Functional dissection of lupus susceptibility loci on the New Zealand black mouse chromosome 1: evidence for independent genetic loci affecting T and B cell activation.

In previous work, we demonstrated linkage between a broad region on New Zealand Black (NZB) chromosome 1 and increased costimulatory molecule expression on B cells and autoantibody production. In this study, we produced C57BL/6 congenic mice with homozygous NZB chromosome 1 intervals of differing lengths. We show that both B6.NZBc1(35-106) (numbers denote chromosomal interval length) and B6.NZBc1(85-106) mice produce IgG anti-nuclear autoantibodies, but B6.NZBc1(35-106) mice develop significantly higher titers of autoantibodies and more severe renal disease than B6.NZBc1(85-106) mice. Cellular analysis of B6.NZBc1(85-106) mice revealed splenomegaly and increased numbers of memory T cells. In addition to these features, B6.NZBc1(35-106) mice had altered B and T cell activation with increased expression of CD69, and for B cells, costimulatory molecules and MHC. Introduction of an anti-hen egg white lysozyme Ig transgene, as a representative nonself-reactive Ig receptor, onto the B6.NZBc1(35-106) background corrected the B cell activation phenotype and led to dramatic normalization of splenomegaly and T cell activation, but had little impact on the increased proportion of memory T cells. These findings indicate that there are multiple lupus susceptibility genes on NZB chromosome 1, and that although B cell defects play an important role in lupus pathogenesis in these mice, they act in concert with T cell activation defects.