We attempt to provide an historical perspective on progress made in understanding the pathogenesis of thyroid-associated ophthalmopathy (TAO), focusing on the roles of orbital fibroblasts (OF) in the diseased orbit (termed GD-OF) and how these cells differ from those residing in the healthy orbit. GD-OF comprise both residential OF and those apparently derived from CD34+ fibrocytes.

CD34+ fibrocytes of the monocyte lineage putatively traffic to the TAO orbit from bone marrow. We believe that these fibroblastic cell populations dictate the activity and severity of TAO. Their impact on disease may be moderated by Slit2, a neuron axon guidance repellent synthesized by and released from residential CD34- OF. Approximately 50% of patients with GD develop clinically meaningful TAO. Relatively few require systemic medical and surgical therapies, while milder disease can be managed with conservative, local care. Determining the intrinsic properties of GD-OF and their expression of Slit2 may explain why some patients with GD develop severe, vision-threatening TAO while others virtually escape any of its manifestations. Such insights should allow for improved and better-tolerated therapies.

Identifying unique characteristics of fibrocytes and GD-OF subsets reveals their apparent roles in tissue activation, inflammation, and remodeling associated with TAO. Better understanding of these cells, their origins, behavior, and factors modulating their activities remains necessary for the development of more targeted, effective, and safe treatments.