Autoimmune kidney damage correlates with autoantibody specificity and inflammatory mononuclear cell phenotype in the CD45 mutant mouse model of lupus
Systemic lupus erythematosus is a complex autoimmune disease with a multi-step pathogenesis that is caused by both environmental and genetic factors. The mechanisms that govern the transition from autoreactivity (presence of autoantibodies) to autoimmunity (end-organ damage) and that determine disease severity remain incompletely understood. Here, we leverage a mouse model where the phenotypic consequences of the same activating point mutation E613R in the phosphatase CD45 depend on genetic background. While both BALB/c and (B6-129) F1 CD45E613R mice develop high titer anti-double stranded (ds) DNA antibodies, only F1 mice develop glomerulonephritis (GN) and die prematurely. Surprisingly, similar immune complex deposition is seen in glomeruli of both strains. We find that genetic background dependent differences in the autoantibody repertoire and renal effector cell populations correlate with development of renal pathology in only F1 CD45E613R mice. Whereas BALB/c CD45E613R mice develop anti-dsDNA antibodies, F1 CD45E613R mice develop a broader autoantibody repertoire that recognizes both DNA- and RNA-containing antigens and that induces a more pro-inflammatory phenotype when cultured with a macrophage cell line. Consistent with this, inflammatory renal mononuclear cells are preferentially expanded in young F1 CD45E613R kidneys prior to disease onset and infiltrate glomeruli over time. This correlates with elevated MCP-1, RANTES, and BAFF levels and functional studies demonstrating F1 CD45E613R macrophages are skewed towards a more pro-inflammatory phenotype. Together, our findings demonstrate that genetic background influences both autoantibody profiles and renal immune cell subsets and provide new insights into mechanisms governing the transition from autoreactivity to autoimmunity in lupus nephritis.