Control of multiple autoantibodies linked with a lupus nephritis susceptibility locus in New Zealand black mice

An NZB locus on distal chromosome 1 has been linked to murine lupus nephritis in backcross analyses of New Zealand mice. This locus, designated Nba2 for New Zealand Black autoimmunity 2, was found to colocalize in both (NZB × SM/))F₁ × NZW and (B6.H2^z × NZB)F₁ × NZB backcrosses, and was most likely situated between 92 and 97 cM from the centromere. This region of mouse chromosome 1 encodes several candidate genes, including the low affinity Fcγ receptor genes. Both backcrosses were examined by interval mapping for quantitative trait loci linked with autoantibody and total Ig production. Nba2 was linked with elevated serum levels of multiple autoantibodies, including a variety of antinuclear Abs (anti-dsDNA, antichromatin and anti-histone) and autoantibodies to gp70, in both backcrosses. Nba2 was also linked (or showed a trend for linkage) with hypergammaglobulinemia and IgG1, IgG2a, and/or IgG3 levels in each backcross. In the (B6.H2^z × NZB)F₁ × NZB backcross, MHC was an additional genetic contribution that interacted with Nba2 in the production of autoantibodies and the development of nephritis. Together, these data provide new insight into the nature of one important genetic contribution to murine lupus and suseest that Nba2 mav act as an immune response gene that influences Ag-driven B cell responses to self and possibly to exogenous Ags.