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Hsu HC, Yang P, Wang J et al.Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9:166-175

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Nature Immunology (Impact Factor: 24.97). 03/2008; 9(2):166-75. DOI: 10.1038/ni1552
Source: PubMed

ABSTRACT Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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    • "It promotes Th17 cells and activates B cells in an autocrine manner. The IL-6-induced Th17 cells orchestrate the development of GC by autoreactive lymphocytes (Hsu et al, 2008), as recently shown to take place in pathological SG (Le Pottier et al, 2009b). We have also provided evidence that IL-6 favors the expression of RAG and therefore secondary Ab gene rearrangements as well as auto-Ab synthesis (Hillion et al, 2007). "
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    • "These cytokines bind to multimeric IL-17 receptors comprised of two IL-17RA subunits and one IL-17RC subunit [19]. Work has focused attention on the pathogenic function of the IL-17A in several organ-specific autoimmune and chronic inflammatory diseases as SLE [20] and in particular, IL-17 has been reported as the central cytokine involved in the spontaneous development of germinal center (GC) B cell-derived autoantibodies in autoimmune BXD2 mice [21]. However, the involvement of IL- 17A in the ASC differentiation and maintenance is still largely unknown. "
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    • "Distinct from its pro-inflammatory effects, IL-17 promotes autoimmune disease by enhancing formation of spontaneous germinal centers (GCs), as shown by autoimmune BXD2 recombinant inbred mouse strain which spontaneously develop glomerulonephritis and erosive arthritis. These mice express more IL-17 than wild-type counterparts and show spontaneous development of GCs by retaining B cells and promoting CD4 T-cell and B-cell interactions, resulting in increased autoimmune antibodies (Hsu et al. 2008). Furthermore, long-lasting apoptosis-resistant Th17 cells activate B cells and their immunoglobulin production mediated by IL-21. "
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