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Functional Dissection of Lupus Susceptibility Loci on the New Zealand Black Mouse Chromosome 1: Evidence for Independent Genetic Loci Affecting T and B Cell Activation¹

Joan E. Wither^2,*,,, Ginette Lajoie^,¶, Svinda Heinrichs^*, Yong-Chun Cai^*, Nan Chang^*, Amelia Ciofani^*, Yui-Ho Cheung^*, and Ralph MacLeod^*

^* Arthritis Center of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada; Departments of Immunology and Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario; and Departments of Medicine and ^¶ Pathology, University Health Network, Toronto, Ontario

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.

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