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Science ; 361(6404): 810-813, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30026316


RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.

Artrite/genética , Doenças Inflamatórias Intestinais/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Imunodeficiência Combinada Severa/genética , Alelos , Artrite/imunologia , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Linfopenia/genética , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Linhagem , Imunodeficiência Combinada Severa/imunologia
J Allergy Clin Immunol ; 137(1): 204-213.e3, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26365387


BACKGROUND: Anti-cytokine autoantibodies (ACAAs) are pathogenic in a handful of rare immunodeficiencies. However, the prevalence and significance of other ACAAs across immunodeficiencies have not yet been described. OBJECTIVE: We profiled ACAAs in a diverse cohort of serum samples from patients with immunodeficiency and assessed the sensitivity and specificity of protein microarrays for ACAA identification and discovery. METHODS: Highly multiplexed protein microarrays were designed and fabricated. Blinded serum samples from a cohort of 58 immunodeficiency patients and healthy control subjects were used to probe microarrays. Unsupervised hierarchical clustering was used to identify clusters of reactivity, and after unblinding, significance analysis of microarrays was used to identify disease-specific autoantibodies. A bead-based assay was used to validate protein microarray results. Blocking activity of serum containing ACAAs was measured in vitro. RESULTS: Protein microarrays were highly sensitive and specific for the detection of ACAAs in patients with autoimmune polyendocrine syndrome type I and pulmonary alveolar proteinosis, detecting ACAA levels consistent with those reported in the published literature. Protein microarray results were validated by using an independent bead-based assay. To confirm the functional significance of these ACAAs, we tested and confirmed the blocking activity of select ACAAs in vitro. CONCLUSION: Protein microarrays are a powerful tool for ACAA detection and discovery, and they hold promise as a diagnostic for the evaluation and monitoring of clinical immunodeficiency.

Autoanticorpos/sangue , Citocinas/imunologia , Síndromes de Imunodeficiência/imunologia , Humanos , Síndromes de Imunodeficiência/sangue , Análise Serial de Proteínas
N Engl J Med ; 365(2): 127-38, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21524210


BACKGROUND: The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS: We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS: We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS: These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).

Células Dendríticas/imunologia , Síndromes de Imunodeficiência/genética , Fatores Reguladores de Interferon/genética , Mutação , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos , Vacina BCG/genética , Vacina BCG/imunologia , Feminino , Genes Dominantes , Humanos , Lactente , Fatores Reguladores de Interferon/deficiência , Interleucina-12/biossíntese , Leucócitos Mononucleares/imunologia , Masculino , Modelos Moleculares , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Linhagem , Conformação Proteica , Alinhamento de Sequência
J Clin Invest ; 120(12): 4220-35, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21084748


Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Mutação , Proteínas de Ligação a RNA/genética , Selenoproteínas/deficiência , Adulto , Idoso , Sequência de Aminoácidos , Animais , Azoospermia/genética , Sequência de Bases , Criança , Pré-Escolar , Códon sem Sentido , DNA/genética , Feminino , Perda Auditiva Neurossensorial/genética , Humanos , Resistência à Insulina/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Distrofias Musculares/genética , Mutação de Sentido Incorreto , Linhagem , Transtornos de Fotossensibilidade/genética , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Selenocisteína/metabolismo , Selenoproteínas/metabolismo , Homologia de Sequência de Aminoácidos , Espermatogênese/genética , Linfócitos T/imunologia
Clin Infect Dis ; 38(1): e10-4, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14679469


We evaluated a patient with disseminated Mycobacterium tuberculosis and Mycobacterium chelonae infection, of which he died. He also developed autoimmune (type I) diabetes and primary hypothyroidism. His serum contained a high titer of immunoglobulin G autoantibody to interferon-gamma (IFN-gamma) capable of blocking in vitro responses to this cytokine by peripheral blood mononuclear cells from normal donors. These results suggest that autoantibodies to IFN-gamma can induce susceptibility to disseminated mycobacterial infection, which may be refractory to chemotherapy.

Autoanticorpos/sangue , Imunoglobulina G/sangue , Interferon gama/imunologia , Infecções por Micobactéria não Tuberculosa/imunologia , Tuberculose/imunologia , Autoimunidade , Diabetes Mellitus Tipo 1/etiologia , Suscetibilidade a Doenças , Humanos , Hipotireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/complicações , Mycobacterium chelonae/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/complicações