Immunopathogenesis of thyroid eye disease: emerging paradigms

Abstract

Graves disease represents a systemic autoimmune process targeting the thyroid, orbit, and pretibial skin. The thyroid dysfunction is treatable, but no consistently effective medical therapy has yet been described for the orbital manifestations of Graves disease, also known as thyroid-associated ophthalmopathy or thyroid eye disease. Several autoantigens are potentially relevant to the pathogenesis of thyroid eye disease. Activating antibodies generated against the thyrotropin receptor can be detected in a majority of patients, and these drive hyperthyroidism. However, stimulating antibodies against the insulin-like growth factor-1 receptor (IGF-1R) may also play a role in the extra-thyroid manifestations of Graves disease. IGF-1R is overexpressed by orbital fibroblasts derived from patients with thyroid eye disease, whereas IGF-1R(+) T and IGF-1R(+) B cells are considerably more frequent in Graves disease. Actions of several cytokines and the molecular interplay peculiar to the orbit appear to provoke the inflammation, fat expansion, and deposition of excessive extracellular matrix molecules in thyroid eye disease. Based upon these new insights, several therapeutic strategies can now be proposed that, for the first time, might specifically interrupt its pathogenesis.

Figure 1

The three predominant forms of soft tissue involvement in TED. Predominantly fat expansion (top), predominantly muscle enlargement (middle), or a combination of both (bottom).

Figure 2

Cartoon of our current model for the interaction between orbital fibroblasts and members of the professional immune system and the small molecules they produce. Chemoattractant molecules such as IL-16 and regulated on activation, normal T cell expressed (RANTES) are generated in response to Graves disease-IgG (GD-IgG) acting on the fibroblast. This in turn leads to the recruitment of T cells and other mononuclear cell members of the immune system. When activated, these cells produce a number of proinflammatory cytokines such as IL-1a, IL-1b, CD154 (CD40 ligand), and IL-6. Cytokines in turn activate proinflammatory genes such as those encoding prostaglandin endoperoxide H synthase-2 (PGHS-2), IL-6, IL-8, hyaluronan synthase (HAS), and UDP glucose dehydrogenase (UGDH). The major factor thus far identified as explaining the exaggerated responses to cytokines concerns the low levels of IL-1 receptor antagonist (IL-1RA) expressed by orbital fibroblasts. In addition, IL-4 and IL-13 induce 15-lipoxygenase exclusively in orbital fibroblasts from patients with GD, perhaps accounting for the different patterns of inflammation found in TAO.