Pathogenesis of Graves' orbitopathy: a 2010 update

Abstract

The most important of the extra-thyroidal manifestations of Graves' disease, Graves' orbitopathy (GO), remains a vexing clinical problem. Treatment of severe active disease has been limited to steroids or radiotherapy. In the relatively rare case where vision is threatened, emergent decompression surgery can be performed. The proptosis, motility, or cosmetic concerns associated with stable GO are commonly remedied with surgical intervention. Substantial obstacles have prevented the development of specific medical therapies for GO, in large part resulting from poor understanding of disease pathogenesis and the absence of preclinical animal models. Fundamental aspects of GO's etiology have been uncovered from studies based in cell culture, extensive analysis of blood constituents, and detailed examination of orbital contents collected at the time of surgical intervention. Many of the published reports resulting from these studies are descriptive and all have failed to yield unifying concepts that integrate the anatomically divergent manifestations of Graves' disease. This brief review covers recent findings of several research groups. While major breakthroughs continue to occur in closely related autoimmune diseases, progress in identifying the pathogenic mechanisms relevant to GO has been limited. As emerging insights into human autoimmunity becomes applied to the study of Graves' disease, we anticipate that improved therapeutic strategies will find their way to our patients with GO.

Fig. 1 -

CD34⁺ LSP-1⁺ TSHR⁺ fibrocytes can be identified in the orbital tissue of patients with thyroid-associated ophthalmopathy (TAO) but are absent in tissues from healthy donors. A) CD34 expression (arrows, green FITC) in TAO-derived tissue (inset, negative control staining). B) Absent CD34 expression in healthy tissue (inset, positive staining control). C) LSP-1 expression in TAO-derived tissue [red, arrows, nuclei counterstained with DAPI (blue)] (inset negative control). D) Absence of LSP-1 expression in healthy tissue (inset negative control). E) CD31 expression in disease-derived tissue is limited to vascular endothelium (red, arrows). F) H and E stained consecutive thin-sections of the same orbital tissue (40 x). G) Fibrocytes present in orbital tissue from patients with TAO co-express CD34 and TSH receptor (TSHR). Thin sectioned tissue from a donor with TAO was stained according to procedures described in “Methods” with anti-CD34 (green) and anti-TSHR (red) antibodies. Nuclei were counterstained with DAPI (blue). Thin sections were then subjected to confocal microscopy. Inset contains a negative staining control. [Reprinted with permission from (32), copyright 2010, The Endocrine Society].

Fig. 2 -

Fibrocytes cultivated from peripheral blood mononuclear cells express high levels of TSH receptor (TSHR) regardless of whether they derive from (A) patients with Graves’ disease (GD) or (B) from healthy donors. (C) These levels are comparable to those found on primary human thyroid epithelial cells. (D) In contrast, undifferentiated orbital fibroblasts fail to express TSHR. (E) Fibrocytes differentiated into adipocytes accumulate intracellular lipid droplets staining with Oil Red O. (F) TSHR levels on fibrocytes remain elevated following differentiation. Fibrocytes, orbital fibroblasts, and thyrocytes were cultivated. In panel A, fibrocytes were pre-incubated with bovine TSH (bTSH) (5 mU/ml) prior to staining with anti-TSHR antibodies. [Reprinted with permission from (32), Copyright 2010, The Endocrine Society].

Fig. 3 -

TSH receptor (TSHR) displayed on fibrocytes generated from peripheral blood mononuclear cells can function to initiate cytokine production. Cultured cells, in this case, from a patient with Graves’ disease, were treated with bovine TSH (bTSH) (5 mU/ml) or inter-leukin (IL)-1β (10 ng/ml) for 48 h. The medium was subjected to enzyme-linked immunososrbent assays specific for (A) IL-6 or (B) tumor necrosis factor (TNF)-α. Data are expressed as the mean±SEM of 3 replicate culture wells from a representative experiment (*p<0.001). [Reprinted with permission from (32), Copyright 2010, The Endocrine Society].