Histocompatibility complex gene products and exposure to oestrogen: two independent disease accelerating factors in murine lupus.

A number of studies have demonstrated that oestrogen exerts a significant impact on the course of experimental autoimmune diseases. Exposure to oestrogen aggravates SLE glomerulonephritis whereas the opposite outcome has been demonstrated in experimental arthritis, vasculitis, thyroiditis, and sialadenitis. In this report we have analysed the respective impact of H-2z linked gene products and long-term treatment with physiological doses of oestradiol on clinical and immunological variables in castrated backcrosses of lupus prone NZB/W and NZB mice. Our results demonstrate that H-2z linked gene products accelerate B-cell activation and stimulate autoantibody production resulting in aggravation of glomerulonephritis and precocious death in renal failure. These H-2z linked gene products do not influence T-cell mediated sialadenitis. Irrespectively of the H-2 haplotype of the mice, administration of oestrogen resulted in intense polyclonal B cell activation and aggravation of glomerulonephritis. However, exposure to oestrogen resulted in amelioration of sialadenitis. Notably, our result indicates that B-cell activation achieved by oestrogen and H-2z gene linked products, respectively is mediated by independent mechanisms. In addition, we have developed a predictive in vivo test that permits forecasts regarding efficiency of oestrogen treatment for suppression of T-cell mediated lesions. Using this test procedure in young, clinically healthy SLE mice we have been able to prove that animals displaying suppressed delayed type hypersensitivity (DTH) after short-term oestrogen exposure showed significantly lower long-term morbidity regarding development of sialadenitis upon continuous treatment with physiological doses of oestradiol.