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ICOS-B7 Homologous Protein Interactions Are Necessary for Mercury-Induced Autoimmunity¹

Yan Zheng^*, Monika Jost, John P. Gaughan, Reiner Class, Anthony J. Coyle and Marc Monestier^2,*

Departments of ^* Microbiology and Immunology and Biostatistics, Temple University School of Medicine, Philadelphia, PA 19140; Department of Radiation Oncology, Drexel University College of Medicine, Philadelphia, PA 19102; and Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139

After exposure to subtoxic doses of heavy metals such as mercury, H-2^s mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we explore the role of one of the members of the CD28-B7 costimulation families, ICOS-B7 homologous protein (B7h), in the regulation of mercury-induced autoimmunity. The expression of ICOS on T cells was more enhanced in susceptible A.SW mice than in non-responsive C57BL/6 and DBA/2 mice after HgCl₂ treatment. Furthermore, in A.SW mice treated with HgCl₂, administration of a blocking anti-ICOS Ab effectively inhibited anti-nucleolar autoantibodies and total serum IgE production. Taken together, these results indicate that the ICOS-B7h costimulation pathway is required for this autoimmune syndrome and suggest that targeting this pathway might have therapeutic benefits for human autoimmune diseases.

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