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It is well established that in susceptible mouse strains, chronic treatment with subtoxic doses of mercuric chloride (HgCl2) induces a systemic autoimmune disease, which is characterized by increased serum levels of IgG1 and IgE antibodies, by the production of anti-nucleolar antibodies and by the development of immune complex-mediated glomerulonephritis. Susceptibility to mercury is partly under the control of major histocompatibility complex genes. To study the susceptibility to mercury further, we investigated the in vivo effects of mercury in young autoimmune disease prone (NZB x NZW)F1 (H-2d/z) mice prior to establishment of spontaneous autoimmune disease. Mercury-susceptible SJL (H-2s) mice and mercury low-responder BALB/c (H-2d) mice were used as positive and negative controls, respectively. In (NZB x NZW)F1 mice, treatment with mercury stimulated an intense antibody formation characterized by increased numbers of splenic IgG1 and IgG3 antibody-producing cells as well as by elevated serum IgE levels. Injection with mercury also induced an increased production of IgG1, IgG2b and IgE antibodies in SJL, but not in BALB/c mice. The mercury-induced IgG1 response in (NZB x NZW)F1 and SJL mice was found to be polyclonal and autoantibodies against double-stranded (ds)DNA, IgG, collagen, cardiolipin, phosphatidylethanolamine as well as antibodies against the hapten trinitrophenol were produced. In addition, SJL, but not (NZB x NZW)F1 or BALB/c mice, produced IgG1 anti-nucleolar antibodies after treatment with mercury. Further studies demonstrated that (NZB x NZW)F1 and SJL mice developed high titers of renal mesangial immune complex deposits containing IgG1 antibodies 3 weeks after injection with mercury. Thus, a mouse strain genetically prone to develop spontaneous autoimmune diseases is highly susceptible to mercury-induced immunopathological alterations.

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SummaryIntrahepatic immune cells (IHIC) are known to play central roles in immunological responses mediated by the liver, and isolation and phenotypic characterization of these cells is therefore of considerable importance. In the present investigation, we developed a simple procedure for the mechanical disruption of mouse liver that allows efficient isolation and phenotypic characterization of IHIC. These cells are compared with the corresponding cells purified from the liver after enzymatic digestion with different concentrations of collagenase and DNase. The mechanical disruption yielded viable IHIC in considerably greater numbers than those obtained following enzymatic digestion. The IHIC isolated employing the mechanical disruption were heterogeneous in composition, consisting of both innate and adaptive immune cells, of which B, T, natural killer (NK), NK T cells, granulocytes and macrophages were the major populations (constituting 37·5%, 16·5%, 12·1%, 7·9%, 7·9% and 7·5% of the total number of cells recovered respectively). The IHIC obtained following enzymatic digestion contained markedly lower numbers of NK T cells (1·8%). The B, T and NK T cells among IHIC isolatedemploying mechanical disruption were found to be immunocompetent, i.e. they proliferated in vitro in response to their specific stimuli (lipopolysaccharide, concanavalin A and a-galactosylceramide respectively) and produced immunoglobulin M and interferon-g. Thus, the simple procedure for the mechanical disruption of mouse liver described here results in more efficient isolation of functionally competent IHIC for various types of investigation.

Mercury-induced autoimmunity is characterized by a T cell-dependent B cell activation (mainly of IgG1 and IgE isotypes), production of anti-nucleolar autoantibodies (ANolA) and the formation of renal IgG deposits. The autoimmunity is to a large extent controlled by genetic factors. We studied 15 different inbred mouse strains of seven H-2 (mouse MHC) genotypes to determine the importance of H-2 and non-H-2 background genes in mercury-induced autoimmunity. The tested strains exhibited a diverse autoimmune response to mercury. In each H-2 genotype, there was at least one strain which responded to mercury by the production of high levels of IgG1 and IgE Ig as well as by the development of high titers of renal IgG1 deposits. Only mouse strains with H-2(s) and H-2(q) genotypes, irrespective of their background genes, produced ANolA after mercury treatment. Only SJL (H-2(s)) and A.SW (H-2(s)) mice were highly susceptible to all characteristics of mercury-induced autoimmunity. NZB (H-2(d)) mice were also highly susceptible, but they did not develop ANolA. Only the DBA/2 (H-2(d)) strain was found to be resistant to all tested mercury-induced autoimmune manifestations, suggesting that non-responsiveness to mercury in DBA/2 mice was largely influenced by non H-2 genes. These findings imply that H-2 genes mainly determine the susceptibility to mercury-induced ANolA production, whereas non-H-2 genes control the susceptibility to and the severity of the B cell activation and renal IgG deposition.