期刊
IMMUNOLOGICAL REVIEWS
卷 294, 期 1, 页码 164-176出版社
WILEY
DOI: 10.1111/imr.12841
关键词
autoimmune disease; regulatory T cells; rheumatoid arthritis; TCR signaling; Th17; ZAP-70
类别
资金
- Japan Society for the Promotion of Science [16H06295, 17K19553]
- Core Research for Evolutional Science and Technology (CREST) Japan Agency for Medical Research and Development (AMED) [JP19gm0010005]
- Leading Advanced Projects for Medical Innovation (LEAP) Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [17K19553] Funding Source: KAKEN
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.
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