Genetic studies in NZB mice

et al. 1979

183

Investigators from this laboratory have been studying sex hormones in normal and autoimmune mice for the past 10 years. We have found that immune responses to DNa are influenced by sex hormones. Androgens reduce and estrogens increase both spontaneous and immunization-induced antibodies to single-stranded DNA in NZB X NZW, NZB X C3H, NZB X CBA, NZB X DBA mice. Treatment of female NZB/W mice with testosterone or 5 alpha dihydrotestosterone retards the progress of autoimmunity. Castration is not necessary for this effect. In contrast, danazol has no favorable effect on the disease process. Estrogens cause a marked acceleration of autoimmunity and a reduction in thymus weight. During the course of these studies, we found that a number of problems or variables arise in studying sex hormone effects, including: 1) X-linked genes, 2) metabolism of testosterone to estrogens, 3) dose of hormone, 4) age at which administration is initiated, 5) differential effects of sex hormones on different autoantibodies and various immune responses.

Approach to the study of the role of sex hormones in autoimmunity

Steinberg

Melez

et al. 1979

183

Studies of the effects of sex hormones on autosomal and x‐linked genetic control of induced and spontaneous antibody production

Tjio

Boegel

et al. 1979

In these studies we investigated the modifying effect of sex hormones on both the levels of induced antibodies after immunization with single-stranded DNA (ssDNA) and the levels of spontaneously produced anti-T cell antibodies (NTA). To learn whether the responses were genetically determined or under hormonal regulation, we analyzed hybrids produced by crossing the autoimmune NZB strain with the nonautoimmune DBA/2 strain. For both anti-ssDNA and NTA, males usually had a lower response than females; this difference could largely be removed by castration of the males. Females given testosterone implants also had decreased antibody levels. The higher responses in females and suppression by testosterone were true for all mice studied except NZB mice. NZB mice appear to have an insensitivity to the suppressive effects of testosterone. NZB mice spontaneously produce a variety of autoantibodies and serve as a model of autoimmunity, particularly systemic lupus erythematosus (SLE) (1). As they age, NZB mice produce antibodies to erythrocytes, thymocytes, T cells, and nucleic acids, especially singlestranded DNA (ssDNA) (2). Because both antibodies against T cells (NTA) and antinucleic acid antibodies are characteristic of NZB mice and may be important in the pathogenesis of autoimmunity, it is critical to investigate the mode of inheritance of the propensity for development of these autoantibodies.Because of the known preponderance of SLE in females (3,4), we studied the effects of sex hormones on the production of anti-T cell antibodies and antissDNA antibodies. An increasing body of evidence suggests that sex hormones influence both spontaneous autoantibody production (5-7) and antibody response to immunization (8). Sex hormones can affect immune responses, but generalizations are difficult to establish due to the variety of experimental systems and pharmacologic doses of hormones frequently employed. There is abundant evidence for enhanced immunologic responses in females over that of males; however, the underlying mechanisms to account for these differences are as yet unknown.Genetic factors have been implicated in the development of autoimmunity in New Zealand mice (9-19). In addition, X-linked immune response genes have been described for synthetic (20) and naturally occurring nucleic acids (21). In the studies discussed here, we investigated the modifying effect of sex hormones on both the levels of induced antibodies after immunization with single-stranded DNA and the levels of spontaneously produced anti-T cell antibodies. In order to determine if these responses were genetically determined or under hormonal regulation, we analyzed hybrids produced by crossing the autoimmune NZB strain with the nonautoimmune DBA/2 strain. The DBAP strain was chosen as one of the parental strains because: 1) it is H-2* like NZB mice (22), 2) like NZB mice it expresses gp70 viral protein antigens in large quantities on the surface of mononuclear cells (23), 3) DBA/2 mice do not spontaneously produce large quantities of either NTA...

Genetic studies in nzb mice

Tjio

Steinberg

1980

Hybrid NZB X NZW or NZB X DBA/2 females have markedly accelerated development of autoimmunity when compared with their respective male littermates. This difference is attributable to the ability of male sex hormones to retard the expression of autoimmunity. In contrast to the sex differences in expression of autoimmunity in F1 mice, parental NZB males and females have only minor differences in disease expression. We have been investigating the basis for the difference in anti‐T cell antibody production between NZB and F1 mice. In this study, the appearance of antibodies cytotoxic for T cells (NTA) was studied in NZB and DBA/2 mice and in their F1 hybrids and backcross progeny. A major sex difference in NTA production was observed in the F1 hybrids; females produced more NTA than did males. Castration of males led to a marked increase in NTA production. Furthermore, the NTA production of castrated male and female F1 mice was significantly suppressed by administration of testosterone in Silastic capsules. In contrast to the studies in F1 mice, we found little difference between intact male and female parental NZB mice at any age studied. Furthermore, NZB mice of both sexes who were given androgen‐containing capsules at 2 weeks of age failed to demonstrate a decrease in NTA production. This result suggested an androgen insensitivity in NZB mice with regard to NTA production. This insensitivity, which appears to be a recessive trait, may help to explain why NZB mice do not manifest the sex differences in disease expression observed in the F1 hybrids.