RESUMO
Signalling through Toll-like receptors (TLRs) may play a role in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). In the present study, the expression of TLR-2, -4 and -9 was significantly higher on CD4+ and CD8+ T-cells from MS patients compared to healthy individuals. Following in-vitro activation, the proportion of interleukin (IL)-17+ and IL-6+ CD4+ and CD8+ T-cells was higher in the patients. In addition, the proportion of IFN-γ-secreting TLR+ CD8+ T-cells was increased in MS patients. Among different IL-17+ T-cell phenotypes, the proportion of IL-17+ TLR+ CD4+ and CD8+ T-cells producing IFN-γ or IL-6 were positively associated with the number of active brain lesions and neurological disabilities. Interestingly, activation of purified CD4+ and CD8+ T-cells with ligands for TLR-2 (Pam3Csk4), TLR-4 [lipopolysaccharide (LPS)] and TLR-9 [oligodeoxynucleotide (ODN)] directly induced cytokine production in MS patients. Among the pathogen-associated molecular patterns (PAMPs), Pam3Csk4 was more potent than other TLR ligands in inducing the production of all proinflammatory cytokines. Furthermore, IL-6, IFN-γ, IL-17 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels produced by Pam3Csk4-activated CD4+ cells were directly associated with disease activity. A similar correlation was observed with regard to IL-17 levels released by Pam3Csk4-stimulated CD8+ T-cells and clinical parameters. In conclusion, our data suggest that the expansion of different T helper type 17 (Th17) phenotypes expressing TLR-2, -4 and -9 is associated with MS disease activity, and reveals a preferential ability of TLR-2 ligand in directly inducing the production of cytokines related to brains lesions and neurological disabilities.
Assuntos
Interleucina-17/metabolismo , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Imunofluorescência , Humanos , Masculino , Esclerose Múltipla/diagnóstico , Índice de Gravidade de Doença , Transdução de Sinais , Receptores Toll-Like/genética , Adulto JovemRESUMO
Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but their potential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W(v) or Wsh/Wsh) and the adoptive transfer of mast cells. Mast cell deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-ß, and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells, and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells.