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1.
J Clin Invest ; 127(1): 306-320, 2017 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-27893462

RESUMO

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.


Assuntos
Alelos , Regulação da Expressão Gênica/imunologia , Predisposição Genética para Doença , Fatores Reguladores de Interferon , Células Matadoras Naturais/imunologia , Mutação , Viroses , Animais , Antígeno CD56/genética , Antígeno CD56/imunologia , Feminino , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/imunologia , Masculino , Camundongos , Camundongos Knockout , Viroses/genética , Viroses/imunologia
2.
Nat Med ; 18(4): 538-46, 2012 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-22447074

RESUMO

Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.


Assuntos
Antibacterianos/uso terapêutico , Basófilos/citologia , Basófilos/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Hipersensibilidade/imunologia , Inflamação/imunologia , Animais , Anticorpos/uso terapêutico , Antígenos CD/metabolismo , Basófilos/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/genética , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Inflamação/tratamento farmacológico , Linfonodos/citologia , Camundongos , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais/imunologia , Células Th2/efeitos dos fármacos
3.
J Leukoc Biol ; 91(3): 427-35, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22140267

RESUMO

It is reported that human and mouse mast cells express the IL-27R, which consists of WSX-1 (the IL-27Rα subunit) and the signal-transducing subunit gp130. Although it has been proposed that IL-27 may negatively regulate mast cell-dependent, immediate hypersensitivity responses directly, this has yet to be examined specifically. We found that mouse BMMC and primary peritoneal mast cells are unresponsive to IL-27. Consistent with this, gp130 protein in resting BMMC was not on the cell surface to a measurable degree but was found intracellularly, and data are consistent with incompletely processed N-linked glycosylation. Furthermore, BMMC constitutively expressed SOCS3, a major negative regulator of gp130 signaling. However, BMMC stimulation with IL-10 and consequential STAT3 activation increased gp130 expression, which resulted in a functional gp130 receptor on the BMMC cell surface. IL-10 has not been previously shown to regulate gp130 expression, which on the BMMC surface, permitted IL-6 trans-signaling, found to increase survival under limiting conditions and enhance IL-13 and TNF-α secretion. This study identifies factors that regulate mouse mast cell gp130 expression and signaling and makes conspicuous the limitations of using cultured mouse mast cells to study the effects of the IL-6/IL-12 cytokine family on mast cell biology.


Assuntos
Receptor gp130 de Citocina/metabolismo , Interleucina-10/farmacologia , Interleucina-6/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Transdução de Sinais , Animais , Células da Medula Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Receptor gp130 de Citocina/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucinas/farmacologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Fase de Repouso do Ciclo Celular , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo
4.
J Thorac Imaging ; 23(3): 162-9, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18728542

RESUMO

PURPOSE: To evaluate computed tomography (CT) scans of individuals with granulomatous-lymphocytic interstitial lung disease and common variable immunodeficiency (CVID) to determine if there are imaging features that distinguish this manifestation of CVID from the more usual imaging findings. MATERIALS AND METHODS: A review of the CVID population at our institution identified a series of 5 patients with CVID who had documented granulomatous disease on biopsy specimens. The initial and follow-up CT examinations were reviewed by 2 radiologists, and imaging findings in the chest and abdomen were tabulated by consensus. In addition, a pathologist reviewed histopathologic specimens and clinical presentations and therapeutic interventions were obtained from patient charts. RESULTS: In all, 5/5 patients (100%) had widespread pulmonary micronodules with a lower lung zone predominance, 4/5 (80%) had smooth interlobular septal thickening with mid to lower lung zone predominance, 1/5 (20%) had mild bronchiectasis, 4/5 (80%) had multifocal pulmonary consolidation, 5/5 (100%) had thoracic or abdominal lymphadenopathy, 2/5 (40%) had hepatomegaly, 5/5 (100%) had splenomegaly, 1/5 (20%) had nonspecific hypoattenuating splenic lesions, and 2/5 (40%) had nonspecific hypoattenuating renal lesions. The pulmonary nodules and lymphadenopathy commonly tended to wax and wane in severity over time, and more marked disease was often associated with areas of focal consolidation. CONCLUSION: Granulomatous-lymphocytic interstitial lung disease, which can occur in patients with CVID, presents with CT findings distinct from the usual airway abnormalities most commonly associated with CVID.


