The Role of the Interferon-Gamma-Jak/STAT Pathway in Rheumatoid Arthritis

Type I IFN- and type II IFN- interferons are important mediators of autoimmunity. Our group recently showed a strong association of IFN- receptor 1 Ifngr1 expression and of IFN- receptor 2 Ifngr2 expression in peripheral blood mononuclear cells PBMC with the presence of RA and its radiographic severity, respectively Arthritis Rheumatol. 2015 671165. IL-2 has essential regulatory function in inflammatory diseases and is considered as a potential therapy for autoimmune disease. We tested the hypothesis that RA is associated with alterations in IFN- and IL-2 STAT signaling within certain subsets of PBMCs. We used a high-definition phospho-flow approach to evaluate the activation of STAT1, STAT3 and STAT5 after IFN- or IL-2stimulation. We analyzed PBMCs from 37 RA patients and 12 healthy controls HC for activation of STATs in specific CD4and CD8 T cells subpopulations, B cells and monocytes. We found that IFN- induced STAT1 activation was significantly greater in RA nave, central memory, Tfh and Treg subsets of CD4 T cell populations compared to HC p0.05. IL-2 very efficiently activated STAT5 in all T and B cell populations in RA and HC. The activation of STAT5 in RA was significantly greater than HC in only one population effector memory CD4 T cells p0.01. Our studies revealed the presence of a STAT5phosphatase in RA T cell subsets that likely counteracts IL-2 regulator activity and contribute to the pathogenesis of RA.