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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.
Front Immunol ; 10: 895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105705

RESUMO

Patients with X-linked agammaglobulinemia (XLA) have failure of B-cell development with lack of immunoglobulin (Ig) production. While immunoglobulin replacement therapy (IgRT) is beneficial, XLA patients remain at risk for infections, structural lung damage, and rarely, neoplasia. Allogeneic stem cell transplantation (alloSCT) may offer a potential cure, but is associated with significant life-threatening complications. Here, we present a 25-year old XLA patient who developed pre-B acute lymphocytic leukemia (ALL) with somatic TP53 mutation, and treatment for this high-risk malignancy involved full myeloablative conditioning and a HLA-matched sibling alloSCT. Full donor chimerism was achieved for CD3+ and CD3- cell fractions. The patient remains in morphological and flow cytometric remission 14 months post-transplant, with late-onset oral GvHD requiring low dose prednisolone and cyclosporin. Following IgRT discontinuation at 4 months post-transplantation, humoral immunity was established within 14 months as reflected by normal numbers of total B cells, memory B cells, serum IgG, IgM, and IgA, and production of specific IgG responses to Prevenar-13 vaccination. This is only the second reported case of an XLA patient with pre-B-ALL, and the most detailed report of engraftment following alloSCT in XLA. Together with the two previous XLA cases treated with alloSCT, our report provides evidence for the potential for successful humoral reconstitution with alloSCT in patients with B-cell intrinsic antibody deficiency. These observations may be relevant given IgRT, while beneficial, remains an imperfect solution to long-term infectious complications.

3.
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.

4.
J Allergy Clin Immunol ; 144(1): 236-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30738173

RESUMO

BACKGROUND: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis. OBJECTIVE: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function. METHODS: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling. RESULTS: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic. CONCLUSION: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations.

5.
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
6.
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
7.
J Exp Med ; 212(6): 855-64, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25941256

RESUMO

Unconventional T cells such as γδ T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not γδ T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor RORγt. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFNγ and TNF. The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.


Assuntos
Fator de Transcrição STAT3/metabolismo , Linfócitos T/citologia , Separação Celular , Citocinas/metabolismo , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucinas/metabolismo , Células Matadoras Naturais/citologia , Leucócitos Mononucleares/citologia , Linfócitos/citologia , Mutação , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12/metabolismo , Receptores de Interleucina-21/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
8.
J Exp Med ; 210(12): 2739-53, 2013 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-24218138

RESUMO

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Memória Imunológica , Plasmócitos/imunologia , Plasmócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Linfócitos B/citologia , Diferenciação Celular , Linhagem da Célula , Humanos , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-21/deficiência , Subunidade alfa de Receptor de Interleucina-21/genética , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Interleucinas/metabolismo , Mutação , Plasmócitos/citologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Blood ; 122(24): 3940-50, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24159173

RESUMO

B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common γ chain (γc)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2Rα) in normal, but not STAT3-deficient, CD40L-stimulated naïve B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naïve B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21.


Assuntos
Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Interleucina-2/farmacologia , Interleucinas/farmacologia , Plasmócitos/efeitos dos fármacos , Fator de Transcrição STAT3/genética , Linfócitos B/citologia , Linfócitos B/metabolismo , Ligante de CD40/farmacologia , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/farmacologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Plasmócitos/citologia , Plasmócitos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcriptoma/efeitos dos fármacos
10.
Blood ; 122(12): 2052-61, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23929855

RESUMO

Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Células T Matadoras Naturais/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos Ly/metabolismo , Sobrevivência Celular/genética , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Imunofenotipagem , Cadeias alfa de Integrinas/metabolismo , Fígado/imunologia , Fígado/metabolismo , Contagem de Linfócitos , Camundongos , Camundongos Knockout , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Timo/imunologia , Timo/metabolismo
11.
J Allergy Clin Immunol ; 132(2): 400-11.e9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23830147

