Induction of autoimmunity through bystander effects. Lessons from immunological disorders induced by heavy metals

Autoreactive T cells exist in healthy individuals and represent a potential reservoir of pathogenic effectors which, when stimulated by microbial adju vants, could trigger an autoimmune disease. Experimental studies have indic ated that xenobiotics, well defined from a chemical point of view, could pr omote the differentiation of autoreactive T cells towards a pathogenic path way. It is therefore theoretically possible that compounds present in vacci nes such as thiomersal or aluminium hydroxyde can trigger autoimmune reacti ons through bystander effects. Mercury and gold in rodents can induce immunological disorders with autoimm une reactions. In vitro, both activate signal transduction pathways that re sult in the expression of cytokines, particularly of IL-4 and IFN gamma. In a suitable microenvironment heavy metals could therefore favour the activa tion of autoreactive T cells. In that respect, genetic background is of maj or importance. Genome-wide searches in the rat have shown that overlapping chromosomal regions control the immunological disorders induced by gold sal t treatment, the development of experimental autoimmune encephalomyelitis a nd the CD45RC(high)/CD45RC(low) CD4(+) T cells balance. The identification and functional characterization of genes controlling these phenotypes may s hed light on key regulatory mechanisms of immune responses. This should hel p to improve efficacy and safety of vaccines. (C) 2001 Academic Press.