Susceptibility to Mercuric Chloride-Induced Glomerulonephritis is Age-Dependent: Study of the Role of IFN-γ

Abstract

The repeated administration of low-dose HgCl 2 to brown Norway (BN) rats induces an autoimmune syndrome which is characterized by polyclonal B cell activation, high-level synthesis of IgE and IgG 1, and massive proteinuria. Data have been presented suggesting that during disease development there is a preferential expansion of CD4 + T cells belonging to the T H2 subset. In the present study it was found that aged BN rats are far less susceptible to the immunopathological effects of HgCl 2 compared to their younger counterparts. Whereas rats at 10 weeks of age develop high-level proteinuria upon three repeated injections with HgCl 2, animals at 18 to 24 months of age do not release urinary protein under these conditions and develop low-level proteinuria with a delayed onset after five repeated injections with HgCl 2. FACScan analysis of splenocytes from old and young rats revealed a defined increase in the frequency of CD45RB(RC) +/CD4 + T cells in the splenocyte population of older rats, suggesting an age-related shift to a more T H1-like phenotype. Moreover, splenocytes of aged rats generated a threefold higher number of IFN-γ-producing cells than those of young rats upon polyclonal activation in vitro. The administration of neutralizing anti-rat IFN-γ mono- and/or polyclonal antibodies to aged BN rats just prior to HgCl 2 exposure significantly augmented IgE and IgG 1 serum levels and exerted a small but significant stimulatory effect on proteinuria in the initial stage but not in the more advanced stages of the renal disease. When antibodies were given 7 days after the beginning of HgCl 2 exposure no stimulatory effect on both IgE/IgG 1 levels and proteinuria was observed. The data indicate that splenic T cells of aged BN rats possess a higher capacity to release IFN-γ than those of young rats and that this cytokine functions to downregulate IgG 1 and IgE synthesis in HgCl 2-exposed BN rats. The findings further suggest that IFN-γ plays a regulatory role in the development of glomerulonephritis.