The findings presented here strongly support a multifaceted role

The findings presented here strongly support a multifaceted role for

ITF2357 solubility dmso IRF5 in the regulation of autoimmunity. Consistent with recent reports [[23]], we show that IRF5 is required for the development of ANAs in response to pristane. We replicate the lack of IgG2a/c autoantibodies in pristane-injected Irf5−/− mice [[24]]; however, in addition, we found that a defect in IgG2a/c class switch recombination (CSR) is already present in naive Irf5−/− mice (Supporting Information Fig. 1B). A similar defect in the generation of IgG2a and 2b was shown in Tlr9- and Myd88-deficient FcγRIIB−/−.B6 lupus mice and T-bet-deficient MRL/lpr mice [[46, 47]]. These results implicate IRF5 as a critical factor regulating both basal and stimuli-induced IgG2a/c class switching.

The finding that Irf5 is required for pristane-induced IgG2a/c and IgG2b hypergammaglobulinemia and not IgG1 hypergammaglobulinemia led us to examine whether the skewing of IgG isotypes was an intrinsic or extrinsic effect. Data from in vitro stimulations examining IgG1 class switching support a B-cell intrinsic defect in Irf5−/− mice (Supporting Information Fig. Raf kinase assay 3). Whether T-cell intrinsic/extrinsic defects in Irf5−/− mice as well contribute to the overall skewing of IgG isotypes is not currently clear. Data from Savitsky et al. [[24]] suggest that in vitro T-cell polarization is unaffected in Irf5−/−mice,

while in vivo data presented here indicate impaired production of IL-4 in CD4+ T cells from pristane-injected Irf5−/− mice (Fig. 4A). Together, these data suggest a T-cell Thiamet G extrinsic defect in Irf5−/− mice. Similar to findings by Richez et al. [[23]], we observed a defect in T-cell activation in Irf5−/− mice (Fig. 4B). Additional studies are required to clarify the role of IRF5 in T-cell polarization, activation, and function. Nevertheless, results from the present study suggest that dysregulation of IRF5 expression in human SLE is likely to affect both B- and T-cell function(s) ultimately contributing to pathogenic autoantibody production. In animal models, TLR9 contributes to the development of anti-chromatin autoantibodies and TLR7 to the development of anti-RNP autoantibodies; MyD88 and a number of transcription factors including IRF5 mediate the effects of TLR7/9 engagement [[48]]. Our data indeed support a downstream role for IRF5 in both TLR pathways since Irf5-deficient mice are unable to generate TLR7- or TLR9-associated IgG2a autoantibodies (Supporting Information Fig. 1A); however, they do not preclude a TLR-independent role for IRF5 in autoantibody production since antigen specificity could not be addressed by studying the IgG2a isotype. Indeed, a thorough analysis of nonisotype-specific autoantibodies in Irf5-deficient RII.Yaa mice led Richez et al.

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