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.

Abstract

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