Background/Purpose

Type 1 interferon (IFN) is strongly implicated in lupus pathogenesis, and patients with SLE frequently express a “type 1 IFN gene signature”. Type 1 IFN promotes B cell activation in vitro suggesting a direct role for type 1 IFN in humoral autoimmunity. However, it is unclear whether type 1 IFN impacts lupus pathogenesis via B cell-intrinsic or –extrinsic mechanisms. We previously described the Wiskott Aldrich syndrome (WAS) model of B cell-driven autoimmunity (Becker-Herman et al., JEM 2011, 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 describe the impact of B cell-intrinsic deletion of the type 1 interferon receptor (ifnar) in the WAS chimera model.

Methods

Proliferation of wild-type (WT), was-/-, ifnar-/- and double-deficient was-/-.ifnar-/- marginal zone B cells was quantified after stimulation with LPS (TLR4 agonist), R848 (TLR7 agonist) and CPG (TLR9 agonist) +/- IFN-β. To test the impact of B cell-intrinsic type 1 IFN activation in lupus pathogenesis in vivo we established bone marrow chimeras in which B cells were WT, was-/-, or was-/-.ifnar-/-; hereafter be referred to as B^WT, B^WAS-/-, and B^W/IFNAR-/-. Chimeras were analyzed for autoantibodies, immune activation and development of immune-complex glomerulonephritis by ELISA, flow cytometry and immunohistochemistry.

Results

We previously showed that autoimmunity in the WAS chimera model is dependent on B cell-intrinsic TLR7 activation (Jackson et al. J Immunol 2014). Ifnar-deficient B cells demonstrated a specific defect in TLR7-induced proliferation, while TLR4 and TLR9 responses were unaffected. In addition, recombinant IFN-β enhanced TLR7 responses, without impacting TLR4/TLR9 activation. These data suggest a role of B cell-intrinsic type 1 IFN signals in lupus pathogenesis. To test this hypothesis, we generated chimeras with B cells double-deficient in was and ifnar. Surprisingly, although type 1 IFN promoted B cell TLR7 activation in vitro, autoantibodies to RNA-associated antigen sm/RNP were equivalent in B^WAS-/- and B^W/IFNAR-/- animals. Further, B cell-intrinsic ifnar deletion had no impact on immune activation manifest by: splenomegaly; CD4+ T cell expansion; and generation of T follicular helper cells and germinal center B cells. Finally, we demonstrate that B cell-intrinsic ifnar deletion does not impact immune-complex glomerulonephritis.

Conclusion

The importance of type 1 IFN in the pathogenesis of SLE has been well established by both human studies and murine lupus models. Type 1 IFN promote TLR7-mediated B cell activation in vitro, suggesting a direct role for type 1 IFN on B cells in lupus pathogenesis. Despite these in vitro data, we demonstrate that TLR7-dependent humoral autoimmunity can develop independently of B cell-intrinsic ifnar activation. To our knowledge, this is the first study to directly address the impact of B cell type 1 IFN activation in murine lupus, of relevance to both the understanding of disease pathogenesis and to efforts to target type 1 IFN therapeutically in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-intrinsic-deletion-of-the-type-1-interferon-receptor-does-not-impact-the-development-of-murine-lupus/