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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

Division of Molecular Medicine (R.S.D., C.J.H., T.J.S.), Department of Medicine, Harbor-University of California Los Angeles (UCLA) Medical Center, Torrance, California 90502; Jules Stein Eye Institute (R.S.D., C.J.H., T.J.S.), Los Angeles, California 90095; Greater Los Angeles Veterans Hospital (R.S.D.), Los Angeles, California 90095; David Geffen School of Medicine at UCLA (R.S.D., T.J.S.), Los Angeles, California 90095; Department of Endocrinology and Metabolism (T.H.B., L.H.), Odense University Hospital, 5000 Odense, Denmark; and The Danish Twin Registry (T.H.B., L.H.), Epidemiology, Institute of Public Health, University of Southern Denmark, 5230 Odense, Denmark

Address all correspondence and requests for reprints to: Terry J. Smith, M.D., Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, Hanley-Hardison Research Building, 1124 West Carson Street, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.

Context: Graves’ disease (GD) is an autoimmune process of the thyroid and orbital connective tissues. The fraction of T and B cells expressing IGF-I receptor (IGF-IR) is increased in GD. It is a potentially important autoantigen in GD. Susceptibility to GD arises from both genetic and acquired factors.

Objective: The aim of the study was to determine whether the increased frequency of IGF-IR-expressing T and B cells in GD results from genetic or nongenetic factors.

Design/Setting/Participants: Display of IGF-IR was assessed on blood lymphocytes from 18 pairs of monozygotic twins in the Danish Twin Registry, including seven discordant pairs, four pairs concordant for GD, and seven healthy pairs.

Main Outcome Measures: Subjects underwent physical examination and laboratory analysis. Surface display of IGF-IR on T and B cells was analyzed by flow cytometry.

Results: Twins with GD display increased IGF-IR-expressing CD3⁺ T cells and T cell subsets including total CD4⁺, CD4⁺ naive, CD4⁺ memory, and CD8⁺ cells (P < 0.0001, P = 0.0001, P = 0.0003, P = 0.01, and P = 0.02, respectively) compared to healthy twins. The frequency of IGF-IR-expressing B cells from affected twins was increased relative to healthy controls (P = 0.009). In pairs discordant for GD, affected twins exhibited increased frequency of IGF-IR⁺ CD3⁺, CD4⁺, and CD4⁺ naive T cells (P < 0.05, P = 0.03, and P = 0.03, respectively) compared to their healthy twin.

Conclusion: Our findings suggest that more frequent IGF-IR⁺ T cells in GD cannot be attributed to genetic determinants. Rather, this skew appears to be acquired. These results underscore the potential role of nongenetic, acquired factors in genetically susceptible individuals.