RESUMO

BACKGROUND: The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown. OBJECTIVE: We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. METHODS: Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro. RESULTS: Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement. CONCLUSION: The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Memória Imunológica , Síndrome de Job/genética , Mutação , Fator de Transcrição STAT3/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Humanos , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , Síndrome de Job/imunologia , Síndrome de Job/patologia , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/imunologia , Receptores de Interleucina-21/metabolismo , Fator de Transcrição STAT3/genética
12.
Am J Clin Nutr ; 96(3): 534-43, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22854412

RESUMO

BACKGROUND: Antioxidant-rich diets are associated with reduced asthma prevalence in epidemiologic studies. We previously showed that short-term manipulation of antioxidant defenses leads to changes in asthma outcomes. OBJECTIVE: The objective was to investigate the effects of a high-antioxidant diet compared with those of a low-antioxidant diet, with or without lycopene supplementation, in asthma. DESIGN: Asthmatic adults (n = 137) were randomly assigned to a high-antioxidant diet (5 servings of vegetables and 2 servings of fruit daily; n = 46) or a low-antioxidant diet (≤2 servings of vegetables and 1 serving of fruit daily; n = 91) for 14 d and then commenced a parallel, randomized, controlled supplementation trial. Subjects who consumed the high-antioxidant diet received placebo. Subjects who consumed the low-antioxidant diet received placebo or tomato extract (45 mg lycopene/d). The intervention continued until week 14 or until an exacerbation occurred. RESULTS: After 14 d, subjects consuming the low-antioxidant diet had a lower percentage predicted forced expiratory volume in 1 s and percentage predicted forced vital capacity than did those consuming the high-antioxidant diet. Subjects in the low-antioxidant diet group had increased plasma C-reactive protein at week 14. At the end of the trial, time to exacerbation was greater in the high-antioxidant than in the low-antioxidant diet group, and the low-antioxidant diet group was 2.26 (95% CI: 1.04, 4.91; P = 0.039) times as likely to exacerbate. Of the subjects in the low-antioxidant diet group, no difference in airway or systemic inflammation or clinical outcomes was observed between the groups that consumed the tomato extract and those who consumed placebo. CONCLUSIONS: Modifying the dietary intake of carotenoids alters clinical asthma outcomes. Improvements were evident only after increased fruit and vegetable intake, which suggests that whole-food interventions are most effective. This trial was registered at http://www.actr.org.au as ACTRN012606000286549.


Assuntos
Antioxidantes/uso terapêutico , Asma/dietoterapia , Frutas , Estresse Oxidativo , Verduras , Adulto , Idoso , Antioxidantes/administração & dosagem , Antioxidantes/efeitos adversos , Asma/sangue , Asma/imunologia , Asma/fisiopatologia , Proteína C-Reativa/análise , Carotenoides/efeitos adversos , Carotenoides/análise , Carotenoides/uso terapêutico , Dieta/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Feminino , Frutas/efeitos adversos , Frutas/química , Humanos , Mediadores da Inflamação/sangue , Licopeno , Lycopersicon esculentum/efeitos adversos , Lycopersicon esculentum/química , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Sistema Respiratório/fisiopatologia , Verduras/efeitos adversos , Verduras/química
13.
J Exp Med ; 209(5): 913-24, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22493517

RESUMO

Patients with the primary immunodeficiency X-linked lymphoproliferative disease (XLP), which is caused by mutations in SH2D1A, are highly susceptible to Epstein-Barr virus (EBV) infection. Nonetheless, some XLP patients demonstrate less severe clinical manifestations after primary infection. SH2D1A encodes the adaptor molecule SLAM-associated protein (SAP), which is expressed in T and natural killer cells and is required for cytotoxicity against B cells, the reservoir for EBV. It is not known why the clinical presentation of XLP is so variable. In this study, we report for the first time the occurrence of somatic reversion in XLP. Reverted SAP-expressing cells resided exclusively within the CD8(+) T cell subset, displayed a CD45RA(-)CCR7(-) effector memory phenotype, and were maintained at a stable level over time. Importantly, revertant CD8(+) SAP(+) T cells, but not SAP(-) cells, proliferated in response to EBV and killed EBV-infected B cells. As somatic reversion correlated with EBV infection, we propose that the virus exerts a selective pressure on the reverted cells, resulting in their expansion in vivo and host protection against ongoing infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação da Expressão Gênica/imunologia , Herpesvirus Humano 4 , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Sequência de Aminoácidos , Sequência de Bases , Linfócitos T CD8-Positivos/metabolismo , Primers do DNA/genética , Éxons/genética , Citometria de Fluxo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência de DNA , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Carga Viral
14.
Blood ; 119(17): 3997-4008, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22403255

RESUMO

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rß1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.


