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Graves' Orbitopathy


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(in vitro), of TNF-α and IL-6 in small preliminary open-label trials has provided evidence for a pathogenic role of these cytokines in the active phase of GO, which probably precedes adipogenesis, but further studies are needed to understand the potential therapeutic implications of such an approach [51].

      There is an epidemiological association between GO and TRAb:

      •TRAbs are detectable in nearly 100% of patients with GO;

      •TRAbs are present in the patients in whom GO is associated with autoimmune thyroiditis.

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      There is experimental evidence that TSH-R-induced immunity is strongly associated with GO. In a preclinical GO mouse model high TRAb levels were detectable in 100% of TSH-R A-subunit immunized mice, and almost all mice developed GO-like disease. However, individual mice developed a mixture of different levels of either stimulating and/or blocking antibodies which are known to differently stimulate or dampen downstream signalling. The resulting net effect could be an explanation why individual mice developed different degrees of inflammation, myopathy or adipogenesis although a direct correlation was not shown [22, 23].

      A possible rationale could be:

      •The patient’s lymphocytes had elevated cyclo-oxygenase 2 expression

      •Therefore, circulating TRAbs could have activated the T-cell subset to produce a PPAR-γ agonist which triggered adipogenesis. As a consequence, orbital TSHR expression would have increased and promoted infiltration of TSH-R-specific T and B cells. These could then elaborate a variety of cytokines (e.g., IL-1β) or autoantibodies (e.g., to IGF-1R) and stimulate HA production by fibroblasts