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of GH. GO can also occur in conjunction with autoimmune thyroiditis, whatever the thyroid status. It is a common observation, however, that there is a gross correlation between the risk of GO and the duration of active GH.

      Three situations/factors appear to precipitate the occurrence of GO:

1.Treatment of GH with ¹³¹I. Treatment of hyperthyroid Graves’ disease (GD) with ¹³¹I can potentially worsen GO (in the case of active GO), especially in smokers and in the presence of markedly elevated T₃ levels [15] and in patients with shorter disease duration [16]. It is likely that GO deterioration results from the well-known exacerbation of thyroid inflammation/autoimmunity which occurs 3–5 months after ¹³¹I irradiation, as evidenced by a rise in blood levels of antithyroid antibodies, including antibodies (TRAbs) against thyroid-stimulating hormone receptor (TSH-R) [17]. Interestingly, glucocorticoid treatment which is able to prevent GO worsening is less efficient in preventing the rise in circulating antibody levels.

2.Occurrence of iatrogenic hypothyroidism. Whatever the treatment modality, but especially after ¹³¹I therapy, iatrogenic hypothyroidism has been recognized as a risk factor for GO [18].

      3.Smoking. See “How Do Environmental Factors such as Smoking Increase the Risk and Severity of Graves’ Orbitopathy?” below.

No condition that would protect against or prevent GO has been identified. However, it is noticeable that in children and adolescents both the prevalence and the severity of GO are low. In a series of 83 patients (≤16 years old), lower lid retraction was present in 38.6%, upper lid retraction in 4.8%, and mild proptosis in 12%; overall, GO was scored as class 2 or less in 64% of the cases. In this series, the largest reported so far, no factor that could create a predisposition to GO was identified [19].

Is Graves’ Orbitopathy Triggered by an Autoimmune Phenomenon? If So, What Is the Nature of the Autoantigen?

      GO is an autoimmune disease which is related to autoimmune thyroid diseases:

•GO is associated in nearly 100% of the cases with autoimmune thyroid diseases. GO may occur even in those cases of typical full-blown GH occurring within the frame of immune reconstitution following highly active antiretroviral therapy for HIV infection or after iatrogenic lymphocyte removal by anti-CD52 monoclonal antibody in multiple sclerosis [20].

      •Orbital tissues are infiltrated with inflammatory and immune cells.

•Although immunization of mice against the TSH-R may induce TRAbs and hyperthyroidism [21], until recently a robust experimental model of immunological GO had not been developed. This has changed with the publication by Banga’s group who established a new approach of genetic immunization of the human TSH-R A-subunit leading to sustained TRAb levels and GO-like disease comprising inflammation, adipogenesis, and fibrosis [22]. The model has been successfully reproduced by other workers, although there are some differences between the 2 centres, the immunized mice recapitulated eye disease of patients with either more myopathy or enlargement of adipose tissue [23]. Moreover, mouse fibroblasts derived from diseased orbital tissue expressed TSH and IGF-1 receptors, underwent adipogenesis and produced excess HA on TSH-R and/or IGF-1R stimulation proving orbital fibroblasts as target cell type of TSH-R-directed immunity [24]. The induction of GO-like disease using TSH-R immunization is strong evidence for its role in GO, but the IGF-1R has also been proposed as a thyroid/orbit-shared antigen.

•The TSH-R is the target of stimulating TRAbs which causes GH. Higher levels of expression of the transcripts of the TSH-R have been observed in orbital tissue specimens from GO as compared to controls. Functional TSH-R protein has also been detected in orbital tissues, although the signalling cascades may differ, e.g., PI3 kinase/pAkt rather than thyroidal TSH-R activation which mainly stimulates the production of cAMP [25]. In vitro, increased expression of the TSH-R parallels the adipogenic differentiation of orbit preadipocyte fibroblasts, and IL-6 enhances both [5, 26]. However, the level of expression of TSH-R in the orbit is very low even in patients with active disease, despite a markedly elevated expression of inflammatory cytokines [27]. In addition, the TSH-R is detectable, both at mRNA and protein levels, in several tissues unrelated to GD and GO. Transduction of orbit preadipocytes with an activating mutant TSH-R, while stimulating adipocyte differentiation, has been shown to block PPAR-γ-induced adipogenesis [28].

•IGF-1R: Kohn et al. [29] reported in 1986 that TRAbs could immunoprecipitate tyrosine kinase receptors, especially the IGF-1R. In 1993, Weightman et al. [30] demonstrated that GD patient IgGs were able to displace IGF-1 from its receptor on orbital fibroblasts. More recently, Pritchard et al. [31] have provided considerable data indicating the potential importance of this receptor in GO. Immunoglobulins from GD patients were able to stimulate IGF-1R-mediated production of the chemoattractants IL-16 and RANTES from GO, but not normal orbital fibroblasts. Despite its ubiquitous expression, the IGF-1R is upregulated in fibroblasts and thyrocytes in GH/GO [32] and IgGs from GO patients stimulate GAG production in these cell types, again in an IGF-1R-dependent manner [33]. The same group has demonstrated a possible association between TSH and IGF-1 receptors in orbital fibroblasts, to produce an autoantigen unique to GO and with distinct signalling capabilities [34] and is currently conducting a clinical trial of GO using antibodies to block IGF-1R activation (Trial No. NCT01868997). This concept has been modified recently by Krieger et al. [35], who reported “cross-talk” between the signalling cascades for TSH-R and IGF-1R. A combined therapy targeting both, the TSH-R and the IGF-1R, might be an effective treatment strategy.

Why Is the Orbit Special and a Target for Thyroid Autoimmunity?

The involvement of orbital tissues results from a combination of factors, including the presence within the unyielding orbit of: (1) antigenic structures recognized by autoreactive T cells involved in thyroid autoimmune diseases; (2) specific local conditions such as the high level of muscle innervation, the presence of fibroblasts/preadipocytes with unique functional characteristics (e.g., exaggerated responses to proinflammatory cytokines) [36] and the lack of hyaluronidase activity (see “What Are the Pathological Changes in Orbital Tissue in Graves’ Orbitopathy?”). Furthermore, the orbital contents are derived from the neural crest, and orbital fat has many of the characteristics

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