Differential responses to autoantibody deposition in CD45E613R BALB/c and C57Bl/6-129 F1 glomeruli is mediated by alterations in the autoantibody repertoire and inflammatory renal mononuclear cells (BA3P.110)

Abstract

Abstract The mechanisms regulating the transition from autoreactivity to autoimmunity are poorly understood. CD45E613R mice express a point mutation in the juxtamembrane wedge that results in dysregulated phosphatase activity. Despite similar hyperactive ITAM-mediated signaling in multiple cell lineages, the phenotypic consequences of this mutation vary with genetic context. While both BALB/c and C57Bl/6-129 F1 CD45E613R mice develop similar high titer anti-nuclear antibodies (ANA) and immune complex deposition in the glomeruli, only F1 mice develop glomerulonephritis (GN). Here, we leverage these distinct phenotypes in the context of a common point mutation to define mechanisms leading to GN. BALB/c ANA are primarily anti-dsDNA while F1 ANA are anti-dsDNA, -H3 and -Sm/RNP. Consistent with this profile, F1 B cells have increased TLR7/9 signaling. Treatment of RAW264.7 cells with aged F1 but not BALB/c CD45E613R sera induces an inflammatory phenotype. Additionally, IL-10, IL-12, MCP-1 and RANTES are elevated in aged F1 CD45E613R mice. Analysis of young, autoantibody-free mice shows increased CD11b+ CD11c+ F4/80+ renal mononuclear cells surrounding F1 but not BALB/c CD45E613R glomeruli. Upon stimulation, only F1 CD45E613R renal mononuclear cells produce TNFα and IFNγ. Together, these data support a model in which an expanded antibody repertoire combined with altered kidney immune cell subsets and altered cytokines mediate the transition from autoreactivity to autoimmunity.