Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity.
Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s)) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s)) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 microg Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 microg Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.
Havarinasab
S
S
Molecular and Immunological Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Pollard
K M
KM
Hultman
P
P
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006046:Gold / Q000633:toxicity; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008297:Male; D008628:Mercury / Q000633:toxicity; D019216:Metals, Heavy / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D012834:Silver / Q000633:toxicity
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D018106:CD28 Antigens; D002868:Chromosomal Proteins, Non-Histone; D016207:Cytokines; D007074:Immunoglobulin G; D015850:Interleukin-6; D019216:Metals, Heavy; C047458:fibrillarin; D015847:Interleukin-4; D012834:Silver; D006046:Gold; D007371:Interferon-gamma; D008628:Mercury