Potential Roles of CD34+ Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy

Context: Orbital tissues in thyroid-associated ophthalmopathy exhibit particular reactivity and undergo characteristic remodeling. Mechanisms underlying these changes have remained largely unexplained. Studies have characterized orbital connective tissues and derivative fibroblasts to gain insights into local manifestations of a systemic autoimmune syndrome. Evidence Acquisition: A systematic search of PubMed was undertaken for studies related to thyroid-associated ophthalmopathy (TAO), orbital fibroblasts, and fibrocytes involved in pathogenesis. Evidence Synthesis: Orbital tissues display marked cellular heterogeneity. Fibroblast subsets, putatively derived from multiple precursors, inhabit the orbit in TAO. Among them are cells displaying the CD34(+)CXC chemokine receptor 4(+) collagen I+ phenotype, identifying them as fibrocytes, derived from the monocyte lineage. Their unique presence in the TAO orbit helps explain the tissue reactivity and characteristic remodeling that occurs in the disease. Their unanticipated expression of several proteins traditionally thought to be thyroid gland specific, including the TSH receptor and thyroglobulin, may underlie orbital involvement in Graves disease. Although no currently available information unambiguously establishes that CD34(+) orbital fibroblasts originate from circulating fibrocytes, inferences from animal models of lung disease suggest that they derive from bone marrow. Further studies are necessary to determine whether fibrocyte abundance and activity in the orbit determine the clinical behavior of TAO. Conclusion: Evidence supports a role for fibrocytes in the pathogenesis of TAO. Recognition of their presence in the orbit now allows development of therapies specifically targeting these cells that ultimately could allow the restoration of immune tolerance within the orbit and perhaps systemically.