Immunopathogenesis of Graves' ophthalmopathy: the role of the TSH receptor

Abstract

Graves' ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves' hyperthyroidism and ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.

Figure 1

Role of the TSH receptor in the immunopathogenesis of Graves’ ophthalmopathy. Circulating TSH receptor autoantibodies of differing potency and affinities recognize the receptor on fibroblasts residing within the orbit. Ligation of the receptor results in activation of the phosphoinositide 3-kinase/Akt signaling cascade, as well as others including the adenylyl cyclase/cAMP pathway. This results in increased production of hyaluronic acid by these cells, with a subset exhibiting enhanced adipogenesis. IGF-1 and other growth factors within the orbit may act on the IGF-1 receptor to modulate these processes within the orbital fibroblasts. This results in accumulation of HA within the orbital tissues and expansion of the orbital fat volume, leading to the varied clinical expressions of the disease.