Assuntos
Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico por imagem , Granuloma/complicações , Granuloma/diagnóstico por imagem , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Feminino , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/patologia , Masculino , Estudos Retrospectivos , Adulto Jovem
5.
J Immunol ; 181(3): 1692-9, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18641305

RESUMO

Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4(+)Foxp3(+) T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that although Th17 cells differentiate from naive alloreactive T cells, these cells do not arise from natural Tregs in either CpG-treated or untreated graft recipients. Finally, we show that CpG impairs natural Treg suppressor capability and prevents Treg-dependent allograft acceptance in an IL-6-independent fashion. Our data therefore suggest that TLR signals do not prevent prolonged graft acceptance by directing natural Tregs into the Th17 lineage or by using other IL-6-dependent mechanisms. Instead, graft destruction results from the ability of CpG to drive Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4(+)Foxp3(+) Tregs.


Assuntos
Rejeição de Enxerto/imunologia , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Animais , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Glicina/análogos & derivados , Glicina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Coração/imunologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Interleucina-17/imunologia , Interleucina-6/deficiência , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Transplante de Pele/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transplante Homólogo/imunologia
6.
J Allergy Clin Immunol ; 121(2 Suppl): S364-9; quiz S412, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18241683

RESUMO

Lymphocytes are white blood cells uniform in appearance but varied in function and include T, B, and natural killer cells. These cells are responsible for antibody production, direct cell-mediated killing of virus-infected and tumor cells, and regulation of the immune response. Advances in immunology have led to the characterization of newly appreciated effector populations such as IL-17-producing T cells, T cells with regulatory function, and natural killer T cells, thus revising established paradigms. This chapter provides an overview of the major lymphocyte populations with emphasis on their development, distinguishing characteristics, and functions.


Assuntos
Linfócitos , Linfócitos T/fisiologia , Animais , Antígenos/imunologia , Linfócitos B/fisiologia , Humanos , Imunidade Inata , Memória Imunológica , Células Matadoras Naturais/fisiologia , Complexo Principal de Histocompatibilidade/imunologia , Linfócitos T/classificação , Linfócitos T/imunologia
7.
Clin Gastroenterol Hepatol ; 6(5): 531-5, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18304887

RESUMO

BACKGROUND & AIMS: The association of sensitization to food allergens, atopic disorders, and eosinophilic esophagitis (EE) is well known in children, but not in adults. Our purpose was to identify the spectrum of specific allergic sensitivities to environmental and food allergens within a series of adult patients with EE. METHODS: The case series consisted of 23 adult patients with biopsy-proven EE referred for allergy evaluation at an academic clinic. All patients had data that included serum measurement of specific immunoglobulin (Ig)E antibodies to common foods and spices. Patients diagnosed with allergic rhinitis had a relevant clinical history of respiratory allergy and evidence of specific IgE to environmental aeroallergens. RESULTS: The series consisted of 16 men and 7 women with a median age of 34 years (range, 18-57 y). Eighteen of 23 had an atopic diathesis, allergic rhinitis being the most common. Seventeen of 21 patients were polysensitized to several different environmental allergens, and 19 of 23 (82%) had serum IgE specific for one or more food-associated allergens (median, 5 foods), with wheat, tomato, carrot, and onion identified most commonly. The preponderance of environmental and food allergy was similar across all age groups and did not favor younger adults. CONCLUSIONS: By using objective measures, our series confirms the high degree of atopy in adults with EE, similar to that seen in the pediatric population. These patients tend to be polysensitized to several environmental allergens, and the profiles of serum IgE specific for food allergens suggest that sensitization may partly be a response to inhaled allergens.


Assuntos
Eosinofilia/diagnóstico , Eosinofilia/imunologia , Esofagite/imunologia , Hipersensibilidade Imediata/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Estudos de Coortes , Dessensibilização Imunológica , Eosinofilia/epidemiologia , Esofagite/diagnóstico , Esofagite/epidemiologia , Feminino , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/epidemiologia , Hipersensibilidade Alimentar/imunologia , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/epidemiologia , Hipersensibilidade/imunologia , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/imunologia , Incidência , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Prognóstico , Teste de Radioalergoadsorção , Fatores de Risco , Índice de Gravidade de Doença , Distribuição por Sexo
8.
Infect Immun ; 75(11): 5200-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17846116

