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Immunoglobulin G from Patients with Graves’ Disease Induces Interleukin-16 and RANTES Expression in Cultured Human Thyrocytes: A Putative Mechanism for T-Cell Infiltration of the Thyroid in Autoimmune Disease

Divisions of Molecular Medicine and Endocrinology and Metabolism (A.G.G., R.S.D., C.S.K., T.J.S.), Harbor-UCLA Medical Center, Torrance, California 90502; Jules Stein Eye Institute (R.S.D., T.J.S.) and the David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California 90095; and the Pulmonary Center (W.W.C.), Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Terry J. Smith, Division of Molecular Medicine, Building C-2, Harbor-UCLA Medical Center, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.

Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves’ disease (GD) are poorly understood. The IGF-I receptor (IGF-IR) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-I or GD-IgGs, provokes the expression of IL-16 and RANTES (regulated upon activation, normal T cell expressed and secreted)-dependent T lymphocyte chemoattraction and hyaluronan synthesis. IL-16 is a CD4⁺-specific ligand, and RANTES is a C-C chemokine. Here we report that IGF-I and GD-IgG could induce IL-16 and RANTES in cultured human thyrocytes in a time-dependent manner. Importantly, human TSH failed to induce either chemoattractant. This induction could be attenuated by dexamethasone. Rapamycin, a specific inhibitor of the FRAP/mammalian target of rapamycin/p70^s6k pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a monoclonal antibody directed at IGF-IR also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. Our findings suggest that thyrocytes can be activated by GD-IgG and IGF-I to express powerful T-cell chemoattractants. These actions of GD-IgG appear to be mediated through pathways independent of the TSH receptor. Thus, in GD, thyrocytes may participate directly in lymphocyte recruitment through their expression of IL-16 and RANTES.

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