Loss of CIKS/Act1, the signaling adaptor for IL-17 family cytokines, significantly ameliorates development of fatal disease in the Fcgamma RIIB-deficient mouse model for lupus (101.18)

Abstract

Abstract CIKS (Act1 or TRAF3IP2) is an adaptor protein required for signaling by receptors of the IL-17 family of cytokines. CIKS has been shown to be vital for disease in autoimmune mouse models of CIA and EAE. IL-17A may promote spontaneous germinal centers formation in the lupus prone BXD2 mice. However, the significance of IL-17 cytokines in the clinical outcome of lupus disease has never been addressed. Here we show that Th17 cell numbers are increased in Fcgr2b-deficient mice and IL-17 cytokine signaling is critically involved in disease development in this lupus model. Loss of CIKS significantly reduced mortality rates in Fcgr2b-deficient mice. Unexpectedly, the reduced mortality was not correlated with lower levels of antibodies to ANA or anti-dsDNA. Nevertheless, loss of CIKS on an FcgR2b-deficient background did reduce the formation of spontaneous germinal centers, which correlated with a diminished rate of isotype switching and plasma cell differentiation; furthermore, the generation of T-cell effectors was slowed. Most importantly, loss of CIKS profoundly reduced severe glomerulonephritis and inflammatory cell infiltrations in kidneys, key events in the fatal outcome of the lupus-like disease in Fcgr2b-deficient mice. These novel findings suggest that IL-17 family cytokines signaling via CIKS play critical roles in the pathogenesis of lupus disease in Fcgr2b-deficient mice; these findings also position CIKS as a potential new target for therapeutic intervention in SLE.