Mercuric Chloride Induced Autoimmunity

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unit 15.15

In genetically predisposed individuals, nontoxic amounts of mercuric chloride (HgCl2), a compound that was once used therapeutically and that is ubiquitous as a pollutant, provoke the appearance of immunologically mediated glomerulopathies. Gold salts, which are used in the treatment of rheumatoid arthritis, also induce immune glomerulopathies in ~10% of patients. Experimental models have been developed mainly in rats. Brown Norway (BN) rats and to a lesser degree H-2s mice develop HgCl2- or gold-salt-induced autoimmunity, while LEW rats and DBA/2 mice (for example) are resistant. In BN rats HgCl2 provokes a B cell polyclonal activation that is under the control of CD4+ TH2-like cells. This activation is responsible for an impressive increase in serum IgE and IgG1 concentration. HgCl2 induces antibodies, mainly of IgG1 isotype, directed against both self antigens (e.g., DNA, laminin, type II collagen) and haptens (trinitrophenol). Kinetics assessment of the antibody response shows that antibody production appears beginning at day 7 after the first HgCl2 injection, peaks between days 14 and 21, and progressively disappears to reach baseline values between days 35 and 42. The anti-laminin antibody response is associated with the development of a glomerulopathy that resembles the one observed in humans. Rats often display transient high proteinuria with the nephrotic syndrome between days 14 and 21. Other clinical manifestations (e.g., alopecia, erythema, mucositis, and arthritis) may also be observed. In BN rats, gold salts induce autoimmune manifestations similar but less severe than those caused by HgCl2.

The frequency of T cells that recognize self major histocompatibility complex (MHC) class II molecules is increased in BN rats that receive either HgCl2 or gold salts. As described below, in the gold salt model anti-MHC class II T cell lines have been obtained. These produce IL-4 and can transfer the disease into CD8+ cell-deprived syngeneic animals.

This unit will describe methods for inducing autoimmune disease in BN rats through HgCl2 injections (see Basic Protocol 1) as well for assessing parameters that characterize the disease by serum IgE concentration assays (see Support Protocol 1), anti-laminin antibody measurement (see Support Protocol 2), and renal immunofluorescence studies to detect autoantibodies (see Support Protocol 3). Also covered are disease induction using autoreactive CD4+ TH2 anti-self MHC class II molecules (see Basic Protocol 2) and preparation of T cell lines (see Support Protocol 4). IL-4 is produced very early after the first HgCl2 injection (beginning at day 3, peaking at day 14, and continuing up to day 30). Thus, IL-4 mRNA expression may be detected in spleen and lymph nodes from HgCl2-injected BN rats (see Support Protocol 5). The fact that HgCl2 induces in vitro mRNA IL-4 gene expression in normal BN T cells but not in LEW T cells is probably crucial to susceptibility to the development of autoimmunity in the sense that it may condition the development of autoreactive T cells into pathogenic TH2 cells; a test for this condition is therefore also included in Support Protocol 5.

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