Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-prone New Zealand Black mice

New Zealand Black (NZB) mice spontaneously produce anti-erythrocyte autoantibodies (AEA) in association with splenomegaly, thus serving as a model for autoimmune hemolytic anemia. Although these autoimmune traits are inherited as a dominant fashion, expression in F1 hybrids of NZB and most non-New Zealand strains is suppressed due to the contribution of wild-type modifying genes present in the latter strains. Using chromosomal microsatellite markers in the (C57BL/6 × NZB)F1 × NZB backcross progeny, we mapped C57BL/6 modifying loci for AEA production and splenomegaly. Generation of AEA was found to be down-regulated by a combined effect of two major independently segregating dominant alleles—one linked to D7MIT30 on chromosome 7 and the other linked to D10MIT42 on chromosome 10. Splenomegaly was modified mainly by a single C57BL/6 allele linked to D4MIT58 on chromosome 4. Thus, the autoimmune hemolytic anemia in the NZB strain is under multigenic control and a combined action of not only susceptibility but also modifying alleles with suppressive activities affects the outcome of disease features in the progeny. There are potentially important candidate genes which may be linked to the regulation of AEA and splenomegaly.