Immune Modulation by Toxic Metals

Lawrence, David A.

doi:10.1016/b978-0-12-294375-1.50016-7

Cited by 29 publications

(13 citation statements)

References 113 publications

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“…In comparison to other heavy metals (e.g., cadmium, lead, and nickel), it remains less certain whether Hg acts as a potent modulator of the hematopoietic/immune system (Woods, 1995;Lawrence & McCabe, 1995). However, HgCl 2 has also been recognized as having a narrow margin between a therapeutic and toxic dose (Bidstrup, 1964); as such, it has the potential to produce diverse effects on the vertebrate immune system.…”

Section: Hg-induced Immunotoxicity In Mammalian Speciesmentioning

confidence: 97%

“…In rodents, HgCl 2 modulates T cells by induction of interleukins (IL) (e.g., IL-1 b ) and immunoglobulins (Ig) (e.g., IgG and IgE) (Griem et al, 1998), and by altering expression of costimulatory molecules (Roos et al, 1996); Hg stimulation of B lymphocytes may also mediate autoimmunity (Druet et al, 1982;Rose, 1993). In rodents, other features of Hg-induced autoimmune disease include generation of autoreactive CD4 + T cells (inhibition of Th1 and enhancement of Th2 subsets); synthesis of autoantibodies; glomerulonephritis; hypergammaglobulinemia; and regulation by IL-2 (Lawrence & McCabe, 1995;Kosuda et al, 1994Kosuda et al, , 1998Jiang & Moller, 1999;Abedi-Valugerdi et al, 1999). Interestingly, significant induction of serum concentrations of IgA, IgG, and IgM (compared to nonexposed healthy subjects) was observed in human workers exposed to Hg occupationally .…”

Section: Hg-induced Immunotoxicity In Mammalian Speciesmentioning

confidence: 97%

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Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

Sweet¹,

Zelikoff²

2001

Journal of Toxicology and Environmental Health Part B: Critical Reviews

206

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This review addresses an important area of environmental and mammalian toxicology by evaluating and comparing mercury-induced effects upon the immune responses of two evolutionarily divergent yet immunologically-related species. The mechanisms of mercury toxicology and immunotoxicology are described herein, including supporting data from the following: sources of exposure; bioavailability and biodistribution; metabolism; and laboratory and field investigations. Based upon the studies presented, the relative sensitivities of fish and human immune cells to mercury exposure are compared and contrasted with regard to mercury's ability to stimulate and/or suppress host immunocompetence. In addition, results from immune assays are compared to mercury tissue burdens, as well as to toxicological threshold level estimates. Such comparisons may help to resolve gaps in our knowledge regarding sensitivity of immunological assays, standardization of immunotoxicological techniques between species, and the extent to which the vertebrate immune system possesses functional reserve and redundancy in response to xenobiotics. A review of this type begins to provide support for the potential usefulness of fish immune cells to serve as indicators for human immunotoxicology risk assessment. Analysis of the reviewed studies supports the following conclusions in both lower and higher vertebrates: a threshold for mercury-induced immunotoxicological effects is likely; multiple exposure scenarios involving high and/or chronic exposures leading to increased body burdens are linked to increased risk of immunomodulation; and highly exposed and/or susceptible subpopulations are at greater risk of toxicological impact.

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Section: Hg-induced Immunotoxicity In Mammalian Speciesmentioning

confidence: 97%

Section: Hg-induced Immunotoxicity In Mammalian Speciesmentioning

confidence: 97%

Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

Sweet¹,

Zelikoff²

2001

Journal of Toxicology and Environmental Health Part B: Critical Reviews

206

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“…Because Pb is carried through the circulatory system by erythrocytes, virtually all tissues in the body can become exposed to the toxic metal (Goering, 1993; Gidlow 2004). Although Pb can damage most of the organ systems, those particularly susceptible to the toxic effects of Pb exposure are the hematopoietic, immune, renal, and nervous systems (Lawrence and McCabe, 1995). …”

