Figure 4.

Cartoon proposed model of Graves’ disease and thyroid-associated ophthalmopathy (TAO) pathogenesis. (A) Thyroid-stimulating immunoglobulins (TSI) drive the over-production of thyroid hormones by activating the thyrotropin receptor (TSHR), thus overriding the normal regulatory role of thyrotropin on the process. B and T cells and antigen-presenting cells which infiltrate the gland produce interleukins 1β, 6, 12, 13, interferon γ, tumor necrosis factor α, and CD40 ligand. These cytokines then activate thyroid epithelial cells, promote inflammation, and induce genes ordinarily unexpressed by these cells such as major histocompatibility complex II (MHC II). Anti-thyroid drugs are useful therapeutically by reducing excess thyroid hormone production as well as modulating the expression of pathogenic intrathyroidal cytokines. (B) The pathogenesis of TAO also involves the infiltration of professional immune cells. Orbital fibroblasts exhibit particularly robust responses to inflammatory mediators. Among these cells are CD34⁺ fibroblasts which we propose derive from fibrocytes, monocyte-derived progenitor cells that traffic from bone marrow. Fibrocytes circulate in Graves’ disease at higher frequency than that found in healthy individuals. When cultivated from the peripheral circulation, fibrocytes express several thyroid-specific proteins, including thyrotropin receptor (TSHR), thyroglobulin, thyroperoxidase and sodium-iodide symporter. They also express MHC constitutively and can present antigens. When exposed to the appropriate culture conditions, they undergo differentiation into myofibroblasts (through Smad pathway activation by TGF-β) and adipocytes (through the activation of PPAR-γ). Many of the genes expressed by fibrocytes are detected at considerably lower levels in CD34⁺ orbital fibroblasts. We have found recently that these lower levels of expression result from the actions of Slit2 which acts through its cognate receptor, Roundabout 1 (ROBO1). When activated, CD34⁺ fibrocytes and CD34⁺ fibroblasts generate several pro-inflammatory or anti-inflammatory cytokines, including interleukins 1β, 6, 8, 10, 12, 16, tumor necrosis factor α, and regulated on activation, normal T expressed and secreted (RANTES), CXCL-12 and CD40-CD154. Both CD34⁺ and CD34^- orbital fibroblasts cell-surface display insulin-like growth factor-I receptor (IGF-IR). Orbital fibroblasts express three mammalian hyaluronan synthase (HAS) isoenzymes and UDP glucose dehydrogenase and synthesize hyaluronan, the glycosaminoglycan associated with expanding orbital tissue in TAO. The vast majority of hyaluronan synthesis occurs in CD34^- orbital fibroblasts. From N. Engl. J. Med, Smith T.J. and Hegedus L., Graves’ Disease, 375; 1552-1565. Copyright ^© (2016) Massachusetts Medical Society. Reprinted with permission.