Lien et al. recently showed that Irf5−/− mice were impaired in their generation

of antigen-specific IgG1 by T cell-dependent or T cell-independent immunogens. [[33]]. A similar analysis revealed contrasting data demonstrating increased antigen-specific IgG1 production from Irf5−/− Selleck LGK 974 mice [[24]]. To clarify the role of IRF5 in generating antigen-specific IgG1 and to determine whether the observed increase in IgG1 hypergammaglobulinemia in Irf5−/− mice (Fig. 2A) results in elevated IgG1 autoantibody production, we analyzed autoantibody isotypes in Irf5+/+ and Irf5−/− mice 6 months postpristane injection. As expected, IgG2a/c and IgG2b autoantibodies against dsDNA, RiboP0, U1A, U1B′/B were absent or significantly reduced in pristane-injected Irf5−/− mice (Supporting Information Fig. 1A and data not shown). Similarly, serum anti-RiboP0 and anti-U1A

IgG1 levels were significantly reduced in Irf5−/− mice, whereas anti-dsDNA IgG1 autoantibodies were similar between Irf5+/+ and Irf5−/− mice (Fig. 2B). Given Selleck INK-128 that Irf5−/− mice have intact IgG1 class switching, the impaired production of certain IgG1 autoantibodies in this model of murine lupus supports the existence of a mechanism(s) other than class switching for the regulation of IgG1 autoantibodies by IRF5. Furthermore, the reduction in IgG1 anti-U1A, but not dsDNA, autoantibodies indicate that the TLR7-IRF5 axis is important for the development of pristane-induced autoantibodies and controls autoantibody

specificity. T helper (Th) 1 and 2 cells promote the production of IgG2a/c and IgG1, respectively; Th1-mediated autoimmune responses Obatoclax Mesylate (GX15-070) generate the more pathogenic autoantibodies and are thus associated with the progression of murine lupus [[34]]. Imbalance of Th1 and Th2 cytokine homeostasis is a prominent feature of both experimental and human SLE [[35, 36]]. Given that IRF5 has been linked to proinflammatory cytokine expression [[17]], and several cytokines, such as IL-4, IL-5, IL-6, and IL-10, are known to promote antibody production [[37-41]], serum cytokine levels in PBS- and pristane-injected Irf5+/+ and Irf5−/− littermates were measured using the MILLIPLEX mouse kit (Millipore, Billerica, MA, USA). As early as 2 weeks postinjection, serum levels of the Th2 cytokine IL-10 were significantly elevated in Irf5−/− mice compared with those of Irf5+/+ mice (Fig. 3A); 6 months postinjection, only Th2 cytokines IL-4 and IL-5 were upregulated (Fig. 3B). There was no difference in serum levels of the Th1 cytokine IL-12p40 (Fig. 3C). As expected, serum levels of IL-6 were decreased in Irf5−/− mice, whereas TNF-α levels remained unchanged between wild-type and Irf5−/− mice (Fig. 3C). The increase in serum Th2 cytokines may contribute to disease protection in Irf5−/− mice since Th2 cells promote production of the least pathogenic IgG1 isotype [[34]] observed in Irf5−/− mice (Fig. 2A).