title: B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis.
abstract: 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.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Douglas
authors.forename: Vibharavi
authors.initials: V
authors.lastname: Naik
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Hwang
authors.forename: Nikoo F
authors.initials: NF
authors.lastname: Afifiyan
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Gianoukakis
authors.forename: Daniel
authors.initials: D
authors.lastname: Sand
authors.forename: Shweta
authors.initials: S
authors.lastname: Kamat
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D003238:Connective Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006111:Graves Disease / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D009915:Orbit / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000276:immunology*; D011989:Receptors, Thyrotropin / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D001323:Autoantibodies; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D011989:Receptors, Thyrotropin; D017526:Receptor, IGF Type 1