Hormones, particularly estrogens and androgens, can cause different immune responses in males and females. Females generally have a more vigorous immune system than males, and while it is clear that differences in sex steroids contribute to immunologic differences between the sexes, the mechanism(s) by which they alter immune responses is unknown. One of the most dramatic sex-related differences in the immune system is the disproportionate prevalence of autoimmune diseases in females. For example, systemic lupus erythematosus (SLE) occurs nine times more frequently in females than males, and rheumatoid arthritis occurs in females at a ratio of three to one over males. Understanding the basis for sex steroid/immune system interactions will greatly elucidate the pathologic states of autoimmune diseases in particular, and immunology in general. Although the reported experimental effects of sex steroids on immune responses vary, estrogens generally increase, and androgens generally decrease, autoimmune reactions. The nature of the interactions between the endocrine and immune system, and how these affect disease, has yet to be determined. In this regard, we intend to address three specific aims: 1.) Define the immune system cell types responsive to estrogen; 2.) identify immune effector molecular regulated by estrogen, and 3.) evaluate the effects of estrogen on an SLE-xenograft mouse model. Different immune cell populations from cultured cell lines and mice will be examined molecularly for the presence of estrogen receptors. Such cells will then be manipulated in cell culture to examine the effect of estrogen treatment on the production of immune effector molecules, such as interferons and interleukins. These studies will allow identification of the sex steroid target cells and well as the molecules these hormones may modulate that could lead to sex-related differences in immune responses. Finally, an animal model of autoimmunity that allowed the in vivo manipulation of human SLE lymphoid cells will be examined for possible sex steroid effects on the transferred disease. To assess these effects, disease parameters will be measured in SCID mice that received parallel lymphocyte transfers of human SLE cells, and the effects of estrogen treatment measured.
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