P A Smathers

Effects of sex hormones on autoantibody production by NZB mice and modification by environmental factors

Abstract In this study we have analyzed the effects of sex hormone treatment upon the autoimmune disease of NZB mice with regard to antibody production to single-stranded DNA and mouse erythrocytes, and survival. In addition, we have noted the effects of environmental factors on the natural history and sex hormone effects in NZB mice, and on the production of antinucleic acid antibodies in NZB × NZW F1 mice. NZB mice show a much less marked difference between the sexes with regard to autoantibody production than do NZB × NZW or NZB × DBA 2 mice. Nevertheless, NZB males lagged behind their female littermates with regard to anti-ssDNA and anti-RBC antibodies. This was abolished by castration of the males and restored by androgen therapy, suggesting that androgen production was the factor allowing males slower development of autoantibody production. The delay in autoantibody production associated with androgen therapy was not sufficient to significantly prolong survival in NZB females. A group of NZB mice exposed to Sendai virus failed to demonstrate a sex difference in autoantibody production. It appeared that an environmental agent could abolish the protective effects of androgens in intact males. Similarly, NZB × NZW F1 females exposed to oncogenic viruses developed antibodies to double-stranded RNA before antibodies to native DNA, whereas the reverse was true of mice housed in a conventional animal room. Taken together, these studies suggest that androgens may suppress autoimmune markers, but that environmental factors may mask such effects. Moreover, environmental factors may increase autoantibody production in NZB mice and alter the order of autoantibody production in NZB × NZW F1 mice.

Virus-induced Diabetes in Autoimmune New Zealand Mice

Infection of autoimmune New Zealand mice with the D variant of encephalomyocarditis (EMC) virus results in beta-cell damage and clinical diabetes. The induction of diabetes in parental NZB and NZW strains was independent of sex. However, the susceptibility to virus-induced diabetes in their F1 offspring was sex dependent. This susceptibility was significantly higher in male (NZB x NZW) F1 mice as compared with female F1 mice. Castration of male F1 mice significantly reduced the susceptibility to diabetes. These results suggest that parental NZB and NZW strains have recessive genes at different loci which do not allow sex hormones to influence the susceptibility to diabetes. It is concluded that both the genetic background of the host and sex hormones influence the development of virus-induced diabetes in autoimmune New Zealand mice.

Effects of the thymic microenvironment on autoantibody production in (NZB × NZW)F1 mice

The effects of the thymic microenvironment on autoantibody production in (NZB X NZW)F1 mice were studied. Neonatally thymectomized male and female F1 mice reconstituted with a parental or F1-irradiated thymic lobe were compared to nonreconstituted and sham-thymectomized controls. While maleness retarded the spontaneous production of ss- and ds-DNA antibodies, thymic grafts did not suppress antibodies to ss-DNA in either sex, but did suppress the production of antibodies to ds-DNA in female mice. A unique property of NZB thymic grafts was the inability to suppress anti-RBC antibodies in male mice. Thus, (i) the gender of the F1 recipient was the most important determinant of production of antibodies to ss-DNA, (ii) either maleness or the thymic microenvironment could retard production of anti-ds-DNA antibodies, and (iii) both gender and the thymic microenvironment were important in the regulation of anti-RBC antibody production. Since the administration of thymosin did not suppress autoantibody production, the effects of the thymic grafts was not solely via thymic hormone production. These studies suggest that sex hormones and/or the thymic microenvironment can exert a suppressive effect on autoantibody production and that autoantibodies differ in their susceptibility to such suppression.

Effect of partial testosterone replacement or thymosin on anti-DNA in castrated (NZB × NZW)F1 males

Castration of young (3-week-old) but not older (3-month-old) male (NZB X NZW)F1 mice was associated with autoantibody production similar to that of untreated female littermates. The castration-induced disease provided a unique model for the evaluation of therapeutic modalities during the first 9 months of life. Castrated male (NZB X NZW)F1 mice were treated with either long-term thymosin (fraction 5) or testosterone for different periods of time. Continuous testosterone replacement abolished the autoimmune disease-accelerating effects of castration at 3 weeks. Brief treatment during either the early or the later periods of life of castrated (NZB X NZW)F1 males was insufficient to prevent accelerated anti-DNA production. Thymosin treatment, when started at the time of castration and continued through life, abolished the rise in anti-DNA. These studies suggest that androgens work throughout the first 7 months of life of the mouse to suppress anti-DNA and that lack of androgens for a relatively brief period allows anti-DNA production to be initiated. Once initiated it cannot be completely suppressed. The cellular basis of the fixed aspect of this process is unknown. A possible role of the thymus is suggested by the ability of thymosin to suppress anti-DNA.