Igs from patients with Graves' disease induce the expression of T cell chemoattractants in their fibroblasts.
Thyroid-associated ophthalmopathy and dermopathy are connective tissue manifestations of Graves' disease (GD). Tissue remodeling is a prominent feature of both and is apparently driven by recruited T cells. In this study, we report that IgG isolated from patients with GD (GD-IgG) up-regulates T lymphocyte chemoattractant activity in GD-derived fibroblasts from orbit, thyroid, and several regions of skin. This chemoattractant activity, absent in fibroblasts from donors without known thyroid disease, is partially susceptible to neutralization by anti-IL-16 and anti-RANTES Abs. IL-16 is a CD4(+)-specific chemoattractant and RANTES is a C-C-type chemokine. IL-16 and RANTES protein levels, as determined by specific ELISAs, are substantially increased by GD-IgG in GD fibroblasts. Addition of the macrolide, rapamycin, to fibroblast culture medium blocked the up-regulation by GD-IgG of IL-16, implicating the FRAP/mTOR/p70(s6k) pathway in the induction of IL-16 expression. These findings suggest a specific mechanism for activation of fibroblasts in GD resulting in the recruitment of T cells. They may provide insight into a missing link between the glandular and extrathyroidal manifestations of GD.
Pritchard
Jane
J
Department of Medicine, Division of Molecular Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90502, USA.
Horst
Noah
N
Cruikshank
William
W
Smith
Terry J
TJ
D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019410:Interleukin-16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*
D018946:Chemokine CCL5; D002630:Chemotactic Factors; D007106:Immune Sera; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D019410:Interleukin-16; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020123:Sirolimus