title: Susceptibility to mercuric chloride-induced glomerulonephritis is age-dependent: study of the role of IFN-gamma.
abstract: The repeated administration of low-dose HgCl2 to brown Norway (BN) rats induces an autoimmune syndrome which is characterized by polyclonal B cell activation, high-level synthesis of IgE and IgG1, and massive proteinuria. Data have been presented suggesting that during disease development there is a preferential expansion of CD4+ T cells belonging to the TH2 subset. In the present study it was found that aged BN rats are far less susceptible to the immunopathological effects of HgCl2 compared to their younger counterparts. Whereas rats at 10 weeks of age develop high-level proteinuria upon three repeated injections with HgCl2, 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 HgCl2. 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 TH1-like phenotype. Moreover, splenocytes of aged rats generated a threefold higher number of IFN-gamma-producing cells than those of young rats upon polyclonal activation in vitro. The administration of neutralizing anti-rat IFN-gamma mono- and/or polyclonal antibodies to aged BN rats just prior to HgCl2 exposure significantly augmented IgE and IgG1 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 HgCl2 exposure no stimulatory effect on both IgE/IgG1 levels and proteinuria was observed. The data indicate that splenic T cells of aged BN rats possess a higher capacity to release IFN-gamma than those of young rats and that this cytokine functions to downregulate IgG1 and IgE synthesis in HgCl2-exposed BN rats. The findings further suggest that IFN-gamma plays a regulatory role in the development of glomerulonephritis.
authors.affiliation: Biomedical Primate Research Centre (BPRC) TNO, Rijswijk, The Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: van der Meide
authors.forename: R J
authors.initials: RJ
authors.lastname: Groenestein
authors.forename: M C
authors.initials: MC
authors.lastname: de Labie
authors.forename: J
authors.initials: J
authors.lastname: Aten
authors.forename: J J
authors.initials: JJ
authors.lastname: Weening
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D008627:Mercuric Chloride / Q000633:toxicity*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D008627:Mercuric Chloride; D007371:Interferon-gamma