Genetic aspects of immunologic abnormalities in New Zealand mouse strains

Since preliminary evidence indicated that a gene locus associated with the chocolate coat color had an inhibitory effect on the spontaneous development of autoimmune hemolytic anemia–which in turn was associated with a dominant gene–we accordingly initiated the development of a congenic line of NZB mice carrying the chocolate coat color locus (and other genes closely linked to this locus). After eight backcross generations to NZB, an inbred line of mice carrying the chocolate coat color gene was established and then studied for incidence of anti-RBC autoantibodies. The congenic line NZB.ch shows a considerably lower incidence of such autoantibodies, particularly in male mice. Although further analysis is still required, we propose that the genetic control of autoimmunity is based on the resultant interaction of several gene loci: 1) a single dominant locus (A) that predisposes to an autoimmune state rather than the maintenance of (self) tolerance, 2) a modifying locus (M) linked to ch., subject to gene dosage, which particularly in the recessive state can inhibit the effect of the A locus, and 3) a cluster of specific immune response genes that are associated with specific autoantibody responses, e.g. antinucleic acid antibodies, and are probably H2 linked. Our current analysis does not suggest that the A or M loci are linked to the MHC. It is also proposed that the wild-type allele of the M locus is carried by normal mouse strains, that NZB mice have a completely inactive allele at this locus, and that NZC mice have a third allele detectable only in the homozygous state.