fosfatidilinositol 3-Quinases/genética , Animais , Afinidade de Anticorpos/imunologia , Células da Medula Óssea/citologia , Diferenciação Celular , Proliferação de Células , Criança , Mutação com Ganho de Função/genética , Humanos , Switching de Imunoglobulina , Imunoglobulinas/metabolismo , Interleucinas/farmacologia , Camundongos , Modelos Animais , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais
8.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.


Assuntos
Regulação da Expressão Gênica/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Transcrição Genética/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Consanguinidade , Citocinas/imunologia , Citocinas/metabolismo , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Homozigoto , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Síndrome de Job/sangue , Síndrome de Job/imunologia , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem , Dedos de Zinco/genética
9.
Elife ; 72018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29537367

RESUMO

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.


Assuntos
Haploinsuficiência/genética , Fatores Reguladores de Interferon/genética , Tropheryma/genética , Doença de Whipple/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença/genética , Humanos , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Penetrância , Tropheryma/patogenicidade , Doença de Whipple/microbiologia , Doença de Whipple/patologia
10.
Immunity ; 47(6): 1142-1153.e4, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29262350

RESUMO

Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long-term humoral immunity. Although expression of the transcription factor BLIMP-1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6+ GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell-surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high-affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses.


Assuntos
Centro Germinativo/imunologia , Imunidade Humoral , Plasmócitos/imunologia , Células Precursoras de Linfócitos B/imunologia , Receptores CCR6/imunologia , Animais , Antígeno B7-2/genética , Antígeno B7-2/imunologia , Diferenciação Celular , Linhagem da Célula/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Centro Germinativo/citologia , Humanos , Memória Imunológica , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Plasmócitos/citologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Células Precursoras de Linfócitos B/citologia , Receptores CCR6/genética , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Transdução de Sinais
11.
Nat Commun ; 8(1): 891, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-29026071

RESUMO

Arginine methylation catalyzed by protein arginine methyltransferases (PRMT) is a common post-translational modification in mammalian cells, regulating many important functions including cell signalling, proliferation and differentiation. Here we show the role of PRMT1 in B-cell activation and differentiation. PRMT1 expression and activity in human and mouse peripheral B cells increases in response to in vitro or in vivo activation. Deletion of the Prmt1 gene in mature B cells establishes that although the frequency and phenotype of peripheral B cell subsets seem unaffected, immune responses to T-cell-dependent and -independent antigens are substantially reduced. In vitro activation of Prmt1-deficient B cells with a variety of mitogens results in diminished proliferation, differentiation and survival, effects that are correlated with altered signal transduction from the B cell receptor. Thus PRMT1 activity in B cells is required for correct execution of multiple processes that in turn are necessary for humoral immunity.PRMT1 is an arginine methyltransferase involved in a variety of cell functions. Here the authors delete PRMT1 specifically in mature B cells to show the importance of arginine methylation for B cell proliferation, differentiation and survival, and thereby for humoral immunity.


Assuntos
Arginina/metabolismo , Linfócitos B/imunologia , Imunidade Humoral/genética , Ativação Linfocitária/genética , Proteína-Arginina N-Metiltransferases/genética , Proteínas Repressoras/genética , Animais , Linfócitos B/metabolismo , Diferenciação Celular/genética , Humanos , Imunidade Humoral/imunologia , Ativação Linfocitária/imunologia , Metilação , Camundongos , Processamento de Proteína Pós-Traducional/genética
12.
J Allergy Clin Immunol ; 139(3): 933-949, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27554822

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. OBJECTIVE: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. METHODS: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. RESULTS: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. CONCLUSION: Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Alérgenos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Masculino , Adulto Jovem
13.
Immunity ; 45(4): 831-846, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27760339

RESUMO

T follicular helper (Tfh) cells are a CD4+ T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection. Furthermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinity, dictated Tfh versus Th2 effector cell differentiation. Collectively, our results define unique functions for LFA-1 in the Tfh cell effector program and suggest that integrin activity is important in lineage decision-making events in the adaptive immune system.


