The Thyrocyte-Fibrocyte Link: Closing the Loop in the Pathogenesis of Graves’ Disease?

摘要

GD) is an antibody-driven autoimmune G process affecting the thyroid gland and extrathyroidal target tissues in roughly 90% of the cases (1). Generation of activating autoantibodies against the TSH receptor (TSHR) leads to excessive thyroid hormone synthesis uniquely in GD (2). However, the mechanisms underlying extrathyroidal tis- sue inflammation and remodeling remain uncertain, as does their relationship with the processes occurring in the thyroid. Manifestations of GD include thyrotoxicosis and several ex- trathyroidal signs including Graves’ orbitopathy (GO), der- mopathy, and acropachy (3). GO and dermopathy are con- nective tissue manifestations of GD. Tissue remodeling is a prominent feature of both and is apparently controlled by adaptive T cells. Lymphocytes and other bone marrow-de- rived cells recruited into the orbit appear to be the major effectors of autoagressive tissue destruction in GO. The most likely sequence of events is that T cells infiltrate the orbital and dermal connective tissue and respond to a depot of or- bital/dermal autoantigens that display an identical structure to have epitopes that cross-react with a thyroid autoantigen (1-3). Orbital fibroblasts comprise a heterogeneous popu- lation of cells possessing divergent phenotypes and potential for differentiation. They represent a bimodal population of cells with regard to the surface display of the glycoprotein, Thy1. Moreover, they exhibit attributes differing from their nonorbital counterparts that may underlie anatomic-selec- tive involvement of the orbit in GD (4). Thus, orbital fibro- blasts exhibit a unique phenotype, including exaggerated re- sponses to proinflammatory cytokines.