Accelerated autoimmune disease and lymphoreticular neoplasms in F 1 hybrid [formula omitted] and [formula omitted] mice

Abstract

This report describes the first studies of inheritance of autoimmunity in inbred Palmerston North (PN) mice, a model of systemic lupus erythematosus (SLE). Mating of PN mice with the nonautoimmune DBA 2 strain produced evidence that PN disease had a recessive mode of inheritance. When PN mice were crossed with autoimmune NZB mice, female offspring from both crosses developed anti-DNA antibodies and died prematurely with vasculitis, renal disease, and lymphomas. In contrast, reciprocal hybrid males had different patterns of mortality; PN NZB males from the PN female × NZB male mating had moderately prolonged life spans, whereas NZB PN males from the opposite cross (NZB female × PN male) had prolonged survival to the mean age of 104 weeks. To determine if testicular hormones were solely responsible for increased longevity in hybrid males, PN NZB and NZB PN mice were castrated at 2 weeks of age and compared to sham-operated littermate controls. Prepubertal castration did not influence longevity in PN NZB males, but loss of gonadal hormones significantly reduced life spans in reciprocal NZB PN males. Female hybrids were not affected by oophorectomy. Because castration changed disease expression only in male hybrids from the NZB female × PN male cross, it was concluded that parentage influenced sensitivity to the protective effects of male hormones. Although surgical sterilization had disparate effects on males, castrated PN NZB and NZB PN males consistently outlived oophorectomized females. The lack of clear-cut reversal of disease in males subjected to early castration suggested that nonhormonal, possibly genetic, factors contributed to longevity in both groups of male hybrids.