Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Abstract

Mutations of the genes encoding T‐cell receptor (TCR)‐proximal signaling molecules, such as ZAP‐70, can be causative of immunological diseases ranging from T‐cell immunodeficiency to T‐cell–mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap‐70 gene, spontaneously develop T‐cell–mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap‐70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self‐peptides/MHC complexes, shifting self‐reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self‐reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self‐peptide/MHC complexes on antigen‐presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL‐6 to drive the arthritogenic T cells to differentiate into arthritogenic T‐helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte‐macrophage colony‐stimulating factor‐secreting effector Th17 cells, mediating chronic bone‐destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune‐suppressing Treg cells to treat and prevent RA.

Protectin DX restores Treg/Th17 cell balance in rheumatoid arthritis by inhibiting NLRP3 inflammasome via miR-20a

“…Rheumatoid arthritis (RA) is a chronic autoimmune disease that progressively destroys the articular cartilage and bones of the joints 1 . Although its precise pathogenesis remains unclear, studies indicate that regulatory T-cell (Treg)/T-helper 17 (T h 17) cell imbalance might play a role in the progression of RA 2 . Notoriously, T h 17 cells mediate the pro-inflammatory response via interleukin-17A (IL-17A) and tumor necrosis factor alpha (TNF-α) secretion, which leads to tissue destruction as well as damage to articular cartilage and bone; 3 meanwhile, Tregs mediate the anti-inflammatory response via IL-10 and TGF-β secretion, which maintains a state of autoimmune tolerance 4 , 5 .…”

Role of Extracellular Vesicles in Autoimmune Pathogenesis

“…In normally functioning immune systems, there are various tolerance mechanisms that play a protective role in preventing an autoreactive lymphocyte response ( 1 ). In autoimmune diseases, immune cell tolerance mechanisms become problematic, leading to the stimulation of autoreactive T and B lymphocytes ( Figure 1 ) ( 2 – 5 ). Additionally, the interaction of various inflammatory cytokines and chemokines can lead to an imbalance between regulatory (e.g., Tregs) and inflammatory cells (e.g., Th17 cells), as well as abnormal autoantigen clearance mechanisms and antigen presentation, all of which can result in the development of autoimmune diseases ( 6 , 7 ).…”

The role and research progress of the balance and interaction between regulatory T cells and other immune cells in obesity with insulin resistance

“…Treg cells can directly interact with macrophages in tissues and inhibit the activation of T effector cells by blocking the interaction of APCs with CD4 + T effector cells [63,64]. Thus, Treg cells may be able to prevent metabolic disorders by interacting with macrophages to reduce the inflammatory response of adipose tissue.…”