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

Abstract

Graves’ disease (GD) is an antibody-driven autoimmune 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, themechanismsunderlyingextrathyroidal tissue inflammation and remodeling remain uncertain, as does their relationshipwith theprocessesoccurring in the thyroid. Manifestations of GD include thyrotoxicosis and several extrathyroidal signs including Graves’ orbitopathy (GO), dermopathy, and acropachy (3). GO and dermopathy are connective 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-derived 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 orbital/dermal autoantigens that display an identical structure to have epitopes that cross-react with a thyroid autoantigen (1–3). Orbital fibroblasts comprise a heterogeneous population 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-selective involvement of the orbit in GD (4). Thus, orbital fibroblasts exhibit a unique phenotype, including exaggerated responses to proinflammatory cytokines. Cytokines play a key role in the development of the extrathyroidal manifestations of GD. These molecules are produced in the orbit of GO patients by infiltrating inflammatory cells as well as orbital fibroblasts. Cytokines can modulate the immune reaction in GO by increasing major histocompatibility complex class II, adhesion molecules, CD40 (a member of the TNFreceptor superfamily), prostaglandin, and heat shock protein expression in the orbit, thereby having a role in localizing and augmenting the inflammatory response (5). Locally released cytokines, particularly IL-1, TNF, and interferon , stimulate fibroblast proliferation and also activate fibroblasts to secrete the hydrophilic glycosaminoglycans (GAG) that cause edema with consequent proptosis. CD40 engagement leads to substantial increases in GAG synthesis in orbital fibroblasts. Also, CD40 ligand up-regulates the synthesis of IL-1 , and blocking this cytokine with exogenous IL-1 receptor antagonist or with IL-1 neutralizing antibodies partially attenuates the induction of prostaglandin endoperoxide H synthase-2. Thus, the CD40/CD40 ligand bridge represents a potentially important activational pathway for orbital fibroblasts that may underlie their cross-talk within the gateway of B-T-cell communication. Finally, smoking may be linked to GO through the generation of partial hypoxia, which increases GAG synthesis by fibroblasts, and by direct effects of cigarette smoke constituents on fibroblast activation (3). The disordered accumulation of the GAG in orbital and dermal connective tissues leads to the distinctive histological features associated with GD-related GO and dermopathy (6). This often occurs in the context of dramatic inflammation and tissue remodeling, which is a prominent feature of the extrathyroidal manifestations of GD and is apparently driven by activated T cells. GAG take part in extracellular matrix organization, the regulation of cell proliferation and differentiation, and the regulation of diffusion of macromolecules through tissues, growth factor attachment, cell-to-cell interaction, and regulation of IL-1 production in local inflammatory response. Hyaluronic acid (HA) is the largest GAG molecule containing several