1188 Genetic Studies in Nzb Mice

The genetic basis for autoimmunity in New Zealand mice has been investigated for two decades. These studies have suggested that several genes underlie the autoimmune process (1-10). The advent of new murine models of autoimmunity that display some of the traits of NZB mice while lacking others has led to a resurgence of interest in the genetic basis for autoimmunity (11-14). The major question is whether there is a single fundamental defect that gives rise to autoimmunity. We have investigated this question by trying to determine whether the autoimmune' traits in NZB mice are linked to or dependent upon another trait for their appearance. We have previously shown (15) by classical genetic analyses of F1 and backcrosses of NZB × DBA/2 mice that antibodies against T cells and antibodies directed against single-stranded DNA (ssDNA)a were genetically determined traits not linked to each other. Moreover, they were expressed in a gene dosage fashion. Other traits, splenic aneuploidy and splenomegaly, were inherited as recessive traits; they were found only in backcross mice (16). By analyzing several other crosses of NZB mice with nonautoimmune mice, we hoped to determine whether these were consistent findings. In addition to classical genetic studies, we have also used a powerful genetic tool, recombinant inbred (RI) lines, to further analyze the inheritance of autoimmunity (17-20). RI lines were obtained by mat ing an NZB mouse with a non-autoimmune mouse. The F2 mice were separately mated to initiate the RI lines and then brothersister mated at each successive generation. Each RI line can have any combination of parental genes. After several generations of inbreeding, individual RI lines become largely homozygous at most loci. Therefore, recessive genes are observed as easily as dominant genes. Our studies indicate that multiple genes underlie NZB disease; no single gene for autoimmunity was discovered.