Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity

Clin Exp Immunol. 2009 Mar;155(3):567-76. doi: 10.1111/j.1365-2249.2008.03831.x. Epub 2008 Dec 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology
  • Antigen-Antibody Complex
  • Autoimmune Diseases / chemically induced*
  • Autoimmune Diseases / immunology
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology*
  • Chromosomal Proteins, Non-Histone / immunology
  • Cytokines / immunology*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Deletion
  • Genetic Predisposition to Disease
  • Gold / toxicity
  • Immunoglobulin G / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-4 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Male
  • Mercury / toxicity
  • Metals, Heavy / toxicity*
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Silver / toxicity

Substances

  • Antibodies, Antinuclear
  • Antigen-Antibody Complex
  • CD28 Antigens
  • Chromosomal Proteins, Non-Histone
  • Cytokines
  • Immunoglobulin G
  • Interleukin-6
  • Metals, Heavy
  • fibrillarin
  • Interleukin-4
  • Silver
  • Gold
  • Interferon-gamma
  • Mercury