GENETIC DISSECTION OF SYSTEMIC LUPUS-ERYTHEMATOSUS PATHOGENESIS - SLE2 ON MURINE CHROMOSOME-4 LEADS TO B-CELL HYPERACTIVITY

Susceptibility to systemic lupus erythematosus in the NZM2410 murine m odel maps to Sle1, Sle2, Sle3, and the H2 loci, To unravel how these l oci contribute to the pathogenesis of lupus, individual NZM2410-derive d genomic intervals bearing these loci have been successfully backcros sed onto the resistant C57BL/6 (B6) background, The focus of this stud y was to understand how Sle2 OH murine chromosome 4 impacts the immune system, Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 ex hibit: a variety of immunophenotypes affecting their B cells, They hav e an early, but transient, expansion of splenic, CD23(low) B cells, Th ereafter, their B cells appear activated by surface phenotype and func tional criteria, paralleled by elevated serum levels of polyreactive/p olyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsi veness to in vitro stimuli and to in vivo antigenic challenge. Finally , they exhibit increased levels of peritoneal and splenic B1 cells, Th us, Sle2 harbors a gene that leads to B cell hyperactivity and elevate d B1 cell formation. However, Sle2 by itself on the normal B6 backgrou nd is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to ampli fy an ongoing autoimmune response.