Effects of mercury on the immune system

Little is known about the principal mechanism by which mercury affects the immune system. An effect on the selection mechanisms in the thymus has been suggested, allowing potentially autoreactive cells to escape into the periphery. A direct mitogenic action on lymphocytes seems to be well established and could result from the chemical effects of this heavy metal on some cell membrane components, such as calcium channels, or direct action on nuclear proteins. Other possible mechanisms would be increased expression of major histocompatibility complex (MHC) class II molecules on cell surfaces, with consequences for antigen presentation, or alterations of surface antigens into immunogenic forms. A well-documented toxic action might cause release of cellular proteins inducing autoimmune reactions.

Mercury has an affinity for SH-groups and may interact with enzymes and other cellular proteins. In several species (such as humans, guinea pigs, rats, mice and rabbits) in vitro culture of lymphocytes (from blood, thymus, lymph nodes or spleen) in the presence of mercuric chloride results in blast transformation and increased mitotic activity. At least in human and murine lymphocytes increased DNA synthesis and mitotic activity is found after treatment with concentrations of mercury compounds close to toxic levels. In BALB/c mice the mitogenic effect seemed to be macrophage dependent. In humans, the responsiveness was reported to increase with age. In guinea pigs, thymocytes from newborn animals were the most easily stimulated by mercury, whereas in older animals spleen cells responded better. In BN strain rats, mercury induces proliferation of both T helper and B lymphocytes in peripheral lymphoid organs, and over-production of different immunoglobulin (Ig) isotypes, preferentially IgE. An early thymic atrophy and increased lymph node weight are also seen.

As shown in BN rat spleen cells, the effects of mercuric chloride are associated with increased production of interleukin 2 (IL-2). In accordance with in vitro results, individuals occupationally exposed to mercury have an increased absolute number of T lymphocytes which correlated with the time of exposure. Of particular interest are the different effects of mercury on T helper cells, T suppressor cells and B cells, obviously of importance in understanding the imbalance of the immune system after such treatment. In BN rats, autoreactive T helper cells were initially induced by mercury, and later the appearance of T suppressor cells was demonstrated. These latter cells may be responsible for the self-limiting nature of this autoimmune response. Mercuric chloride is responsible for inhibition of suppressor T cells in PVG/c rats, which develop immune complex glomerulonephritis and antinuclear antibodies. In contrast, in LEW (Lewis) rats, MRC OX-8 1 cells (suppressor cells) are increased and associated with immunosuppression. These suppressor cells are possibly responsible for mercury-mediated protection against experimental allergic encephalomyelitis in these animals. It seems that in nonresponding strains there is no proliferative response among T helper cells.

In some studies, very low levels of methylmercuric chloride or mercuric chloride inhibit RNA and DNA synthesis, mitogen responses and immunoglobulin production. They furthermore cause downregulation of some receptors, reduced viability and signs of apoptosis. It has been reported that different immunoglobulin isotypes are differentially affected, IgGl being the most easily inhibited. Methylmercuric chloride and, to a lesser extent, mercuric chloride also may inhibit activation of mouse (BALB/c and C57BL) lymphocytes, both by mitogen and by MLC stimulation. In guinea pigs, in vivo experiments with mercuric chloride resulted in inhibition of thymocyte proliferation (as in Wistar rats) but at the same time decreased negative selection, possibly resulting in formation of an increased fraction of potentially autoimmune cells.

The mechanism by which mercury causes these effects is not known. According to studies with mouse (strain ddY) lymphocytes, methyl mercury increases intracellular Ca2+. It was also shown to be incorporated into lymphocyte nuclei and to increase phosphorylation of nuclear proteins. Some evidence indicates that interaction with immune function is due to inactivation of glutathione. Antigen-specific sensitization to mercury can occur in both humans and experimental animals. BALB/c mice are readily sensitized to mercury by epicutaneous exposure. Certain inbred guinea pig strains can also be sensitized to mercury.

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