17β-Estradiol (E-2) administration to male (NZB × SWR)F1 mice results in increased IdLNF1-reactive memory T-lymphocytes and accelerated glomerulonephritis

Abstract

While it has been shown that estradiol treatment accelerates the onset of lupus nephritis with autoantibody production and kidney damage in both male and female lupus-prone mice, the specific mechanism(s) involved are unknown. Our previous work has shown that alterations in IdLNF1-reactive T cells and IdLNF1+ antibodies correlated closely with the onset of autoimmune nephritis in female F1 progeny of SWR and NZB (SNF1) mice, supporting a critical role for the IdLNF1 idiotype in the development of disease. Since male SNF1 mice normally do not develop nephritis, we tested whether administration of 17β-estradiol (E-2) to male SNF1 mice would increase IdLNF1 IgG levels and autoreactive T cells, and further, induce nephritis. We found that E-2-treated male SNF1 mice developed nephritis with the same time course and mean survival as normal female SNF1 mice. Moreover, it appeared that the mechanism involved increased serum IdLNF1+IgG and its deposition in kidney glomeruli, preceded by astriking twofold increase in T-lymphocytes expressing the memory phenotype (CD44+CD45RBlo) predominantly in the IdLNF1-reactive T-cell population. In addition, we noted that cells with this phenotype were increased in the nephritic kidneys of treated mice, suggesting a direct involvement of those cells in the renal pathology. E-2 treatment also induced increased numbers of pathogenic IdLNF1+ antibody-producing B cells and elevated presentation of pathogenic IdLNF1+ peptide. Taken together, these results suggest a mechanism of E-2-induced acceleration of autoimmune disease in lupus-prone mice may involve expansion of autoreactive idiotypic T and B-cell populations.