Abstract
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 HgCl(2) treatment. Furthermore, in A.SW mice treated with HgCl(2), 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Antinuclear / biosynthesis
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Antibodies, Blocking / administration & dosage
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD / metabolism*
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Antigens, CD / physiology
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism*
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Autoimmune Diseases / chemically induced*
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Autoimmune Diseases / genetics
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Autoimmune Diseases / prevention & control
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B7-1 Antigen / metabolism*
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B7-1 Antigen / physiology
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B7-2 Antigen
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Down-Regulation / immunology
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Female
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Genetic Predisposition to Disease
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Immune Tolerance / genetics
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Immunoglobulin E / biosynthesis
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Immunoglobulin G / biosynthesis
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Inducible T-Cell Co-Stimulator Protein
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / physiology
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Mercuric Chloride / toxicity*
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Mice
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Mice, Inbred A
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Mice, Inbred C57BL
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Mice, Inbred DBA
Substances
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Antibodies, Antinuclear
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Antibodies, Blocking
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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B7-1 Antigen
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B7-2 Antigen
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Cd86 protein, mouse
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ICOS protein, human
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Icos protein, mouse
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Immunoglobulin G
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Inducible T-Cell Co-Stimulator Protein
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Membrane Glycoproteins
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Immunoglobulin E
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Mercuric Chloride