Assuntos
Diferenciação Celular , Interleucina-12/farmacologia , Mutação/genética , Receptores de Interleucina-12/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Linfócitos T Auxiliares-Indutores/citologia , TYK2 Quinase/genética , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/metabolismo , Humanos , Hospedeiro Imunocomprometido , Ativação Linfocitária , Camundongos , Receptores de Interleucina-12/deficiência , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/deficiência , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , TYK2 Quinase/metabolismo , Fatores de Transcrição/metabolismo
15.
J Exp Med ; 208(11): 2305-20, 2011 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-22006977

RESUMO

In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA(+)CCR7(-) phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/fisiologia , Sobrevivência Celular/imunologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Proliferação de Células , Humanos , Síndromes de Imunodeficiência/imunologia , Memória Imunológica/imunologia , Sinapses Imunológicas/imunologia , Ativação Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Orthomyxoviridae/fisiologia , Fenótipo , Quimeras de Transplante
17.
J Allergy Clin Immunol ; 110(3): 450-6, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12209093

RESUMO

BACKGROUND: Atopic disease is associated with skewing of immune responses away from a T(H)1 toward a T(H)2 profile. Previous studies have implicated this cytokine imbalance in the development of disease. However, it is not known whether normalization of this imbalance is conversely associated with disease resolution. OBJECTIVE: To further delineate the role of reduced T(H)1 and increased T(H)2 cytokine production in the pathogenesis of atopic disease and to determine whether disease resolution is associated with alteration of cytokine profiles, we investigated cytokine responses in a cohort of adult patients with asthma followed from childhood. METHODS: A cohort of wheezy children and control subjects aged 7 to 10 years were recruited from 1964 to 1967. Subjects were reevaluated every 7 years to monitor the outcome of childhood asthma. At the 42-year follow-up, 89 subjects from this cohort were evaluated for mitogen and house dust mite (HDM)-induced T(H)1 (IFN-gamma) and T(H)2 (IL-4, IL-5, and IL-13) cytokine responses. Cytokine responses were compared in patients with ongoing asthma, patients with resolved asthma, and control subjects. RESULTS: Patients with severe ongoing asthma had significantly reduced HDM-induced IFN-gamma production compared with that of control subjects and patients with resolved asthma. In contrast, HDM-induced IFN-gamma production in patients with resolved asthma was equivalent to that seen in control subjects. Patients with ongoing and resolved asthma produced significantly higher levels of IL-5 in response to HDM compared with that seen in control subjects, with levels being equivalent in patients with active and resolved asthma. HDM-induced IL-13 production was significantly increased in the patients with resolved asthma when compared with that seen in the control subjects. PHA-induced cytokine responses did not parallel HDM-induced responses. CONCLUSION: Patients with persistent and severe atopic asthma have a reduced HDM-induced T(H)1 response, whereas those with resolved asthma do not. This suggests that reduced HDM-induced IFN-gamma production might be an important factor contributing to ongoing severe asthma and that normalization of allergen-induced T(H)1 responses might be important for disease resolution. The finding that all subjects with a history of asthma displayed increased HDM-induced T(H)2 (IL-5 and IL-13) cytokine responses, irrespective of the presence or absence of asthma, suggests that increased T(H)2 responses reflect the presence of the atopic state per se rather than being specifically linked to asthma.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Citocinas/biossíntese , Interferon gama/biossíntese , Adulto , Animais , Asma/diagnóstico , Células Cultivadas , Criança , Estudos de Coortes , Feminino , Seguimentos , Humanos , Imunoglobulina E/biossíntese , Imunoglobulina E/imunologia , Ativação Linfocitária , Masculino , Ácaros/imunologia , Mitógenos/farmacologia , Células Th1/imunologia , Células Th2/imunologia
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