Abstract
Graves' disease (GD) is associated with T cell infiltration, but the mechanism for lymphocyte trafficking has remained uncertain. We reported previously that fibroblasts from patients with GD express IL-16, a CD4-specific chemoattractant, and RANTES, a C-C chemokine, in response to GD-specific IgG (GD-IgG). We unexpectedly found that these responses result from a functional interaction between GD-IgG and the insulin-like growth factor (IGF)-I receptor (IGF-IR). IGF-I and the IGF-IR-specific IGF-I analog, des(1-3), mimic the effects of GD-IgG. Neither GD-IgG nor IGF-I activates chemoattractant expression in control fibroblasts from donors without GD. Interrupting IGF-IR function with specific receptor-blocking Abs or by transiently transfecting fibroblasts with a dominant negative mutant IGF-IR completely attenuates signaling provoked by GD-IgG. Moreover, GD-IgG displaces specific (125)I-labeled IGF-I binding to fibroblasts and attenuates IGF-IR detection by flow cytometry. These findings identify a novel disease mechanism involving a functional GD-IgG/IGF-IR bridge, which potentially explains T cell infiltration in GD. Interrupting this pathway may constitute a specific therapeutic strategy.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / metabolism
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Adjuvants, Immunologic / physiology
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Autoantigens / biosynthesis
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Autoantigens / genetics
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Autoantigens / metabolism
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Autoantigens / physiology
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Cell Movement / immunology
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Cells, Cultured
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Chemokine CCL5 / biosynthesis*
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Chemokine CCL5 / physiology
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Chemotaxis, Leukocyte / genetics
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Chemotaxis, Leukocyte / immunology
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Fibroblasts / immunology*
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Graves Disease / immunology*
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Graves Disease / pathology
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Humans
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Immunoglobulin G / metabolism
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Immunoglobulin G / pharmacology*
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Interleukin-16 / biosynthesis*
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Interleukin-16 / physiology
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Iodine Radioisotopes / metabolism
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Protein Binding / immunology
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Receptor, IGF Type 1 / biosynthesis
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism
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Receptor, IGF Type 1 / physiology*
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Signal Transduction / immunology*
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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Transfection
Substances
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Adjuvants, Immunologic
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Autoantigens
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Chemokine CCL5
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Immunoglobulin G
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Interleukin-16
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Iodine Radioisotopes
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Receptor, IGF Type 1