GENETIC DISSECTION OF SLE PATHOGENESIS - SLE1 ON MURINE CHROMOSOME-1 LEADS TO A SELECTIVE LOSS OF TOLERANCE TO H2A H2B/DNA SUBNUCLEOSOMES/

One of the hallmarks of SLE is the loss of tolerance to chromatin. The genes and mechanisms that trigger this loss of tolerance remain unkno wn, Our genetic studies in the NZM2410 lupus strain have implicated ge nomic intervals on chromosomes 1 (Sle1), 4 (Sle2), and 7 (Sle3) as con ferring strong lupus susceptibility, Interestingly, B6 mice that are c ongenic for Sle1 (B6.NZMc1) have elevated IgG antichromatin Abs, This study explores the antinuclear antibody fine specificities and underly ing cellular defects in these mice. On the B6 background, Sle1 by itse lf is sufficient to generate a robust, spontaneous antichromatin Ab re sponse, staining Hep-2 nuclei homogeneously, and reacting primarily wi th H2A/H2B/DNA subnucleosomes. This targeted immune response peaks at 7-9 mo of age, affects both sexes with equally high penetrance (> 75%) , and interestingly, does not ''spread'' to other subnucleosomal chrom atin components, Sle1 also leads to an expanded pool of histone-reacti ve T cells, which may have a role in driving the anti-H2A/H2B/DNA B ce lls, However, these mice do not exhibit any generalized immunological defects or quantitative aberrations in lymphocyte apoptosis, We hypoth esize that Sle1 may lead to the presentation of chromatin in an immuno genic fashion, or directly impact tolerance of chromatin-specific B ce lls.