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. © The Author(s), 2012.
