Pathogenesis of SLE: Linkage Analysis of Critical Signaling Pathways

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In contrast to normal mice, autoimmune-prone New Zealand Black (NZB) mice are defective in susceptibility to tolerance induced by deaggregated bovine gamma globulin (DBGG). Susceptibility loci for this defect were examined by genome-wide analysis using F2 intercross of non-autoimmune C57BL/6 (B6) and NZB mice. One NZB locus on the telomeric chromosome 1, designated Dit (Defective immune tolerance)-1, showed a highly significant linkage. This locus overlapped with t a locus coding for polymorphic Fcgr2b and Slam family genes. The similar defective tolerance was observed in Fcgr2b-deficient mice with autoimmune-type Slam family genes, but not in Fcgr2b-deficient mice with normal C57BL/6-type Slam family genes indicating that epistatic interaction of both polymorphic genes is involved. Thus, this epistatic interaction is likely playing a pivotal role in the genetic predisposition to autoimmunity in NZB and related autoimmune-prone strains inclusing SLE model (NZB x NZW) F1 mice.