The Expression Of Costimulatory Molecules And Their Biological Roles In Graves' Disease

Graves' disease (GD) is a common autoimmune thyroid disease. It is immunologically characterized by lymphocytic infiltration of the thyroid gland with increasing levels of circulating activated T lymphocytes and thyroid-specific autoantibodies against thyroid-specific-antigen such as the thyrotropin (TSH) receptor, thyroid peroxidase (TPO) and thyroglobulin. Lately, it has been well known that atuoantibody TRAb is an effector of the disease, but not an initiator. So, exploring the mechanisms responsible for initating abnormal immune response and breaking immune tolerance were attracted a more and more attention. The 'two-signal' concept of lymphocyte activation was proposed to explain discrimination of self from non-self and has provided a useful model of T-cell activation and tolerance. Costimulatory signal, a new model for the activation of T cells, plays a pivotal regulating role in specific immune response. Due to costimulatory molecules going awry, autoreactive T cells escape deletion and control by the immune system and lead to autoimmune disease. Therefore, at first it was of interest to study expression of costimulatory molecules in thyroid tissues of patients with GD. Then the study was done in an effort to further characterize the roles and mechanisms of costimulatory signal in the pathogenesis of GD and to evaluate abnormal autoreactive CD4TCD28" T cell subsets with respect to thyroid function, extrathyroidal manifestations and presence of TRAb.1. The expression of costimulatory molecules in thyroid tissues ofGraves' diseaseWe studied the expression of costimulatory molecules in thyroid tissues of patients with Graves' disease and its relationship to the pathogenesis of GD. The thyroid tissues of patients were collected in surgical operation, including 10 cases with GD and 10 casesThe expression of costimulatory molecules and their biological roles in Graves' disease Abstractwith nontoxic goiter (NTG). The total RNA of these samples was extracted by Trizol. The gene expression of costimulatory molecules was assayed by RT-PCR and 1 % agarose gel electrophoresis. Thyrocytes were cultured in the absence or presence of cytokines. The expression of costimulatory molecule on thyroid follicular cells was further measured by flow cytometry. Our results showed that the levels of costimulatory molecule gene expression in GD were relatively higher than in NTG, especially the levels of gene expressions of CD40 (P < 0.05), CD40L (P < 0.05), and ICOS (P < 0.01). The rates of CD40 positive cell in 5 cases with GD and 6 cases with NTG of primary thyroid follicular cells were 44.62% and 39.47%, respectively. Proinflammatory cytokines IFN- y, IL-6 and TNF- a cause significant increasing in expression of costimulatory molecules CD40 (P< 0.01) and GL50 (P < 0.05) on thyroid follicular cells. These results suggest that costimulatory signal, especially CD40-CD40L and ICOS-GL50 signals may exert important role in the initiation and progression of autoimmune response through T cell mediated B cell activation in GD.2. The role of costimlatory signal in the biological behavior of thyroidfollicular cellsCD40mAb (mAbSCll) was utilized to investigated the biological effects of CD40-CD40L signal on human thyrocytes. The results showed that CD40mAb stimulated the growth of thyroid follicular cells in a dose-dependent manner. CD40mAb significantly promoted TFC to synthesize free triiodothyronine (FT3, P=0.015) and free thyroxine (FT4, P=0.033) and to secrete thyroglobulin (/>=0.016), CD40mAb in combination with human thyrotropin (hTSH) stimulation obviously increased the thyrocyte proliferation and thyroglobulin release (all P < 0.01) and enhanced the synthesis of thyroid hormones in a certain extent. While CD40mAb combined with IFN- Y can partly restore IFN- Y -inhibited thyrocyte proliferation. The results above showed that CD40-CD40L signal may directly affect the growth and function of thyroid follicular cells.In vitro, human thyrocytes were cultu...