Eye muscle antibodies in Graves’ ophthalmopathy: Pathogenic or secondary epiphenomenon?

Abstract

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.

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

“…Patients treated with RTX were studied at 4,8,12,16,20,30,50, and 70-75 weeks, while those treated with IVGC were studied at 8, 20, 30, and 50 weeks after the first drug infusion (Fig. 1).…”

“…It is known that both Th1 and Th2 cytokine patterns are involved and that the TSH receptor is expressed on orbital preadipogenic fibroblasts and may be a target for immunoglobulin G-stimulated hyperproduction of adipose tissue (5,6). There is no evidence of pathogenic autoantibodies, TRAb (7) and eye muscle-directed antibodies (8) occurring only at a second pathogenetic step or epiphenomena. Elevated serum TRAb levels have been correlated to the active phase of TAO (9), but this may not imply a role in the disease pathogenesis, since their titers have been shown not to vary in relation to the stabilization (10)(11)(12) and the duration of the clinical features (M Salvi et al unpublished observations).…”

Pathogenesis of Graves' Ophthalmopathy: The Role of Autoantibodies

“…More recent characterization of muscle antigens has focused on two proteins termed "G2s" and "Fp" (32). G2s is strongly expressed in thyroid and extraocular muscle, but is also present in skeletal muscle, myocardium, and other organs.…”

Pure Eye Muscle Involvement in Endocrine Orbitopathy

“…On the basis of clinical information and neuro-imaging as well as serological data one can differentiate 2 subgroups of endocrine orbitopathy: ocular myopathy with pronounced swelling of the extra-ocular eye muscles, double vision and eye muscle paresis without significant inflammatory involvement of the orbital connective tissue on the one side, and orbitopathy with inflammatory changes of the periorbital fat body and proptosis with more or less involvement of the eye muscles [14]. The latter type is much more frequent compared to the first.…”

“…Moreover, these authors found patients with involvement of both compartments which may represent a so-called mixed orbitopathy. Some antibodies are associated with the eye muscle type of endocrine orbitopathy (anti-G2s and anti-Fp antibodies), and other antibodies are more likely to be associated with the connective tissue type [14]. …”