How can a chemical element elicit complex immunopathology? Lessons from mercury-induced autoimmunity

Schiraldi, Michael; Monestier, Marc

doi:10.1016/j.it.2009.07.005

Cited by 54 publications

(44 citation statements)

References 101 publications

(105 reference statements)

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“…Research suggests that mercury induces autoimmune processes (Schiraldi and Monestier 2009 ), and may be mutagenic at low concentrations (Schurz et al 2000 ). Immunotoxic effects could potentially enhance susceptibility to infections, to malaria (Silbergeld et al 1998 ) or immunologically-mediated diseases (McCabe and Lawrence 1994 ).…”

Section: Absorption Distribution and Toxicity Of Mercurymentioning

confidence: 99%

Mercury Toxicity and Neurodegenerative Effects

Carocci

Rovito

Sinicropi

et al. 2013

Reviews of Environmental Contamination and Toxicology

161

116

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Mercury is among the most toxic heavy metals and has no known physiological role in humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury has been used by man since ancient times. Among the earliest were the Chinese and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink (Clarkson et al. 2007). Mercury has also been used to purify gold and silver minerals by forming amalgams. This is a hazardous practice, but is still widespread in Brazil's Amazon basin, in Laos and in Venezuela, where tens of thousands of miners are engaged in local mining activities to find and purify gold or silver. Mercury compounds were long used to treat syphilis and the element is still used as an antiseptic,as a medicinal preservative and as a fungicide. Dental amalgams, which contain about 50% mercury, have been used to repair dental caries in the U.S. since 1856.Mercury still exists in many common household products around the world.Examples are: thermometers, barometers, batteries, and light bulbs (Swain et al.2007). In small amounts, some organo mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and phenylmercury nitrate) are used as preservatives in some medicines and vaccines (Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++, respectively)occur. Chronic exposure to inorganic mercury produces stomatitis, erethism and tremors. Chronic MeHg exposure induced symptoms similar to those observed in ALS, such as the early onset of hind limb weakness (Johnson and Atchison 2009).Among the organic mercury compounds, MeHg is the most biologically available and toxic (Scheuhammer et a!. 2007). MeHg is neurotoxic, reaching high levels of accumulation in the CNS; it can impair physiological function by disrupting endocrine glands (Tan et a!. 2009).The most important mechanism by which mercury causes toxicity appears to bemitochondrial damage via depletion of GSH (Nicole et a!. 1998), coupled with binding to thiol groups ( -SH), which generates free radicals. Mercury has a high affinity for thiol groups ( -SH) and seleno groups ( -SeH) that are present in amino acids as cysteine and N-acetyl cysteine, lipoic acid, proteins, and enzymes. N-acetylcysteine and cysteine are precursors for the biosynthesis of GSH, which is among the most powerful intracellular antioxidants available to protect against oxidative stress and inflammation.Mercury and methylmercury induce mitochondrial dysfunction, which reduces ATP synthesis and increases lipid, protein and DNA peroxidation. The content of metallothioneines, GSH, selenium and fish high in omega-3 fatty acids appear to be strongly related with degree of inorganic and organic mercury toxicity, and with the protective detoxifying mechanisms in humans. In conclusion, depletion of GSH,breakage of mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA in ...

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Section: Absorption Distribution and Toxicity Of Mercurymentioning

confidence: 99%

Mercury Toxicity and Neurodegenerative Effects

Carocci

Rovito

Sinicropi

et al. 2013

Reviews of Environmental Contamination and Toxicology

161

116

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“…Apart from the well-known significance of Ni in developing contact dermatitis, other metals such as aluminum, Be, chromium, cobalt, copper, gold (Au), iridium, mercury, palladium, platinum, rhodium and titanium represented emerging causes of skin hypersensitivity [1]. Heavy metals, such as, Au, cadmium and mercury, can induce human autoimmune diseases [2]. Exposure to mercury vapors can result in elevated IgE levels and increased T lymphocyte numbers in humans [3, 4].…”

