Assuntos
Anti-Infecciosos/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Anti-Infecciosos/história , Antimaláricos/história , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/história , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Doenças Transmissíveis/história , História do Século XX , História do Século XXI , Humanos , Prêmio NobelRESUMO
Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-naïve African cohort to investigate the association with incident pulmonary and/or extra-pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron-related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed.
Assuntos
Infecções por HIV/sangue , Hepcidinas/sangue , Tuberculose Pulmonar/sangue , Tuberculose/sangue , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Gâmbia/epidemiologia , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Fatores de Tempo , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Adulto JovemRESUMO
The iron overload disease hereditary haemochromatosis (HH) occurs in about 1 in 300 Caucasians; the protein mutated in this disorder is termed HFE.(1) HFE is homologous to major histocompatibility complex (MHC) class I proteins, but unlike MHC class I molecules, HFE does not present peptides to T cells.(2) The transferrin receptor (TfR) is a ligand for HFE, and the crystal structure of the HFE-TfR complex has been determined.(3) The many interesting features of this structure illustrate the diverse roles of the MHC fold in nature and clarify how HFE affects TfR function. Whether the interaction between HFE and TfR explains the pathogenesis of HH is not so clear.
Assuntos
Antígenos HLA/química , Antígenos HLA/fisiologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/fisiologia , Proteínas de Membrana , Hemocromatose/genética , Hemocromatose/imunologia , Hemocromatose/metabolismo , Proteína da Hemocromatose , Humanos , Ferro/metabolismo , Mutação , Receptores da Transferrina/metabolismoRESUMO
Immune responses against foreign antigens are initiated and controlled by dendritic cells (DCs). Accumulating evidence suggests that autoimmunity, involving T cells directed against self, can also be primed by DCs. We propose that DCs could induce autoimmunity following their differentiation by certain cytokines, or because of intrinsic defects in genes controlling DC function. Both processes result in DCs that behave deviantly.
Assuntos
Doenças Autoimunes/imunologia , Células Dendríticas/fisiologia , Animais , Doenças Autoimunes/genética , Diferenciação Celular/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Interferon gama/genética , Interferon gama/farmacologia , Interleucina-6/genética , Interleucina-6/farmacologia , Camundongos , Camundongos Knockout , Mutação , Ratos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
T cells recognizing poorly displayed self determinants escape tolerance mechanisms and persist in the adult repertoire. The process by which these T cells are primed is not clear, but once activated, they can cause autoimmunity. Here, we show that dendritic cells treated with interleukin 6 (IL-6) process and present determinants from a model native antigen in a qualitatively altered hierarchy, activating T cells in vitro and in vivo against determinants that were previously cryptic because of poor display. IL-6 does not induce conventional maturation of dendritic cells but alters the pH of peripheral, early endosomal compartments and renders the cells more susceptible to killing by chloroquine. Acidification of endosomes by ouabain mimics the effect of IL-6 and allows processing of the same cryptic determinant. These results suggest that cytokines such as IL-6 could initiate and help to propagate an autoimmune disease process by differentiating dendritic cells into a state distinct from that induced by normal maturation.
