Mercury autoimmune response

Attention has been given to mercury as a cause of autoimmune responses, especially in the kidney (69). Exposure to mercury can cause immune responses to various auto-antigens and autoimmune disease of the kidney and other tissues. Although epidemiological studies have shown that occupational exposure to mercury does not usually result in autoimmunity, mercury can cause the formation of antinuclear antibodies,... 

Some rat and mice strains that are susceptible to autoimmune responses develop kidney damage as a result of an immune response when exposed to relatively low levels of mercury vapor or mercury chloride. 

Langworth et al. 1992b). There is limited information in humans that suggests that certain individuals may develop an autoimmune response when exposed to mercury. Deposition of IgG and complement C3 have been observed in the glomeruli of two workers with mercury-induced proteinuria (Tubbs et al. 

The immune system reaction to mercury has been extensively studied in animals. Although it has not been completely described, a great deal of information exists about the changes that occur in the immune system in response to mercury exposure (Bigazzi 1992 Goldman et al. 1991 Mathieson 1992). Animal strains that are susceptible or predisposed to develop an autoimmune response show a proliferation of autoreactive T-cells (specifically CD4+ T-cells) (Pelletier et al. 1986 Rossert et al. 1988). The fundamental change caused by mercury that results in the autoimmune response appears to be in these... 

Michaelson JH, McCoy JP, Hirzel P, et al. 1985. Mercury-induced autoimmune glomerulonephritis in inbred rats—part I Kinetics and species specificity of autoimmune responses. Surv Synth Pathol Res 4 401-411. 

Rodent susceptibility to the systemic autoimmunity induced by mercury(II) chloride is genetically controlled (see chapter 7). Both MHC class II genes and non-MHC genes determine responsiveness (Hultman et al., 1996 Hanley et al., 1998 Schuppe et al., 1998 Abedi-Valugerdi Moller, 2000 Hultman Nielsen, 2001). The induction and development of autoimmune responses in susceptible strains vary across species. Rats become resistant to mercury-induced autoimmunity after a subsequent challenge, whereas mice do not show resistance to subsequent mercury exposures (see also chapter 10). 

Rowley Monestier (2005) reviewed mechanisms of the induction of autoimmunity by the heavy metal mercury in the rat and mouse. In contrast to the rat autoimmune model, in the mouse model for autoimmunity induced by mercury, the autoantibody response is specifically targeted towards nucleolar antigens and is associated with induction of antifibrillarin autoantibodies. Second, exposure to low doses of mercury can dramatically worsen the development of autoimmune responses in lupus mouse models. A third difference is the nature of the interaction of heavy metals such as mercury with thiol groups and the role of this affinity in the availability of certain thiol-containing molecules for immature cells. 

An autoimmune response to mercury vapor, such as increased levels of serum IgE and antilaminin autoantibodies, deposition of IgG deposits in the renal glomeruli and proteinuria was observed in a susceptible strain of rats (Hua et al. 1993, Druet et al. 

Hultman, P., and Enestrom, S., Dose-response studies in murine mercury-induced autoimmunity and immune-complex disease. Toxicol. Appl. Pharmacol., 113, 199, 1992... 

Haggqvist B, Hultman P Effects ofdeviatingtheTh2-response In murine mercury-induced autoimmunity towards aThI-response. Clin Exp Immunol 2003 134 202-9. 

Over the past decade there has, as result of experimental studies, been a growing appreciation that mercury may exert an effect on the immune system. As summarized by Silbergeld and Devine [72], mercury has at least two types of effects on the immune system. First, mercury induces autoimmunity to renal basement membrane proteins, causing mercury-induced glomerulonephritis in certain strains of mice and rats. Secondly, mercury exposure impairs cell-mediated and humoral immunity by affecting Thl and Th2 responses, which in turn impairs the body s ability to effectively... 

The immune response to mercury exposure is complex, depending in part on the dose of mercury and the genetic characteristics of the exposed population (see Section 2.4). Administration of 14.8 mg Hg/kg/day as mercuric chloride to B6C3F, mice 5 days a week for 2 weeks resulted in a decrease in thymus weight (NTP 1993), suggesting immune suppression. However, a 2-week exposure to 0.7 mg Hg/kg/day as mercuric chloride in the drinking water resulted in an increase in the lymphoproliferative response after stimulation with T-cell mitogens in a strain of mice particularly sensitive to the autoimmune effects of mercury (SJL/N) (Hultman and Johansson 1991). In contrast, a similar exposure of a strain of mice (DBA/2) not predisposed to the autoimmune effects of mercury showed no increase in lymphocyte proliferation. 

Antilaminin antibodies induced by mercuric chloride have been demonstrated to be detrimental to the development of cultured rat embryos (Chambers and Klein 1993). Based upon that observation, those authors suggested that it might be possible for an autoimmune disease induced by a substance such as mercury at an early age to persist into later life, acting as a teratogen independent of both dose-response relationships and time of exposure, but that possibility remains to be experimentally demonstrated. 

WarfVinge K, Hansson H, Hultman P. 1995. Systemic autoimmunity due to mercury vapor exposure in genetically susceptible mice Dose-responses studies. Toxicol Appl Pharm 132 299-309. 

Hu, H., G. Moller, and M. Ahedi-Valugerdi. 1999. Mechanism of mercury-induced autoimmunity Both T helper 1- and T helper 2-type responses are involved. Immunology 96(3) 348-57. 

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). 

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