Experimental Gold-Induced Autoimmunity

Abstract

The pathogenesis of gold-induced autoimmunity and membranous glomerulopathy is not well understood. HgCl2 and D-penicillamine, other chemicals known to trigger membranous glomerulopathy in humans, induce autoimmune manifestations in Brown-Norway (BN) rats but not in Lewis (LEW) rats. These chemicals trigger T-cell clones which are specific for self class II molecules from the major histocompatibility complex and are probably responsible for the polyclonal B-cell activation observed. The aim of this work was to test the effects of aurothiopropanolsulphonate (ATPS) in BN and LEW rats. In BN rats, ATPS induced a polyclonal B-cell activation marked by lymphoproliferation, hyperimmunoglobulinaemia affecting mainly IgE, and by the production of numerous autoantibodies. A glomerulonephritis occurred, initially due to anti-glomerular basement membrane antibody deposition, and later to the formation of granular deposits, occasionally resulting in a typical membranous glomerulopathy. Self class-II-specific T-cells were found that might be responsible for the polyclonal B-cell activation. Lewis rats were free of glomerulopathy but, like BN rats, exhibited an interstitial nephritis and some degree of polyclonal B-cell activation. These findings demonstrate that, depending on the strain, ATPS triggers different B-cell clones inducing different degrees of autoimmunity.

Metals and Kidney Autoimmunity

“…Autoantibodies reacting with the renal GBM, and in particular with laminin 1 (a component of the extracellular matrix), were found in all animals injected with aurothiopropanolsulfanate (84). Other autoantibodies (against nuclear antigens, double-stranded DNA, thyroglobulin, actin, myosin, and tubulin) were detected in gold-treated BN rats.…”

“…Brown Norway (BN) rats treated with gold salts develop autoimmunity (83,84). Autoantibodies reacting with the renal GBM, and in particular with laminin 1 (a component of the extracellular matrix), were found in all animals injected with aurothiopropanolsulfanate (84).…”

Mercury: god of Th2 cells?

“…The chemical has a propensity to bind to sulfhydryl groups of proteins and nonprotein thiols, and other agents such as gold salts and penicillamine which induce similar autoimmune phenomena in susceptible animals [20,21] share this characteristic. Chemical modification of MHC class II molecules, T cell receptors, autoantigenic peptides or some other cell-surface molecules has been postulated [3], but there is no direct evidence for these effects.…”

“…HgCl2 can induce apoptosis in T cells in vitro [22], and this effect may be enhanced by IL-4 [23]. Increasingly, molecular immunology has turned its attention to intracellular signalling events: an intriguing recent observation is that HgCU induces aggregation of cell surface proteins such as CD4, CD3, CD45 and Thy-1 on T cells in vitro, followed by dramatic tyrosine phosphorylation of several cellular proteins, including the nonreceptor protein tyrosine kinase p56''^'' [20]. These effects were dependent on the bivalent thiol reactivity of HgCl2.…”

“…These effects were dependent on the bivalent thiol reactivity of HgCl2. However, it should be noted that very high concentrations of HgCl2 were used, sufficient to induce rapid death of the cells [20]. Alteration of intracellular redox potential via effects on glutathione have been demonstrated in vitro after exposure of T cells to HgCl2 (Aten, data presented at 9th International Congress of Immunology, San Francisco, July 1995); the effects of HgCl2 on IFN-7 production by spleen cells in vitro differ between susceptible and resistant strains, and this seems to be at least partly explained by variations in sensitivity to the effects of depletion of reduced glutathione [18].…”