T helper involvement in proteoglycan-induced arthritis

Proteoglycan-induced arthritis (PGIA) is a murine model of rheumatoid arthritis (RA) mimicking many aspects of human disease. Similar to RA, PGIA is an autoimmune disease critically dependant on CD4+ T helper cells. Here we investigate the requirements of a variety of T helper transcription factors and cytokines in promoting autoimmune inflammation. We have previously described PGIA as being a T1 (IFN-gamma) mediated disease operating via STAT4, a transcription factor activated by the antigen-presenting cell (APC) derived cytokine IL-12. Recently IL-12 has been delineated into a family of related cytokines and has revealed a new pathogenic T helper subset that secretes IL-17 (Th17) to be responsible for the inflammation seen in two prominent mouse models of autoimmunity previously thought to be IFN-gamma mediated. IFN-gamma has been found to regulate the expression of IL-17. In light of these data we sought to reexamine the role of multiple components of the Th1 and Th17 pathways in PGIA.;Here we re-assert the Th1 nature of PGIA by demonstrating the utilization of the IL-12/STAT4/IFN-gamma pathway. We describe the central function of STAT4 in PGIA as a result of its ability to generate IFN-gamma and IL-17 and for the clearance of subsequent inflammation via CCR5.;We also find a redundant role for the important Th1 transcription factor T-bet for inflammation in PGIA and reveal the disease in T-bet-/- mice correlates with significantly elevated IL-17, a phenomena requiring STAT4 for IFN-gamma and IL-17 production. Further examination of the disease in T-bet-/- mice revealed a crucial role for IL-17 as determined using mice deficient in both T-bet and IL-17. Importantly, we conclude the IL-17 dependence of disease seen in IFN-gamma impaired or ablated mice (T-bet -/- and IFN-gamma-/- mice, respectively) demonstrates both Th1 and Th17 populations as capable of mediating autoimmunity in a classically Th1 disease model.