RESUMO
CD4+ T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4+ T cells pathogenic functions. Here, we identified a TLR4+ follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4+ T cells possess a two-pronged pathogenic activity whereby direct TLR4+ engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4+ T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4+ T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program.
Assuntos
Artrite Reumatoide/metabolismo , Líquido Sinovial/química , Linfócitos T/metabolismo , Receptor 4 Toll-Like/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor 4 Toll-Like/metabolismoRESUMO
This review provides an overview of the biochemistry of thiol redox couples and the significance of thiol redox homeostasis in neurodegenerative disease. The discussion is centred on cysteine/cystine redox balance, the significance of the xc(-) cystine-glutamate exchanger and the association between protein thiol redox balance and neurodegeneration, with particular reference to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and glaucoma. The role of thiol disulphide oxidoreductases in providing neuroprotection is also discussed.
Assuntos
Doenças Neurodegenerativas/patologia , Compostos de Sulfidrila/química , Cisteína/química , Cisteína/metabolismo , Glaucoma/metabolismo , Glaucoma/patologia , Glutarredoxinas/química , Glutarredoxinas/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Oxirredução , Peroxirredoxinas/química , Peroxirredoxinas/metabolismo , Compostos de Sulfidrila/metabolismo , Tiorredoxinas/química , Tiorredoxinas/metabolismoRESUMO
T cells are required for an effective adaptive immune response. The principal function of T cells is to promote efficient removal of foreign material by identifying and mounting a specific response to nonself. A decline in T cell function in aging is thought to contribute to reduced response to infection and vaccination and an increase in autoimmunity. This may in part be due to the age-related decrease in naïve CD4(+) T cells and increase in antigen-experienced CD4(+) T cells, loss of redox homeostasis, and impaired metabolic switching. Switching between subsets is triggered by the integration of extracellular signals sensed through surface receptors and the activation of discrete intracellular metabolic pathways. This article explores how metabolic programming and loss of redox homeostasis during aging may contribute to age-associated changes in T cell phenotype and function.
