| Murine mercury-induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. In susceptible H-2s mice, subtoxic doses of mercuric chloride (HgCl2) induce an autoimmune syndrome characterized by production of anti-nucleolar antibodies (ANoA) and increased serum IgG1 and IgE levels.; In this study, we first explore the role of two inhibitory immunoreceptors, CTLA-4 and FcgammaRIIB, in the regulation of chemically-induced autoimmunity. Administration of a blocking anti-CTLA-4 antibody not only exacerbates the diseases in susceptible A.SW mice, but also overcomes the genetic restriction of diseases, leading to ANoA production in resistant DBA/2 mice. In FcgammaRIIB-/- mice, HgCl2 did not trigger ANoA production, but resulted in an increase in IgE levels. We also examine one of the members of the CD28-B7 costimulation families, inducible costimulator (ICOS)-B7 homologous protein (B7h). HgCl2-induced expression of ICOS on T cells was more significantly enhanced in A.SW mice. A blocking anti-ICOS antibody effectively inhibited ANoA and IgE production in HgCl2-treated A.SW mice.; We then show that HgCl2 administration in A.SW mice results in the elevated production of BAFF (B cell-activating factor of the TNF family). A TACI-Ig fusion protein, which neutralizes interactions between BAFF and its several receptors, inhibited HgCl2-induced ANoA or serum IgE production. These results are discussed in the context of the inhibitory effect of TACI-Ig on B cell maturation at the transitional stage.; Finally, we show that tolerance to HgCl2 can be induced in susceptible mice. It also can be established in naive susceptible mice by adoptive transfer of regulatory T cells from tolerized mice. Pre-activation of dendritic cells or depletion of regulatory T cells leads to the inability of establishing tolerance. Further, depletion of regulatory T cells and/or activation of dendritic cells not only aggravate the autoimmune manifestations in susceptible and resistant mice, but also result in a loss of tolerance in already tolerized mice.; All of these suggest several checkpoints for the immunotherapy of autoimmune diseases. |