Section: Metal and Immune Systemsmentioning

confidence: 99%

Structural basis of metal hypersensitivity

Wang

Dai

2012

Immunol Res

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Metal hypersensitivity is a common immune disorder. Human immune systems mount the allergic attacks on metal ions through skin contacts, lung inhalation and metal-containing artificial body implants. The consequences can be simple annoyances to life-threatening systemic illness. Allergic hyper-reactivities to nickel (Ni) and beryllium (Be) are the best-studied human metal hypersensitivities. Ni-contact dermatitis affects 10 % of the human population, whereas Be compounds are the culprits of chronic Be disease (CBD). αβ T cells (T cells) play a crucial role in these hypersensitivity reactions. Metal ions work as haptens and bind to the surface of major histocompatibility complex (MHC) and peptide complex. This modifies the binding surface of MHC and triggers the immune response of T cells. Metal-specific αβ T cell receptors (TCRs) are usually MHC restricted, especially MHC class II (MHCII) restricted. Numerous models have been proposed, yet the mechanisms and molecular basis of metal hypersensitivity remain elusive. Recently, we determined the crystal structures of the Ni and Be presenting human MHCII molecules, HLA-DR52c (DRA*0101, DRB3*0301) and HLA-DP2 (DPA1*0103, DPB1*0201). These structures revealed unusual features of MHCII molecules and shed light on how metal ions are recognized by T cells.

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“…Because mercury has previously been shown to increase by Th1 and Th2 cytokine levels in animal models of mercury-induced autoimmunity [27], we examined a wide panel of cytokines in the spleen using multiplex kits. Mercury exposure on its own induces elevated CCL4, and significantly decreases TNF-α, IL-1β, and RANTES (PBS and Hg groups in Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Low-dose mercury heightens early innate response to coxsackievirus infection in female mice

et al. 2014

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Objective Mercury is a ubiquitous environmental contaminant with toxic outcomes over a range of exposures. In this study, we investigated the effects of mercury exposure on early immune responses to coxsackievirus B3 (CVB3) infection in a murine model of autoimmune heart disease. Materials and Methods Female BALB/c mice, susceptible to CVB3-induced autoimmune myocarditis, were treated with mercuric chloride (200 μg/kg body weight every other day for 2 weeks) prior to infection with CVB3. Six hours post-infection, immune cells were isolated from the spleen and peritoneum for flow cytometry, gene expression, and cytokine profiling. Thirty-five days post-infection, hearts were collected for histological examination of immune cell infiltration. Results As for male mice, mercury exposure significantly increased autoimmune myocarditis and immune infiltration into the heart. During the innate response six hours post-infection, mercury increased expression of co-stimulatory molecules and innate immune receptors on peritoneal macrophages. At the same time point, the alternatively-activated macrophage gene, arginase, was increased while the classically-activated macrophage gene, inducible nitric oxide synthase, was unaffected. Expression of activation markers were decreased on peritoneal B cells with mercury exposure while T cells were unaffected. Mercury increased production of pro-inflammatory mediators in the spleen. Macrophage-recruiting chemokines and activating cytokines such as CCL2, CCL4, and IL-6 were increased with mercury following CVB3 infection. Conclusions Thus, mercury treatment exacerbates autoimmune myocarditis in female mice and alters early innate signaling on peritoneal macrophages. Mercury also modulates the cytokine profile in the spleen toward a macrophage-activating milieu, and upregulates alternatively-activated macrophage genes, providing evidence that mercury exposure promotes inflammation in the context of infection.

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How can a chemical element elicit complex immunopathology? Lessons from mercury-induced autoimmunity

Cited by 54 publications

References 101 publications

Mercury Toxicity and Neurodegenerative Effects

Mercury Toxicity and Neurodegenerative Effects

Structural basis of metal hypersensitivity

Low-dose mercury heightens early innate response to coxsackievirus infection in female mice

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