In Irf5−/− and Irf5+/− RII Yaa mice, all four IgG isotypes were d

In Irf5−/− and Irf5+/− RII.Yaa mice, all four IgG isotypes were dramatically decreased, whereas sera IgG1 levels in Irf5+/− RII mice were comparable with Irf5+/+ RII mice [[23]]. In the pristane-induced model of murine lupus, we found that JAK drugs Irf5−/− mice had only striking reductions in IgG2a/c and IgG2b antibody levels whereas IgG1 levels were elevated. These data suggest

that a lack of Irf5 does not reduce long-lived IgG1 expressing plasma cells. After class switching, autoreactive B cells may undergo further selection and expansion. In order to address the role of IRF5 in selecting or expanding B-cell clones with autoreactive specificity, we examined the production of antigen-specific IgG1. We found that Irf5−/− mice are deficient in their production of lupus IgG1 autoantibodies, suggesting that a mechanism other than class switching regulates antigen specificity in these mice. Instead, IRF5 may be critical for selection or expansion of autoreactive clones from the B-cell repertoire. The selective impairment of TLR7- and not TLR9-associated IgG1 autoantibody production indicates

a distinct and likely more critical role for IRF5 in mediating TLR7 signaling in pristane-induced lupus. Whether this proves true in human SLE is not currently known. CSR of B cells from IgM to IgG is dependent on the cognate interaction of B cells with Th cells [[49]]. Although CD40L–CD40 interaction is necessary to initiate Ab isotype switching [[50]], it is assumed that Th cell-derived cytokines determine whether B cells are switched to IgG1 or IgG2a [[51]]. IFN-γ and IL-4 are key cytokines of Th1 and Th2 cells, respectively, although IL-5, Small Molecule Compound Library IL-10, and IL-13 are also produced by Th2 cells. To determine whether the cytokine milieu in Irf5−/− mice contribute to their production

(or inhibition) of IgG isotypes, we measured serum cytokine levels in response to pristane. The Th2 cytokines IL-4 and IL-5 were significantly upregulated in the serum of pristane-injected Irf5−/− mice; intracellular IL-4 was also elevated Alanine-glyoxylate transaminase in CD4+ T cells from pristane-injected Irf5−/− mice (Fig. 4A). IL-4 and IL-5 have been shown to be protective against SLE in certain murine models [[35, 52]]. These data support a Th2 polarization in Irf5−/− mice that would be expected to drive IgG1 class switching. However, Th2 polarization does not necessarily entail inhibition of Th1 as Th1/Th2 coexist and tipping the balance one way or the other is all that may be required to affect a systemic autoimmune disease such as lupus [[53, 54]]. Indeed, we did not observe downregulation of the key Th1 cytokine IFN-γ in T cells. Given that IgG2a/c CSR is induced by IFN-γ, and Irf5−/− mice make sufficient levels to induce IgG2a CSR (Fig. 4A), the inability of Irf5−/− mice to produce IgG2a/c autoantibodies in the presence of IFN-γ provides further support for an intrinsic defect in IgG2a/c CSR.

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