Genetic Control of Resistance to Mercury‐Induced Immune/Autoimmune Activation

Abedi‐Valugerdi, Manuchehr; Hansson, Monika; Möller, Göran

doi:10.1046/j.1365-3083.2001.00932.x

Cited by 18 publications

(29 citation statements)

References 22 publications

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“…12 Organic Hg compounds have been show to influence various immune responses mostly in the animal models. [13][14][15][16][17][18][19][20] Thimerosal, a sulfhydryl reagent, calcium mobilizer, and cell function modulator, is composed of two moieties, the thiosalicylic acid and mercury linked to sulfur. 22 Therefore, we examined the effects of thimerosal on apoptosis in T cells.…”

Section: Discussionmentioning

confidence: 99%

“…12 Hg has been shown to induce a number of immunological and neurotoxic changes, including increased production of Th2 cytokines, increased levels of IgE, decreased activity of T cells and NK cell, suppression of IgG, production of autoantibodies to a variety of self antigens (eg, neural antigens), and apoptosis in microglia and astrocytes. [13][14][15][16][17][18][19][20][21] The majority of these studies have been performed both in vitro and in vivo in experimental animals. Because of likely exposure to high levels of Hg via vaccines containing thimerosal and its possible effects on the immune system, we examined the effect of thimerosal in concentrations well within exposure on biochemical and molecular steps of T cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

et al. 2002

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The major source of thimerosal (ethyl mercury thiosalicylate) . Thimerosal and not thiosalcylic acid (nonmercury component of thimerosal), in a concentration-dependent manner, induced apoptosis in T cells as determined by TUNEL and propidium iodide assays, suggesting a role of mercury in T cell apoptosis. Apoptosis was associated with depolarization of mitochondrial membrane, release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria, and activation of caspase-9 and caspase-3, but not of caspase-8. In addition, thimerosal in a concentrationdependent manner inhibited the expression of XIAP, cIAP-1 but did not influence cIAP-2 expression. Furthermore, thimerosal enhanced intracellular reactive oxygen species and reduced intracellular glutathione (GSH). Finally, exogenous glutathione protected T cells from thimerosal-induced apoptosis by upregulation of XIAP and cIAP1 and by inhibiting activation of both caspase-9 and caspase-3. These data suggest that thimerosal induces apoptosis in T cells via mitochondrial pathway by inducing oxidative stress and depletion of GSH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

et al. 2002

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“…1 The disease can be induced experimentally in non-autoimmune mice by injection of cells, antigens or some inorganic compounds. [1][2][3][4] Also, there is a particular combination of mouse strains, the F 1 (NZB · NZW), that develops a disease characterized by lethal immune complex glomeronephritis and high plasma levels of anti-double-stranded DNA (anti-dsDNA) antibodies. These antibodies have been reported to play a role in glomerular injury.…”

Section: Introductionmentioning

confidence: 99%

Long‐term administration of IgG2a anti‐NK1.1 monoclonal antibody ameliorates lupus‐like disease in NZB/W mice in spite of an early worsening induced by an IgG2a‐dependent BAFF/BLyS production

et al. 2008

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Summary The role of natural killer (NK) T cells in the development of lupus‐like disease in mice is still controversial. We treated NZB/W mice with anti‐NK1.1 monoclonal antibodies (mAbs) and our results revealed that administration of either an irrelevant immunoglobulin G2a (IgG2a) mAb or an IgG2a anti‐NK1.1 mAb increased the production of anti‐dsDNA antibodies in young NZB/W mice. However, the continuous administration of an anti‐NK1.1 mAb protected aged NZB/W mice from glomerular injury, leading to prolonged survival and stabilization of the proteinuria. Conversely, the administration of the control IgG2a mAb led to an aggravation of the lupus‐like disease. Augmented titres of anti‐dsDNA in NZB/W mice, upon IgG2a administration, correlated with the production of BAFF/BLyS by dendritic, B and T cells. Treatment with an anti‐NK1.1 mAb reduced the levels of interleukin‐16, produced by T cells, in spleen cell culture supernatants from aged NZB/W. Adoptive transfer of NK T cells from aged to young NZB/W accelerated the production of anti‐dsDNA in recipient NZB/W mice, suggesting that NK T cells from aged NZB/W are endowed with a B‐cell helper activity. In vitro studies, using purified NK T cells from aged NZB/W, showed that these cells provided helper B‐cell activity for the production of anti‐dsDNA. We concluded that NK T cells are involved in the progression of lupus‐like disease in mature NZB/W mice and that immunoglobulin of the IgG2a isotype has an enhancing effect on antibody synthesis due to the induction of BAFF/BLyS, and therefore have a deleterious effect in the NZB/W mouse physiology.

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“…Lag-3 −/− C57BL/6 mice were crossed with B6.SJL (H2 S ) mice to generate Lag-3 −/− B6.SJL mice. Homozygosity for LAG-3 targeted deletion and for H2 S was determined by PCR as described before [26], [27]. All mice used for the experiments were at least 2 months old.…”

Section: Methodsmentioning

confidence: 99%

Lymphocyte Activation Gene-3 (LAG-3) Negatively Regulates Environmentally-Induced Autoimmunity

et al. 2014

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Environmental factors including drugs, mineral oils and heavy metals such as lead, gold and mercury are triggers of autoimmune diseases in animal models or even in occupationally exposed humans. After exposure to subtoxic levels of mercury (Hg), genetically susceptible strains of mice develop an autoimmune disease characterized by the production of highly specific anti-nucleolar autoantibodies, hyperglobulinemia and nephritis. However, mice can be tolerized to the disease by a single low dose administration of Hg. Lymphocyte Activation Gene-3 (LAG-3) is a CD4-related, MHC-class II binding molecule expressed on activated T cells and NK cells which maintains lymphocyte homeostatic balance via various inhibitory mechanisms. In our model, administration of anti-LAG-3 monoclonal antibody broke tolerance to Hg resulting in autoantibody production and an increase in serum IgE level. In addition, LAG-3-deficient B6.SJL mice not only had increased susceptibility to Hg-induced autoimmunity but were also unresponsive to tolerance induction. Conversely, adoptive transfer of wild-type CD4+ T cells was able to partially rescue LAG-3-deficient mice from the autoimmune disease. Further, in LAG-3-deficient mice, mercury elicited higher amounts of IL-6, IL-4 and IFN-γ, cytokines known to play a critical role in mercury-induced autoimmunity. Therefore, we conclude that LAG-3 exerts an important regulatory effect on autoimmunity elicited by a common environmental pollutant.

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Genetic Control of Resistance to Mercury‐Induced Immune/Autoimmune Activation

Cited by 18 publications

References 22 publications

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

Biochemical and molecular basis of thimerosal-induced apoptosis in T cells: a major role of mitochondrial pathway

Long‐term administration of IgG2a anti‐NK1.1 monoclonal antibody ameliorates lupus‐like disease in NZB/W mice in spite of an early worsening induced by an IgG2a‐dependent BAFF/BLyS production

Lymphocyte Activation Gene-3 (LAG-3) Negatively Regulates Environmentally-Induced Autoimmunity

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