Preliminary analysis of the contributions of major histocompatibility complex-H2 to autoantibody production in a murine model of systemic lupus erythematosus. (BA3P.116)

Abstract

Abstract The stochastic and heterogeneous nature of Systemic Lupus Erythematosus (SLE) supports a model whereby multiple genetic and/or environmental hits culminate in loss of tolerance and autoantibody production. Consistent with this model, the phenotype of CD45E613R mice that contain a single point mutation in the juxtamembrane wedge of CD45 depends on genetic context. Despite similar dysregulated phosphatase activity in all immune cells, CD45E613R mice on a C57Bl/6 (B6) background have no overt phenotype while BALB/c (BA) mice develop anti-double stranded (ds) DNA antibodies. An unbiased genome-wide screen for modifiers of autoantibody production between CD45E613R B6 and BA mice identified two candidate loci: Wedge Associated Modifier (Wam) 1 on Chromosome (Chr) 9 encompassing tlr9 and Wam2 on Chr 17 encompassing MHC H2. Previous work has shown that the hyporesponsive BA TLR9 allele permits anti-ds DNA antibodies while the B6 TLR9 allele is resistant. Here, we analyze the contribution of the MHC to this phenotype. CD45E613R BALB/c mice congenic for the B6 H2 locus develop anti-Sm antibodies while B6 mice congenic for the BALB/c H2 locus develop anti-Sm and anti-dsDNA antibodies. H2 congenic CD45E613R BALB/c mice have increased transitional B cells and a trend in increased B1 cells compared to congenic B6 mice. Thus, we hypothesize that MHC influences autoantibody specificity.