A BALB/c locus on chromosome 12 confers resistance to lupus in FcγR2-/- mice. (93.23)

Abstract

Abstract FcγR2B-deficient (R2-/-) mice develop autoantibodies and glomerulonephritis with a pathology resembling human lupus when on the C57Bl/6 background. The same mutation on the BALB/c background does not lead to spontaneous disease, suggesting differences in lupus susceptibility between the BALB/c and B6 strains. An F2 genetic analysis from a B6/BALB cross identified region from the B6 chromosome 12 with positive linkage for autoantibodies. We have generated a congenic strain (B6.R2-/-sbb2) that contains the suppressor allele from the BALB/c centromeric region of chromosome 12 in an otherwise B6.R2-/- background. We have observed that the presence of sbb2 renders B6.R2-/- mice resistant to lupus disease by suppressing all antibody autoreactivity and spontaneous immune cell activation. Mixed bone marrow reconstitution experiments indicated that the sbb2 resistant allele is most likely T cell intrinsic. The sbb2 congenic interval contains several candidate genes that are currently being investigated. We generated transgenic lines containing BAC DNA insertions spanning the sbb2 interval. The new BAC transgenic strains were tested in the induced model of lupus by pristane administration. Newly generated BAC transgenic strains were also bred to B6.R2-/- to test for suppression of lupus in spontaneous disease. The goal of our experiments is to identify a new lupus susceptibility gene within the sbb2 interval that is able to suppress lupus disease by altering T cell function.