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Igs from Patients with Graves’ Disease Induce the Expression of T Cell Chemoattractants in Their Fibroblasts¹

Jane Pritchard^*,, Noah Horst, William Cruikshank and Terry J. Smith^2,*,

^* Department of Medicine, Division of Molecular Medicine, Harbor-University of California, Los Angeles Medical Center, Torrance, CA 90502; School of Medicine, University of California, Los Angeles, CA 90095; and Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA 02118

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.

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