Eye muscle antibodies in Graves' ophthalmopathy: pathogenic or secondary epiphenomenon?

The extra ocular (eye) muscles are one of the principal tissues involved in the autoimmune-mediated inflammation of Graves' ophthalmopathy (GO). Several eye muscle proteins are targeted by autoantibodies or sensitized T lymphocytes, or both, and include: G2s, which is now identified as the terminal 141 amino acids of the winged-helix transcription factor FOXP1, the flavoprotein (Fp) subunit of the mitochondrial enzyme succinate dehydrogenase, the so-called "64kDa protein", a non-tissue specific membrane protein called 1D and the calcium binding protein calsequestrin. Of these, antibodies against G2s and Fp are the most sensitive markers of eye muscle damage in patients with thyroid autoimmunity even though neither antigen is specific to eye muscle and neither antibody is specific to GO. However, the recent finding that the calsequestrin gene is 4.7 times more expressed in eye muscles than other skeletal muscles suggests that we should reconsider the possible role of anti-calsequestrin autoantibodies in ophthalmopathy. GO may comprise two main subtypes with different pathogenetic mechanisms, namely ocular myopathy in which eye muscle inflammation predominates and congestive ophthalmopathy where inflammatory changes occur in the periorbital connective tissues in the absence of eye muscle dysfunction. Anti-G2s and anti-Fp antibodies are closely associated with the ocular myopathy subtype of GO while antibodies targeting type XIII collagen, the only member of the collagen family to have a transmembrane domain, are closely linked to congestive ophthalmopathy. Since both G2s and Fp are intracellular antigens it is unlikely that either antibody causes eye muscle fiber damage in GO, although a role in the later stages of the disease when the fiber has released its cellular contents has not been excluded. Eye muscle antibodies that are cytotoxic to eye muscle cells in antibody-dependent cell-mediated cytotoxicity (ADCC) are more likely to play a role in eye muscle fiber damage since they target a putative eye muscle cell membrane antigen, the identity of which is currently being investigated. While anti-G2s and anti-Fp antibodies are probably secondary to an underlying reaction, such as cytotoxic T lymphocyte targeting of an eye muscle membrane antigen that has yet to be identified, they are reliable markers of immunologically mediated eye muscle fiber damage in patients with Graves' hyperthyroidism. In conclusion, while a pathogenic role for eye muscle antibodies has not been excluded, they are most likely secondary to cytotoxic T cell reactions in GO and, as such, good markers of this autoimmune disease.