Thyrocyte proliferation by cellular adhesion to infiltrating lymphocytes through the intercellular adhesion molecule-1/lymphocyte function-associatedantigen-1 pathway in Graves' disease

Graves' disease (GD) is an autoimmune thyroid disease characterized by infi ltration of lymphocytes into the thyroid, and intrathyroid lymphocytes are known to play an important role in the pathogenesis of GD. However, it rema ins to be understood how lymphocytes adhere to thyrocytes and regulate the thyrocyte function through cellular adhesion. We studied the mechanisms of T cell adhesion to thyrocytes using intrathyroid mononuclear cells (ITMC) a nd thyrocytes purified from the thyroids of patients with GD. The following novel features of cellular adhesion of ITMC to thyrocytes in the regulatio n of the thyrocyte function in GD were observed: 1) GD-ITMC expressed lymph ocyte function-associated antigen (LFA)-1, which became an active adhesive configuration much higher than peripheral blood mononuclear cells (PBMC) fr om normal volunteers and GD patients; 2) GD-thyrocytes expressed a high qua ntity of intercellular adhesion molecule (ICAM)-1; 3) GD-ITMC adhered to GD -thyrocytes, whereas normal PBMC required activation stimuli by phorbol myr iacetate, a pharmacological integrin-trigger, to adhere to GD- thyrocytes; 4) monoclonal antibody-blocking studies showed that the adhesion of the act ivated PBMC and ITMC to thyrocytes was mainly mediated by the LFA-1/ICAM-1 pathway; 5) the adhesion of GD-thyrocytes to the activated-PBMC or ITMC ind uced the proliferation of the thyrocytes, which was blocked by the addition of ICAM-1 and/or LFA-1 monoclonal antibodies; and 6) in GD thyrocytes of e arly cultures, ICAM-1 expression on GD-thyrocytes and its adhesion to LFA-1 on phorbol myriacetate-activated PBMC or ITMC were not modulated by the ad dition of interleukin-1 beta or interferon-gamma, and proliferation of thyr ocytes by the cellular adhesion via the ICAM-YLFA-1 pathway was independent of the proliferative response of these cytokines. Taken together, these re sults suggest that lymphocytes infiltrating GD thyroid induce proliferation of GD-thyrocyte by the cellular adhesion to thyrocytes via ICAM-1/LFA-1, w hich may lead to the development of a goiter.