title: Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals.
abstract: Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adjuvants, could trigger an autoimmune disease. Experimental studies have indicated that xenobiotics, well defined from a chemical point of view, could promote the differentiation of autoreactive T cells towards a pathogenic pathway. It is therefore theoretically possible that compounds present in vaccines such as thiomersal or aluminium hydroxyde can trigger autoimmune reactions through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimmune reactions. In vitro, both activate signal transduction pathways that result in the expression of cytokines, particularly of IL-4 and IFNgamma. In a suitable microenvironment heavy metals could therefore favour the activation of autoreactive T cells. In that respect, genetic background is of major importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold salt treatment, the development of experimental autoimmune encephalomyelitis and the CD45RC(high)/CD45RC(low)CD4(+)T cells balance. The identification and functional characterization of genes controlling these phenotypes may shed light on key regulatory mechanisms of immune responses. This should help to improve efficacy and safety of vaccines.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U28, Institut Fédératif de Recherche (IFR) 30, Hôpital Purpan and Université Paul Sabatier, Toulouse, France. gfournie@purpan.inserm.fr
authors.forename: G J
authors.initials: GJ
authors.lastname: Fournié
authors.forename: M
authors.initials: M
authors.lastname: Mas
authors.forename: B
authors.initials: B
authors.lastname: Cautain
authors.forename: M
authors.initials: M
authors.lastname: Savignac
authors.forename: J F
authors.initials: JF
authors.lastname: Subra
authors.forename: L
authors.initials: L
authors.lastname: Pelletier
authors.forename: A
authors.initials: A
authors.lastname: Saoudi
authors.forename: D
authors.initials: D
authors.lastname: Lagrange
authors.forename: M
authors.initials: M
authors.lastname: Calise
authors.forename: P
authors.initials: P
authors.lastname: Druet
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D006046:Gold / Q000276:immunology; D006304:Health Status; D006801:Humans; D007154:Immune System Diseases / Q000139:chemically induced / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008627:Mercuric Chloride / Q000276:immunology; D019216:Metals, Heavy / Q000009:adverse effects* / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015262:Xenobiotics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019216:Metals, Heavy; D015262:Xenobiotics; D015847:Interleukin-4; D008627:Mercuric Chloride; D006046:Gold; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens