[Relationship between OX40/4-1 BB (CD134/CD137) costimulatory molecules expression on T lymphocytes and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves' disease].

Abstract

CD134 (OX-40) and CD137 (4-1 BB) are glycoprotein molecules provides the potent costimulatory signal for T cells activation and proliferation (to Th1 and Th2 subpopulation) via interactions with their ligands CD134L/CD137L molecule, present on the surface of Ag-presenting cells (APC). The present study was performed to elucidate the relationship between CD134/CD137 molecules and stimulating (TSAb) or blocking (TBAb) antibodies to the TSH-receptor in Graves' disease. The aim of the study was to estimate the expression of OX-40 and 4-1 BB molecules on peripheral blood cells in patients with Graves' disease (GD) (n=28, mean age 16.3 years), in patients with nontoxic nodular goiter (NTNG) (n=28, mean age 15.8 years) in comparison with sex- and age-matched healthy control subjects (n=28, mean age 15.9 years). The expression of the costimulatory molecules on mononuclear cells were analyzed by the three-color flow cytometry using a Coulter EPICS XL cytometer. Detection of stimulating and blocking antibodies to the TSH-receptor using JPO9 CHO cells in unfractionated serum were measured by a highly sensitive commercial radioimmuno assay. In untreated Graves' patients we observed a significant increase of CD134+ (p<0.001, p<0.01, p<0.04) and CD137+ (p<0.04, p<0.035, p<0.01) T lymphocytes in comparison to the healthy control subjects, non-toxic nodular goiter patients and euthyroid Graves' patients. After 6-12 months of methimazole therapy, the percentages of these cells in peripheral blood of hyperthyroid patients returned to the normal values. The analysis of CD3+ T lymphocytes co-expressing CD134 and CD137 antigens on peripheral blood revealed an increased percentages of OX-40/CD137 positive cells in patients with Graves' disease (p<0.025) compared to the controls, while CD134L (OX-40L) molecules were detected in some hyperthyroid patients on activated monocytes. In addition, 75% of children with untreated hyperthyroidism had positive TSAbs, whereas TBAbs were measured in 3 out of 7 TSAb negative patients with Graves' disease. In untreated Graves' patients a correlation between percentage of CD134+ T cells and serum level of stimulating (p<0.025) and blocking (p<0.04) antibodies to the TSH-receptor was found, while no such correlation was detected in relation to CD137+ T cells. We conclude that the changes of the expression of costimulatory molecules on peripheral blood mononuclear cells could be an important marker of activity of autoimmune process in children and adolescents with Graves' disease and that their levels are modulated by thyrostatic treatment.