Background/Purpose: Type 1 interferon (IFN) is strongly implicated in lupus pathogenesis, and SLE patients frequently express a “type 1 IFN gene signature”. The type 2 interferon, IFN gamma (IFN-γ), has also been implicated in lupus development via direct activation of autoreactive T cells. Although B cells are critical in lupus pathogenesis, whether these cytokines exert cell-intrinsic impacts on autoantibody-producing B cells has not been studied. We recently developed a chimeric murine lupus model in which Wiskott-Aldrich syndrome protein (WAS)-deficient B cells promote spontaneous humoral autoimmunity (Jackson, et al. J Immunol 2014). An important advantage of the WAS chimera model is that dysregulated immune responses are limited to the B cell compartment, allowing genetic manipulation in a B cell-intrinsic fashion. In the current study, we contrast the impact B cell-intrinsic type 1 interferon and IFN-γ signals on serum autoantibody titers, systemic inflammation and the development of lupus nephritis.

Methods: Using the WAS chimera model of spontaneous humoral autoimmunity, we deleted the type 1 IFN receptor (IFNAR) or IFN-γ receptor (IFNgR) on all hematopoietic cells (“global deletion”), or specifically on B cells (“B cell-intrinsic”). Chimeras were analyzed for autoantibodies, immune activation and immune-complex glomerulonephritis (IC GN) by ELISA, flow cytometry and immunohistochemistry.

Results: Surprisingly, although type 1 IFN enhanced B cell responses in vitro, B cell-intrinsic IFNAR deletion exerted minimal impacts on lupus pathogenesis. To address whether other cytokines promote B cell activation in this model, we quantified cytokine production ex vivo, and noted prominent CD4 T cell IFN-γ production in diseased WAS chimeras. Consistent with this, global IFNγR deletion prevented autoantibody (Ab) production and systemic inflammation in WAS chimeras. Strikingly, cell-intrinsic deletion of IFN-γR on either T cells or B cells recapitulated the phenotype of global IFNγR deficiency. Mechanistically, deletion of IFNγR on B cells prevented the formation of spontaneous germinal centers (GCs), required for class-switched Ab formation. Consistent with lack of serum autoantibodies, lupus nephritis was abrogated in B cell IFNγR-null chimeras.

In addition to Ab formation, B cells promote autoimmunity via antigen presentation and production of cytokines. Based on prominent B cell IFN-γ production in this model, we hypothesized that B cell-derived IFN-γ enhances spontaneous GC formation. In contrast, rendering B cells unable to produce IFN-γ did not alter the development of murine lupus suggesting that other cellular IFN-γ sources compensate for lack of B cell-derived IFN-γ.

Conclusion: We report the novel observation that IFN-γ, and not type 1 IFN, signals promote systemic lupus via direct actions on B cells. Mechanistically, IFN-γ promotes the formation of spontaneous autoimmune GCs via reciprocal activation of GC B cells and T follicular helper cells. To our knowledge, this study is the first to directly address the impact of B cell IFN-γ activation in murine lupus, of relevance to both the understanding of disease pathogenesis and to efforts to target IFN-γ therapeutically in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-intrinsic-interferon-gamma-signals-promote-the-development-of-systemic-lupus-erythematosus-by-enhancing-the-formation-of-spontaneous-autoimmune-germinal-centers/