RESUMO

Challenge with the intracellular protozoan parasite Toxoplasma gondii induces a potent CD8+ T-cell response that is required for resistance to infection, but many questions remain about the factors that regulate the presentation of major histocompatibility complex class I (MHC-I)-restricted parasite antigens and about the role of professional and nonprofessional accessory cells. In order to address these issues, transgenic parasites expressing ovalbumin (OVA), reagents that track OVA/MHC-I presentation, and OVA-specific CD8+ T cells were exploited to compare the abilities of different infected cell types to stimulate CD8+ T cells and to define the factors that contribute to antigen processing. These studies reveal that a variety of infected cell types, including hematopoietic and nonhematopoietic cells, are capable of activating an OVA-specific CD8+ T-cell hybridoma, and that this phenomenon is dependent on the transporter associated with antigen processing and requires live T. gondii. Several experimental approaches indicate that T-cell activation is a consequence of direct presentation by infected host cells rather than cross-presentation. Surprisingly, nonprofessional antigen-presenting cells (APCs) were at least as efficient as dendritic cells at activating this MHC-I-restricted response. Studies to assess whether these cells are involved in initiation of the CD8+ T-cell response to T. gondii in vivo show that chimeric mice expressing MHC-I only in nonhematopoietic compartments are able to activate OVA-specific CD8+ T cells upon challenge. These findings associate nonprofessional APCs with the initial activation of CD8+ T cells during toxoplasmosis.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos de Protozoários/metabolismo , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Antígenos de Protozoários/imunologia , Feminino , Genes Reporter , Ativação Linfocitária/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/imunologia , Ovalbumina/metabolismo
9.
Cancer Res ; 67(14): 7011-9, 2007 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-17638914

RESUMO

5,6-Di-methylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity. Although classified as a "vascular disrupting agent," we have recently conducted studies showing that DMXAA has remarkable efficacy in a range of tumors, working primarily as an immune modulator that activates tumor-associated macrophages and induces a subsequent CD8(+) T-cell-mediated response. To more completely analyze the effect of DMXAA on CD8(+) T-cell generation, we treated mice bearing tumors derived from EG7 thymoma cells that express the well-characterized chicken ovalbumin neotumor antigen. Treatment with DMXAA led to cytokine release, tumor cell necrosis, and ultimately reduction in tumor size that was lymphocyte dependent. Within 24 h of administration, we observed dendritic cell activation in tumor-draining lymph nodes (TDLN). This was followed by a rapid and marked increase in the number of tetramer-specific CD8(+) T cells in the spleens of treated animals. In contrast, the vascular disrupting agent combretastatin A4-phosphate, which caused a similar amount of immediate tumor necrosis, did not activate dendritic cells, nor induce an effective antitumor response. Using in vitro systems, we made the observation that DMXAA has the ability to directly activate mouse dendritic cells, as measured by increased expression of costimulatory molecules and proinflammatory cytokine release via a pathway that does not require the Toll-like receptor adaptor molecule MyD88. DMXAA thus has the ability to activate tumor-specific CD8(+) T cells through multiple pathways that include induction of tumor cell death, release of stimulatory cytokines, and direct activation of dendritic cells.


Assuntos
Células Dendríticas/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Linfócitos T Citotóxicos/metabolismo , Xantonas/farmacologia , Animais , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Galinhas , Citocinas/metabolismo , Células Dendríticas/citologia , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Transplante de Neoplasias , Ovalbumina/metabolismo
10.
Ann Allergy Asthma Immunol ; 98(5): 483-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17521034

RESUMO

BACKGROUND: Patients with primary hypogammaglobulinemia have been reported to have encephalopathy, but progressive multifocal leukoencephalopathy (PML) due to JC virus reactivation is a rare cause. OBJECTIVE: To provide the clinical details and case discussion of a patient diagnosed as having common variable immunodeficiency (CVID) who has progressive neurodegenerative symptoms and was found to have PML and an abnormal CD8+ T-cell subset distribution. METHODS: A detailed case report providing the patient's immunodeficiency history, diagnostic evaluation, and medical management and a review of related literature. RESULTS: Before his neurodegenerative illness, the patient was found to have hypogammaglobulinemia, poor specific antibody responses, low circulating B-cell levels, and abnormal delayed-type hypersensitivity responses; there was no Bruton tyrosine kinase (BTK) mutation. The PML was diagnosed using brain biopsy and was confirmed using a DNA probe specific for JC virus. Peripheral blood flow cytometry at the time of PML diagnosis revealed an accumulation of naive CD8+ T cells (CD3+CD8+CD45RA+) and a deficiency of memory CD8+ T-cell subsets (CD3+CD8+CD45RA- or CD3+CD8+CD45RO+). Despite aggressive treatment with interleukin 2, interferon-gamma, and intravenous cidofovir, the patient died. CONCLUSIONS: JC virus infection should be considered in the differential diagnosis of the patient with CVID and signs and symptoms of encephalopathy. The role of this patient's abnormal CD8' T-cell subset distribution in the development or control of this rare infection is worthy of consideration and has encouraged us to enumerate naive and memory CD4+ and CD8+ T-cell subsets in patients diagnosed as having CVID, even in the absence of neurodegenerative symptoms.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunodeficiência de Variável Comum/complicações , Leucoencefalopatia Multifocal Progressiva/etiologia , Adulto , Encéfalo/patologia , Imunodeficiência de Variável Comum/imunologia , Humanos , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/imunologia , Masculino , Ativação Viral
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