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Altered Th17/Treg balance and dysregulated IL-1β response influence susceptibility/resistance to experimental autoimmune arthritis

This study was aimed at gaining an insight into immune mechanisms of differential susceptibility to autoimmunity of individuals sharing the same major histocompatibility complex by studying arthritis-susceptible Lewis (LEW) and arthritis-resistant Wistar Kyoto (WKY) rats (both RT.1l) using the adjuvant arthritis (AA) model of rheumatoid arthritis (RA). Lymph node cells (LNC) and synovium-infiltrating cells (SIC) of LEW and WKY rat subjected to an arthritogenic challenge were tested. The frequency of T helper 17 (Th17) and T regulatory (Treg) cells was determined by flow cytometry, whereas serum and spleen adherent cell (SAC)-derived supernatant were analyzed for specific cytokines and chemokines. We observed that WKY rats are not deficient in generating a Th17 response to the arthritogenic challenge in LNC (periphery); however, the Th17/Treg ratio is markedly reduced in the joint (target organ) of WKY versus LEW rats because of reduced Th17 levels therein in WKY rats. These results suggest differential and selective decrease in Th17 cell migration into the joints of WKY rats. Interestingly, serum levels of chemokines RANTES and MCP-1 were reduced in WKY rats. Furthermore, WKY rats showed reduced serum IL-1β level in vivo but no defect in IL-1β production by SAC in vitro, suggesting an effective in vivo regulation of IL-1β response. We also unraveled the role of interferon-γ (IFNγ), which we have previously reported to be increased in WKY versus LEW rats, in regulation of IL-1β. Thus, reduced Th17/Treg ratio in the target organ (joints) and decreased systemic IL-1β might contribute to the AA-resistance of WKY rats; whereas the converse factors render LEW more vulnerable to AA.