Section: Introductionmentioning

confidence: 99%

Impact of developmental lead exposure on splenic factors

Kasten‐Jolly

Heo

Lawrence

2010

Toxicology and Applied Pharmacology

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Lead (Pb) is known to alter the functions of numerous organ systems, including the hematopoietic and immune systems. Pb can induce anemia and can lower host resistance to bacterial and viral infections. The anemia is due to Pb’s inhibition of hemoglobin synthesis and Pb’s induction of membrane changes, leading to early erythrocyte senescence. Pb also increases B-cell activation/proliferation and skews T-cell help (Th) toward Th2 subset generation. The specific mechanisms for many of the Pb effects are, as yet, not completely understood. Therefore, we performed gene expression analysis, via microarray, on RNA from the spleens of developmentally Pb-exposed mice, in order to gain further insight into these Pb effects. Splenic RNA microarray analysis indicated strong up-regulation of genes coding for proteolytic enzymes, lipases, amylase, and RNaseA. The data also showed that Pb affected the expression of many genes associated with innate immunity. Analysis of the microarray results via GeneSifter software indicated that Pb increased apoptosis, B-cell differentiation, and Th2 development. Direct up-regulation by Pb of expression of the gene encoding the heme-regulated inhibitor (HRI) suggested that Pb can decrease erythropoiesis by blocking globin mRNA translation. Pb’s high elevation of digestive/catabolizing enzymes could generate immunogenic self peptides. With Pb’s potential to induce new self-peptides and to enhance the expression of caspases, cytokines, and other immunomodulators, further evaluation of Pb’s involvement in autoimmune phenomena, especially Th2-mediated autoantibody production, and alteration of organ system activities is warranted.

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“…Alteration of human PMN functions by low-level Hg have been reported previously both in vitro (Malamud et al, 1985;Contrino et al, 1988;Obel et al, 1993) and in vivo (Perlingeiro & Queiroz, 1994, 1995, but it is not known whether part of these effects is related to inhibition of PMN spontaneous apoptosis. Genetically prone animal models of Hg-induced autoimmunity are described in rodents (reviewed in Lawrence & McCabe, 1995), and there is some evidence from clinical studies suggesting that exposure to Hg may result in autoimmune responses to various self-antigens in humans (Schrallhammer-Benkler et al, 1992;Bigazzi, 1999;El-Fawal et al, 1999). It is conceivable that attenuation of PMN constitutive apoptosis by Hg may lead to excessive accumulation of senescent PMN, and this may contribute to Hg-induced autoimmunity.…”

Section: Discussionmentioning

confidence: 96%

“…The toxic potential of this heavy metal to numerous organ systems, including the immune system, has been well recognized (Lawrence & McCabe, 1995;Moszczynski, 1997;Pollard & Hultman, 1997). Hence, data from several animal models and clinical observations in humans indicate that the immunotoxicity produced by Hg encompasses all the known categories of immune alterations, including direct immunosuppression or immunostimulation, hypersensitivity reactions, and autoimmunity (Kosuda et al, 1994;Nadarajah et al, 1996;Ratcliffe et al, 1996;Loftenius et al, 1998;Descotes et al, 2000;Sweet & Zelikoff, 2001).…”

Section: Prolongation Of Human Neutrophil Survival By Low-level Mercumentioning

confidence: 98%

Prolongation of Human Neutrophil Survival by Low-Level Mercury via Inhibition of Spontaneous Apoptosis

Moisan¹,

Arbour²,

Nguyen³

et al. 2002

Journal of Toxicology and Environmental Health, Part A

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Low levels of organic and inorganic mercury compounds have been reported previously to induce cell death by apoptosis in human peripheral blood mononuclear cells (MNC). but little is known about their potential effects on the viability and death of polymorphonuclear neutrophils (PMN). In contrast to MNC, PMN are known to undergo readily spontaneous apoptosis both in vivo and in vitro. Therefore, it was hypothesized that PMN may differ from MNC in their reactions to low mercury levels. The effects of methylmercuric chloride (MeHgCl) and mercuric chloride (HgCl2) were evaluated in concentration-response and time-course studies on human PMN viability and on their modes of cell death after in vitro incubation at 37 degrees C. Cell death by apoptosis or necrosis was assessed by annexin V-fluorescein isothiocyanate binding to externalized phosphatidylserine in conjunction with propidium iodide, and flow cytometry analysis. Morphologic counting of pyknotic nuclei and the fluorescence properties of the DNA-binding dye Hoechst 33342 in combination with propidium iodide were used to further confirm apoptotic cell death and to characterize the sequence of Hg-induced cell death. Results show that low concentrations of MeHgCl (1-7.5 microM) that were cytotoxic to MNC actually inhibited PMN spontaneous apoptosis. Low-level HgCl, reproduced the anti-apoptotic effects of MeHgCl on PMN, but to a lower extent. Higher concentrations of MeHgCl and HgCl2 were necrogenic to PMN, but MeHgCl was about an order of magnitude more toxic, and discrete differences were observed in the modalities of cell death induced by both species. These data reveal for the first time that (1) low levels of organic and inorganic mercury species protect human PMN from cell death via inhibition of spontaneous apoptosis, and (2) PMN are more resistant than MNC to mercury-induced cytotoxicity. Since delayed apoptosis and increased resistance to toxicant-induced cell death may lead to excessive accumulation of senescent PMN, evidence indicates that findings of this study may have implications for mercury-induced autoimmunity and inflammation.

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Immune Modulation by Toxic Metals

Cited by 29 publications

References 113 publications

Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

Toxicology and Immunotoxicology of Mercury: A Comparative Review in Fish and Humans

Impact of developmental lead exposure on splenic factors

Prolongation of Human Neutrophil Survival by Low-Level Mercury via Inhibition of Spontaneous Apoptosis

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