Assuntos
Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Cultivadas , Centro Germinativo/imunologia , Humanos , Imunidade Humoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/imunologia
14.
J Immunol ; 197(8): 3008-3017, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27619997

RESUMO

Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20+CD38+CD27lowCD95+CD10+ cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3 To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquinsan/san lupus mouse model. Il27ra-/-Roquinsan/san mice exhibited significantly reduced GCs, IgG2a(c)+ autoantibodies, and nephritis. Mixed bone marrow chimeras confirmed that IL-27 acts through B cell- and CD4+ T cell-intrinsic mechanisms to support GCs and alter the production of pathogenic Ig isotypes. To our knowledge, our data provide the first evidence that IL-27 signals directly to B cells promote GCs and support the role of IL-27 in lupus.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Centro Germinativo/imunologia , Interleucina-27/metabolismo , Nefrite Lúpica/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Interleucina-27/imunologia , Nefrite Lúpica/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Citocinas/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Ubiquitina-Proteína Ligases/genética
15.
J Exp Med ; 213(8): 1589-608, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27401342

RESUMO

Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rß1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rß1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.


Assuntos
Diferenciação Celular/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Diferenciação Celular/genética , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Células Th1/citologia , Células Th17/citologia
16.
J Exp Med ; 212(10): 1641-62, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26304966

RESUMO

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/ß, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/ß. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.


Assuntos
Síndrome de Job/etiologia , TYK2 Quinase/deficiência , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-10/farmacologia , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Interleucina-6/farmacologia , Síndrome de Job/complicações , Síndrome de Job/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Mutação , Infecções por Mycobacterium/etiologia , Linfócitos T/metabolismo , Linfócitos T/patologia , TYK2 Quinase/genética , TYK2 Quinase/metabolismo , Viroses/etiologia , Adulto Jovem
17.
Science ; 349(6248): 606-613, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26160376

RESUMO

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αß T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.


Assuntos
Candida albicans/imunologia , Candidíase Mucocutânea Crônica/genética , Imunidade/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Imunodeficiência Combinada Severa/genética , Tuberculose Bovina/genética , Tuberculose Pulmonar/genética , Alelos , Animais , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/imunologia , Bovinos , Criança , Pré-Escolar , Análise Mutacional de DNA , Exoma/genética , Feminino , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Camundongos , Mutação , Mycobacterium bovis/imunologia , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Linhagem , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Timo/anormalidades , Timo/imunologia , Tuberculose Bovina/imunologia , Tuberculose Pulmonar/imunologia
18.
J Allergy Clin Immunol ; 136(4): 993-1006.e1, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26162572

RESUMO

BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.


Assuntos
Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tirosina Quinase da Agamaglobulinemia , Linfócitos B/imunologia , Ligante de CD40/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Humanos , Quinase I-kappa B/genética , Imunidade Humoral/genética , Síndromes de Imunodeficiência/genética , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Interferon gama/genética , Interferon gama/metabolismo , Ativação Linfocitária , Mutação/genética , Proteínas Tirosina Quinases/genética , Receptores de Citocinas/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
19.
Science ; 345(6204): 1623-1627, 2014 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-25213377

RESUMO

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3(+) regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21(lo) B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.


Assuntos
Antígeno CTLA-4/genética , Mutação em Linhagem Germinativa , Haploinsuficiência , Doenças do Sistema Imunitário/genética , Imunidade/genética , Adulto , Animais , Linfócitos B/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Camundongos , Camundongos Mutantes , Linhagem , Linfócitos T Reguladores/imunologia , Adulto Jovem
20.
Nat Immunol ; 15(1): 88-97, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24165795

RESUMO

The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.


Assuntos
Senescência Celular/genética , Mutação em Linhagem Germinativa , Síndromes de Imunodeficiência/genética , Fosfatidilinositol 3-Quinases/genética , Linfócitos T/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Diferenciação Celular/genética , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Feminino , Genes Dominantes , Humanos , Immunoblotting , Síndromes de Imunodeficiência/tratamento farmacológico , Masculino , Linhagem , Fosfatidilinositol 3-Quinases/química , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Viremia/tratamento farmacológico , Viremia/genética , Viremia/virologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA