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The Journal of Experimental Medicine
Year: 2010  |  Volume: 207  |  Issue: 8  |  Page No.: 1757 - 1773

Myeloid cells, BAFF, and IFN-{gamma} establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice

P Scapini, Y Hu, C. L Chu, T. S Migone, A. L DeFranco, M. A Cassatella and C. A. Lowell    

Abstract:

Autoimmunity is traditionally attributed to altered lymphoid cell selection and/or tolerance, whereas the contribution of innate immune cells is less well understood. Autoimmunity is also associated with increased levels of B cell–activating factor of the TNF family (BAFF; also known as B lymphocyte stimulator), a cytokine that promotes survival of self-reactive B cell clones. We describe an important role for myeloid cells in autoimmune disease progression. Using Lyn-deficient mice, we show that overproduction of BAFF by hyperactive myeloid cells contributes to inflammation and autoimmunity in part by acting directly on T cells to induce the release of IFN-. Genetic deletion of IFN- or reduction of BAFF activity, achieved by either reducing myeloid cell hyperproduction or by treating with an anti-BAFF monoclonal antibody, reduced disease development in lyn–/– mice. The increased production of IFN- in lyn–/– mice feeds back on the myeloid cells to further stimulate BAFF release. Expression of BAFF receptor on T cells was required for their full activation and IFN- release. Overall, our data suggest that the reciprocal production of BAFF and IFN- establishes an inflammatory loop between myeloid cells and T cells that exacerbates autoimmunity in this model. Our findings uncover an important pathological role of BAFF in autoimmune disorders.

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