Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves' disease is mediated through the insulin-like growth factor I receptor pathway.
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.
Pritchard
Jane
J
Division of Molecular Medicine, Department of Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA.
Han
Rui
R
Horst
Noah
N
Cruikshank
William W
WW
Smith
Terry J
TJ
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006111:Graves Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology*; D019410:Interleukin-16 / Q000096:biosynthesis* / Q000502:physiology; D007457:Iodine Radioisotopes / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014162:Transfection
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D018946:Chemokine CCL5; D007074:Immunoglobulin G; D019410:Interleukin-16; D007457:Iodine Radioisotopes; D017526:Receptor, IGF Type 1