Gold-Induced Autoimmunity

Balazs, T.Jmmunogenetically controlled autoimmune reactions induced by mercury, gold and D-penicillamine in laboratory animals A review from the vantage point of premarketing safety studies. Toxicol. Ind. Health., 3, 331, 1987... 

Tournade, H. et al., Experimental gold-induced autoimmunity. Nephrol. Dial. Transplant., 6, 621, 1991... 

Tournade, H., Guery, J.C., Pasquier, R., Nochy D., Hinglais, N., Guilbert, B., Druet, P. and Pelletier, L. (1991) Experimental gold induced autoimmunity Nephrology, Dialysis, Transplantation, 6, 621—630. 

Tournade FI, Pelletier L, Guery JC, Pasquier R, Nochy D, Flinglals N, Gullbert B, Druet P Experimental gold-induced autoimmunity. Nephrol. Dial.Transplant. 1991 6 621-630. 

Tournade H, Guery J-C, Pasquier R, Vial MC, Mandet C, Druet E, Dansette PM, Druet P, Pelletier L Effect of the thiol group on experimental gold-induced autoimmunity. Arthritis Rheum. 1991 34 1594-1599. 

It is notable that cadmium as well as mercury and gold can initiate or aggravate autoimmune manifestations in normal or autoimmune-prone animals, respectively. It would seem likely that these heavy metals have the same effects on humans, presumably by a similar mechanism. Autoimmune manifestations induced by heavy metals include lupus-type nephritis, autoimmune haemolytic anaemia, and skin diseases, such as pemphigus and scleroderma-like lesion. Some manifestations of immune-mediated nephritis and elevation of circulating autoantibodies have been noted in case-studies of persons exposed to gold and cadmium as well as mercury (Ohsawa, 1993 Bigazzi, 1994, 1999). 

Autoimmune-like phenomena in Brown Norway rats induced by mercuiy(II) chloride peak around day 10 after the last of five subcutaneous injections. After 20 days, immune alterations are mostly at control level, and the kidney effects (e.g. proteinuria) are clearly less than on day 10 (Aten et al., 1988). In addition, low-dose pretreatment of Brown Norway rats with mercuiy(II) chloride prevents development of adverse immunity (Szeto et al., 1999), and neonatal injection of mercury(II) chloride in Brown Norway rats renders them tolerant to mercury-induced (but not gold-induced) autoimmune phenomena (Field et al., 2000). These phenomena, transience of autoimmune effects as well as low-dose protection, are shown to be due at least in part to the development of regulatory immune cells. In the case of mercury(II) chloride, these cells have been identified as either IFN-y-producing CD8+CD45RC high regulatory T cells (Pelletier et al., 1990 Mathieson et al., 1991 Szeto et al., 1999 Field et al., 2003) or RT6.2+ T cells (Kosuda et al., 1994). In view of this, it is relevant to note that Lewis rats that produce predominantly CD8+ regulatory T cells ( suppressor T cells) in response to mercury(II) chloride are resistant to mercury-induced autoimmunity and instead display a polyclonal immunosuppressive response (Pelletier et al., 1987). Based on these differences in strain sensitivity, it is clear that susceptibility to mercury-induced autoimmune effects is dependent on MHC class II haplo-type (Aten et al., 1991). 

The reasons why LEW rats are resistant to the development of gold-induced autoimmunity are unknown. However, two points are interesting 1) LEW MHC is permissive since Brown-Norway.IL rats, which have the same MHC as LEW rats and non MHC genes from the BN background, develop gold-induced disease as Brown-Norway rats and 2) administration of anti-IFN-y mAb render LEW rats partially susceptible to allochrysine-induced autoimmunity with the appearance of anti-laminin antibodies even if their titer is 5 times lower than in Brown-Norway rats [76]. This mild response could explain why IgG deposits are not found in the kidneys of LEW rats injected with allochrysine and anti-IFN-Y antibodies. 

Many drugs, especially quinidine and heparin, induce antibodies leading to thrombocytopenia. In most cases the antibodies are drug-dependent however, there are many examples in which the antibodies are autoimmune in nature [42], even for drugs, such as quinidine that are classically associated with drug-dependent antibodies [43], Gold therapy, in particular, is associated with autoimmune-thrombocytopenia [44],... 

Drugs can cause a wide variety of other autoimmune reactions. One example is myasthenia gravis, which is characterized by muscle weakness and is mediated by antibodies against the acetylcholine receptor at the neuromuscular junction. It has been reported in association with penicillamine [66], gold salts [67], and procainamide [68]. Another form of drug-induced autoimmunity is polymyositis, which is an autoimmune disease... 

Of all rat strains, the Brown Norway (BN) rat is used most frequently in relation to chemical-induced autoimmunity. This strain displays clinically manifested autoimmune disease following exposure to a number of chemicals. HgCl2 is the most scrutinized compound in the BN rat but D-penicillamine [6-8], gold-salts [9,10],hexachlorobenzene (HCB) [11-14] and recently, nevirapine [15], have all been shown to induce clinical effects. Captopril [7] and felbamate [16] appeared not to induce autoimmune effects in BN rats. 

Studies of xenobiotic-induced immune dysregulation in animal models. Hydralazine and procainamide-induced autoimmunity HgClj and gold salt-induced autoimmunity The impact of genetic studies in our understanding of immunological-mediated toxic-induced renal disease ... 

The fact that normal BN T-cells incubated with HgCl2 transferred the disease [131] suggested that the effect of the metal on T-cells was sufficient for the induction of autoimmunity. Figure 3 summarizes some events by which HgCl2 or gold salts may induce autoreactivity. 

The exact phenotype of the regulatory T cells in the case of low-dose D-penicillamine tolerance is not known, and non-lymphoid cells probably play a role as well. In another example of drug-induced autoimmune responses, the phenotype of regulatory T cells was identified as CD4+CD25+ (Layland et ah, 2004). In this study, CD4+CD25+ cells isolated from mice (A/J strain) exposed to procainamide, mercuiy(II) chloride, or gold salts were capable of preventing antinuclear antibody formation in similarly treated recipient mice, but also in mice subsequently treated with one of the other two chemicals. 

Gold salts also induce an autoimmune syndrome in the Brown Norway rat similar to that observed with mercury(II) chloride (and... 

A number of studies have been performed to induce systemic immunosensitization and autoimmunity (i.e. autoantibody formation or autoreactive T cells) in mice, and, again, occurrence of disease appears to be strain dependent. Robinson et al. (1986) compared in one study a large number of MHC-defined mouse strains with respect to induction of antinuclear autoantibodies by mercury(II) chloride (subcutaneously, detected after 0.5-2 months), gold salts (intramuscularly, detected after 1-5 months), and D-penicillamine (orally, detected after 4.5-5 months) and reported that A.SW mice were high responders to all three chemicals. 

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