Systemic Lupus Erythematosus: Immunity, Genetics and Sex Hormones in Murine Models

Abstract

The influence of sex hormones and the lpr gene on immune reactivity and the clinical course of murine lupus has been studied. In addition, the genetic basis for sex hormone modulation of immune responsiveness in healthy and autoimmune mice has been analysed. Inbred (NZBxNZW)F1 (NZB/W) and MRL1pr/1pr (MRL/1) mouse strains spontaneously develop severe autoimmune disease resembling systemic lupus erythematosus (SLE).

The study demonstrated that castrated MRL/1 mice continuously treated with physiological doses of 17 B-oestradiol display significant acceleration of immune-complex mediated glomerulonephritis, elevation of serum levels of immunoglobulins and autoantibodies as well as reduced life span. Also, early life short-term treatment with oestradiol increases mortality and accelerates renal disease in MRL/1 mice.

The homozygous Ipr (lymphoproliferation) gene has previously been regarded as mandatory for the early onset of lupus disease, T cell dysfunctions and polyclonal B cell activation in MRL/1 mice. The present study contradicts this assumption. Thus, it is demonstrated that the expression of heterozygous +/1pr gene, on MRL background also induces impaired T cell reactivity, polyclonal B cell activation and autoantibody production. Furthermore, MRL+/1pr mice display acceleration of immune complex mediated glomerulonephritis and sialadentis, compared with MRL+/+ mice lacking the Ipr gene.

Using an in vivo contact sensitivity (DTH) assay, the present study is the first to demonstrate the presence of a genetically linked sensitivity to oestradiol in the mouse immune system. Oestradiol suppression of DTH is shown to be dominantly inherited. Interestingly, the results clearly demonstrate that oestradiol suppression of DTH in SLE prone NZB/W mice is a trait inherited from the healthy NZW and not from the autoimmune NZB parental strain. This genetically linked sensitivity to oestradiol may be of great importance for the development of the autoimmune disease in NZB/W mice. It is thus possible that the healthy NZW parental strain contributes to the lupus disease of NZB/W mice by genetically encoded sensitivity to oestrogen. This sensitivity leads to acceleration of the autoimmune disease, the latter feature being inherited from the NZB parental strain.

Key Words:

• systemic lupus erythematosus
• autoimmunity
• mice
• oestrogen
• delayed-type hypersensitivity
• T-cell
• 1pr-gene