NZB;NZW chimeras develop strong autoimmunity earlier than NZB/NZW F1

Abstract

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease caused by an immune response to many self-antigens, including DNA, histones, and RNA-binding proteins. One of the most physiologically relevant mouse models is the NZB/NZW F1 hybrid mouse, which develops SLE at high penetrance, in contrast to either parental strain. However, the critical genetic contributions of each parent, which must somehow interact to cause SLE, have remained unresolved. We have determined that NZB;NZW embryonic chimeras develop an accelerated form of autoimmunity characterized by the presence of auto-antibodies 6 months earlier, and at titers 10-fold greater, than the NZB/NZW F1 hybrids. The chimeras also developed glomerulonephritis, severe lymphadenopathy, and splenomegaly. Within each chimera, expansion of activated T cells of NZB/BINJ origin and a predominance of B cells of NZW/LacJ origin was observed with respect to the relative proportions of myeloid cells. Furthermore, the expansion of NZB/BINJ T cells correlates with autoantibody production. This SLE phenotype was specific for the NZB/BINJ;NZW/LacJ combination, and occurs despite the fact that neither parental strain develops SLE-like autoimmunity in a non-chimeric environment. Understanding the pathogenesis of SLE in the NZB;NZW embryonic chimeras may elucidate causes of autoimmunity by identifying the intercellular transactions between these two strains that lead to disease.