Genetic control of the defective immune tolerance in systemic lupus erythematosus-prone New Zealand Black mice.

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The F1 hybrid of autoimmune hemolytic anemia-prone NZB and phenotypically normal NZW strains of mice has been studied as a murine model of systemic lupus erythematosus. Both NZB and F1 hybrid mice show age-dependent spontaneous activation of peripheral CD4^+ T cells as reflected by the elevated frequencies of CD4+ T cells positive for CD69 early activation marker. Both strains also show age-dependent abnormal decrease of the frequencies of CD62L+ naive CD4+ T cells and/or NTA260+ memory CD4^+ T cells in the spleen. We studied the multigenic control of these abnormal features of peripheral CD4^+ T cells in (NZB x NZW) F1 x NZW backcross mice by QTL mapping and by association rule analysis. The abnormally elevated frequencies of CD69^+CD4^+ T cells and decreased frequencies of CD62L^+ naive and/or NTA260^+ memory CD4^+ T cells were under the common genetic control, in which the interaction between MHC and a hitherto unknown locus, designated Sta-1 (spontaneous T-cell activation) on chromosome 12, plays a major role. The allelic effects of these loci likely predispose CD4^+ T cells to the loss of self-tolerance, and are responsible for the accelerated autoimmune phenotypes of (NZB x NZW) F1 hybrid m