Type I interferons (IFNalpha/beta) participate to the development of protective (anti-viral) and abnormal (auto) immune responses. Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease associated with high titers of auto-antibodies specific for nuclear antigens (e.g. anti-dsDNA) that form immune-complexes at the origin of tissue damages (skin, kidney, cerebral). SLE patients display an over expression of type I IFN that correlates with disease activity, suggesting that type I IFN represent key pathogenic factors in SLE. Type I IFN induce monocyte differentiation into mature DC (that contribute to break tolerance to self antigens) and also participate to the unusual features of blood B cells in SLE. SLE therapy is based on nonspecific immunosuppressants; a curative treatment is particularly needed to prevent disease progression to irreversible organ damages. Different strategies based on the inhibition of type I IFN signaling are currently studied. Nowadays, the mechanisms that lead to the unabated type I IFN production in SLE remain discussed. Microbial-derived components that signal via some pattern recognition receptors (such as endosomal members of the Toll-like receptors (TLR) family and RNA helicases) are usually considered as the main type I IFN inducers. In SLE, it has been proposed that DNA-anti-DNA immune-complexes may contribute to sustained type I IFN secretion by plasmacytoid dendritic cells (via CD32 and TLR9). In our laboratory, we have identified the first cytokine that induces type I IFN production by immune cells (plasmacytoid dendritic cells and natural killer cells), IL-26. IL-26 is a recently identified cytokine from the IL-10-related cytokine family whose production and biological activities remain poorly understood. Our data also demonstrate that IL-26 acts on immune cells via a receptor composed of IL-10R2 and of a still unidentified element. Surprisingly, we observed that serum from SLE patients displayed elevated levels of IL-26, compared to healthy subjects, which correlated with disease activity. Based on this original information, the aim of this project is to define the role of IL-26 in SLE pathogenesis and in type I IFN over expression in order to determine whether IL-26 and/or its receptor may constitute future therapeutic target(s) in SLE. Consequently, in a first axis, we will study the biology of IL-26 by identifying (i) the second chain of the IL-26 receptor expressed by immune cells, (ii) the cell types and stimuli involved in IL-26 production, and (iii) the cells that are sensitive to IL-26 and analyze their response to IL-26 with a focus on type I IFN production and on the repercussion on B cell growth and differentiation. In a second axis, we will determine the role of IL-26 in SLE physiopathology by (i) identifying in vitro and ex vivo, by immunofluorescence on biopsies from SLE damaged tissues, the nature of the IL-26-producing cells in SLE, (ii) analyzing and comparing in vitro the type I IFN-inducing capacity of circulating IL-26 versus IC and, (iii) by determining the in vivo role of IL-26 in the unabated expression of type I IFN and in the initiation versus progression of SLE; as mice do not express the IL-26 gene and are not sensitive to human IL-26, we will used an established model of SCID mice engrafted with cells from SLE patients. In addition to highlighting a new pathway involved in the regulation of type I IFN production, the ambition of this project is to determine whether IL-26 and/or its receptor may constitute novel therapeutic target(s) in the treatment of SLE, and potentially other auto-immune disorders associated to unabated type I IFN production (rheumatoid arthritis, dermatomyositis,…). The fact that IL-26 may act downstream type I IFN renders IL-26 as a promising target. Such an approach may allow to design therapies that are more specific and with fewer side effects. The close collaboration established between the physicians of the Nephrology Dpt and the Medical Biologists of the Immunology Dpt (both having expertise in the follow up of patients with auto-immune disorders) and the immunologists of the INSERM U564 (staff 2, specialized in the role of innate immunity on adaptive immune responses) is a major asset for a fruitful development of this project that involves both fundamental and pre clinical research.