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

Abstract

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...

Differential effects of sex hormones on autoantibody production and proteinuria in chronic graft-versus-host disease-induced experimental lupus nephritis

“…In this model, testosterone treatment both decreased the anti-DNA autoantibody response [21,22] and showed less evidence of glomerulonephritis [21]. Oestrogens increased autoantibody levels in these mice [21][22][23]. Androgen treatment of castrated female NZB/NZW mice improved clearance of IgG-sensitized erythrocytes, whereas oestrogen-treated male NZB/NZW mice showed delayed clearance [24].…”

Susceptibility to immunosuppression by ultraviolet B radiation in the mouse

“…Some of these characteristics have been demonstrated to be hormonally regulated (Raveche et al 1979;Roubinian et al 1977). In view of the greater sensitivity of NZB females to UV suppression, it is interesting to note that the human autoimmune disease, photosensitive lupus, which is initiated by exposure to ultraviolet B radiation (reviewed in Kochevar 1985), is predominantly observed in females (Crow and Christian 1992).…”

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

“…traits: impaired responsiveness to androgens and hyperdiploidy (10,13). It is likely that lack of responsiveness to androgens may auow for deranged regulatory responses with expression of abnormalities in a variety of phenotypes.…”