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Cytokine. 2008 Feb;41(2):105-13. Epub 2007 Dec 3.

Act1 modulates autoimmunity through its dual functions in CD40L/BAFF and IL-17 signaling.

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  • 1Department of Immunology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.


Coordinated regulation of T and B cell-mediated immune responses plays a critical role in the control and modulation of autoimmune diseases. This review is focused on the adapter molecule Act1 and its regulation of autoimmunity through its impact on both T and B cell-mediated immune responses. Whereas Act1 molecule is an important negative regulator for B cell-mediated humoral immune responses through its function in CD40L and BAFF signaling, recent studies have shown that Act1 is also a key positive signaling component for IL-17 signaling pathway, critical for T(H)17-mediated autoimmune and inflammatory responses. The dual functions of Act1 are evident in Act1-deficient mice that displayed B cell-mediated autoimmune phenotypes (including dramatic increase in peripheral B cells, lymphadenopathy and splenomegaly, hypergammaglobulinemia and Sjogren's disease in association with Lupus Nephritis), but showed resistance to T(H)17-dependent EAE and colitis. Such seemingly opposite functions of Act1 in CD40-BAFFR and IL-17R signaling are orchestrated by different domains in Act1. Whereas Act1 interacts with the IL-17R through the C-terminal SEFIR domain, Act1 is recruited to CD40 and BAFFR indirectly, which is mediated by TRAF3 through the TRAF binding site in Act1. Such delicate regulatory mechanisms may provide a common vehicle to promote balance between host defense to pathogens and tolerance to self.

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