In susceptible H‐2s mice, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by production of anti‐nucleolar antibodies (ANoA) and increased serum levels of IgG1 and IgE antibodies. The increase in serum IgG1 and IgE, which are under IL‐4 control, suggests a role for the Th2 subset in the induction of this syndrome. We have previously shown that administration of IL‐12, a potent Th1‐promoting cytokine, resulted in a dramatic reduction of the HgCl2‐induced anti‐nucleolar antibody titres and inhibited serum IgG1 increase. These results suggest that Th1 T cells can down‐regulate ANoA, and support a role for the Th2 subset in ANoA production, possibly via IL‐4. To examine the role of IL‐4 in this syndrome, C57Bl/6 mice (H‐2b) with a targeted deletion of the IL‐4 gene were mated with A.SW mice (H‐2s) to yield H‐2s mice lacking IL‐4. We then analysed ANoA and serum immunoglobulin levels in these mice after HgCl2 treatment. While mercury‐treated IL‐4−/− H‐2s mice had virtually no detectable serum IgG1 or IgE, and very low levels of IgG1 ANoA, these mice had levels of IgG2a and IgG2b class ANoA comparable to mercury‐treated IL‐4+ H‐2s mice, indicating that IL‐4 is not required for the ANoA response in mercury‐induced autoimmunity.

We examined the role of CD40/CD40L interactions on the development of experimental autoimmune uveoretinitis (EAU), a cell-mediated, Th1-driven autoimmune disease that serves as a model for autoimmune uveitis in humans. EAU-susceptible B10.RIII mice immunized with the retinal autoantigen interphotoreceptor retinoid binding protein in CFA and treated with anti-CD40L Ab (MR1) had reduced incidence and severity of disease. Real-time PCR analysis revealed that the innate and adaptive responses of protected mice were reduced, without an obvious shift toward a Th2 cytokine profile. In contrast to some other reports, no evidence was found for regulatory cells in adoptive transfer experiments. To determine whether CD40L blockade resulted in long-term tolerance, mice protected by treatment with MR1 Ab were rechallenged for uveitis after circulating MR1 Ab levels dropped below the detection limit of ELISA. MR1-treated mice developed severe EAU and strong cellular responses to interphotoreceptor retinoid binding protein, comparable to those of control mice. These responses were higher than in mice that had not received the primary immunization concurrently with anti-CD40L treatment. We conclude that 1) CD40/CD40L interaction is required for EAU and its disruption prevents disease development; 2) CD40L blockade inhibits the innate response to immunization and reduces priming, but does not result in immune deviation; and 3) protection is dependent on persistence of anti-CD40L Abs, and long-term tolerance is not induced. Furthermore, immunological memory develops under cover of CD40L blockade causing enhanced responses upon rechallenge. Taken together, our data suggest that ongoing CD40/CD40L blockade might be required to maintain a therapeutic effect against uveitis.

B7‐1 (CD80) and B7‐2 (CD86) molecules on antigen presenting cells play important roles in providing co‐stimulatory signals required for activation and expansion of autoreactive T cells. Moreover, some reports have suggested that these molecules may have distinct functions in the differentiation of Th1 and Th2 cells. Mercury‐induced autoimmunity in H‐2s mice is characterized by lymphoproliferation of T and B cells, serum increases in IgG1 and IgE and production of antinucleolar antibodies (ANoA). The mechanisms responsible for the various manifestations of this syndrome have yet to be elucidated. To examine the contributions of B7 co‐stimulatory molecules to this model, susceptible mice were treated with antibodies to B7‐1, B7‐2, or both during the development of mercury‐induced autoimmunity. The combination of anti‐B7‐1 and anti‐B7‐2 antibodies prevented Hg‐induced disease in H‐2s mice. Additionally, single anti‐B7‐1 antibody treatment was sufficient to prevent Hg‐induced ANoA production, but not IgG1 and IgE hypergammaglobulinaemia. Further, single antibody treatment with anti‐B7‐2 resulted in a partial reduction of ANoA titres but had no significant effect on total serum IgG1 and IgE levels. Taken together, these results indicate that B7‐1 and B7‐2 molecules are critical for the development of Hg‐induced autoimmunity and suggest that the different manifestations of the syndrome are regulated by independent mechanisms.

Human exposure to certain compounds or therapeutic drugs can result in the development of an autoimmune syndrome. Mercury (Hg) induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. After receiving subtoxic doses of Hg or other heavy metals, susceptible mouse strains rapidly develop highly specific antibodies to nucleolar antigens. In addition, these animals display a general activation of the immune system, especially pronounced for the Th2 subset and a transient glomerulonephritis with immunoglobulin deposits. Like many human autoimmune diseases, this syndrome is associated with the expression of susceptible major histocompatibility complex (MHC) class II genes. In this article, we review the essential features of this model, and we discuss the putative mechanisms by which Hg creates such a severe immune dysfunction.

Experimental models of chemically induced autoimmunity have contributed to our understanding of the development of autoimmune diseases in humans. Heavy metals such as mercury induce a dramatic activation of the immune system and autoantibody production in genetically susceptible rats and mice. This autoimmune syndrome is dependent on T cells, which are important for B-cell activation and cytokine secretion. Several studies have focused on the roles of T-helper (Th)1 and Th2 cells and their respective cytokines in the pathogenesis of mercury-induced disease. This article reviews recent studies that have examined the patterns of cytokine gene expression and where investigators have manipulated the Th1 and Th2 responses that occur during mercury-induced autoimmunity. Finally, we will discuss some biochemical/molecular mechanisms by which heavy metals may induce cytokine gene expression.