Cytokines, Graves' disease, and thyroid-associated ophthalmopathy

Abstract

Graves' disease, an autoimmune process associated with thyroid dysfunction, can also manifest as remodeling of orbital connective tissue. Affected tissues exhibit immune responses that appear to be orchestrated by resident cells and those recruited from the bone marrow through their expression and release of cytokines and surface display of cytokine receptors. Cytokines are small molecules produced by many types of cells, including those of the "professional" immune system. Aberrant cytokine expression appears to play an important role in the pathogenesis of many human diseases, including thyroid autoimmunity. The skewed pattern of cytokine expression in the thyroid, including the T helper cell bias, may condition the response to apoptotic signals and determine the characteristics of an autoimmune reaction. Furthermore, chemoattractant cytokines, including IL16, RANTES, and CXCL10, elaborated by resident cells in the thyroid and orbit may provoke mononuclear cell infiltration. Other cytokines may drive cell activation and tissue remodeling. Thus cytokines and the signaling pathways they activate represent attractive therapeutic targets. Interruption of these might alter the natural course of Graves' disease and its orbital manifestations.

FIG. 1.

Cytokine-mediated cellular interactions in autoimmune thyroid disease. Resident cells recruit those of the “professional” immune system by elaborating chemoattractant cytokines. These cells infiltrate target tissue and contribute to the cytokine milieu. The cytokine profile is dependent on the T cell subtype recruited. Cytokine actions are mediated predominantly through their ligating cognate receptors. Autoantibodies also target and activate cells through their occupancy of cell surface receptors, including TSHR and IGF-1R. PGE₂ and hyaluronan production is provoked by pro-inflammatory cytokines.