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B Cells from Patients with Graves’ Disease Aberrantly Express the IGF-1 Receptor: Implications for Disease Pathogenesis¹

Raymond S. Douglas^*,,, Vibharavi Naik, Catherine J. Hwang, Nikoo F. Afifiyan^*, Andrew G. Gianoukakis^*,, Daniel Sand^*, Shweta Kamat^* and Terry J. Smith^2,*,,

^* Division of Molecular Medicine, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502; Jules Stein Eye Institute, Los Angeles, CA 90095; and David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

Graves’ disease (GD) is an autoimmune process involving the thyroid and connective tissues in the orbit and pretibial skin. Activating anti-thyrotropin receptor Abs are responsible for hyperthyroidism in GD. However, neither these autoAbs nor the receptor they are directed against have been convincingly implicated in the connective tissue manifestations. Insulin-like growth factor-1 receptor (IGF-1R)-bearing fibroblasts overpopulate connective tissues in GD and when ligated with IgGs from these patients, express the T cell chemoattractants, IL-16, and RANTES. Disproportionately large fractions of peripheral blood T cells also express IGF-1R in patients with GD and may account, at least in part, for expansion of IGF-1R⁺ memory T cells. We now report a similarly skewed B cell population exhibiting the IGF-1R⁺ phenotype from the blood, orbit, and bone marrow of patients with GD. This expression profile exhibits durability in culture and is maintained or increased with CpG activation. Moreover, IGF-1R⁺ B cells produce pathogenic Abs against the thyrotropin receptor. In lymphocytes from patients with GD, IGF-1 enhanced IgG production (p < 0.05) and increased B cell expansion (p < 0.02) in vitro while those from control donors failed to respond. These findings suggest a potentially important role for IGF-1R display by B lymphocytes in patients with GD in supporting their expansion and abnormal Ig production.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants EY008976, EY011708, DK063121, EY016339, and RR00425, an unrestricted grant from Research to Prevent Blindness, a Research to Prevent Blindness Career Development Award, and the Bell Charitable Foundation.

² Address correspondence and reprint requests to Dr. Terry J. Smith, Division of Molecular Medicine, Harbor-UCLA Medical Center, Building C-2, 1124 West Carson Street, Torrance, CA 90502. E-mail address: tjsmith{at}ucla.edu

³ Abbreviations used in this paper: GD, Graves’ disease; IGF-1R, insulin-like growth factor-1 receptor; MFI, mean fluorescence intensity; TAO, thyroid-associated ophthalmopathy; TSHR, thyrotropin receptor.

This article has been cited by other articles:

				R. S. Douglas, T. H. Brix, C. J. Hwang, L. Hegedus, and T. J. Smith Divergent Frequencies of IGF-I Receptor-Expressing Blood Lymphocytes in Monozygotic Twin Pairs Discordant for Graves' Disease: Evidence for a Phenotypic Signature Ascribable to Nongenetic Factors J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1797 - 1802. [Abstract] [Full Text] [PDF]