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

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 Id^LNF₁-reactive T cells and Id^LNF₁+ 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 Id^LNF₁ 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 Id^LNF₁ 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 Id^LNF₁ ⁺IgG and its deposition in kidney glomeruli, preceded by astriking twofold increase in T-lymphocytes expressing the memory phenotype (CD44⁺CD45RB^lo) predominantly in the Id^LNF₁-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 Id^LNF₁+ antibody-producing B cells and elevated presentation of pathogenic Id^LNF₁+ 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.