B cells from patients with Graves’ disease aberrantly express the IGF-1 receptor: Implications for disease pathogenesis

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. But neither these auto-Abs 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 over-populate 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 antibodies against the thyroid stimulating hormone receptor. In lymphocytes from patients with GD, IGF-1 enhanced IgG (p<0.05) production 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 immunoglobulin production.