Reactivity against the Flavine Adenosine Nucleotide (FAD) Cofactor of Bacterial Enzymes May Explain Positive Flavoprotein Antibody Tests in Patients without Ophthalamopathy

Background: We have re-visited a possible role of autoantibodies targeting a "64 kDa muscle membrane protein" in the pathogenesis of thyroid-associated ophthalmopathy (TAO). This antigen was identified as the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase (SDH). We have addressed the possibility that "molecular mimicry" reactions against SDH can be explained by cross reactivity against the FAD cofactor used by this and other mitochondrial enzymes including bacterial sarcosine dehydrogenase (SarcDH).

Methods: Serum antibodies against SDH, SarcDH, dimethylglycine dehydrogenase (DMGDH) and FAD tested, in patients with TAO, Graves’ Hyperthyroidism (GH) including 11 patients who developed ophthalmopathy following treatment of their hyperthyroidism, and control subjects, by enzyme-linked immunosorbent assay (ELISA) in a prospective study.

Results: Sera from 85% of patients with active TAO and 37% with eye muscle involvement contained antibodies which reacted with SDH only, compared to 37% with Hashimoto's thyroiditis, 29% with type 1 diabetes, 28% with GH and in 32% of normal subjects (Table 2). Conversely, positive responses against SDH could be explained by reaction against the FAD cofactor in over 56% of subjects without ophthalmopathy, but in only 32% of patients with active eye muscle inflammation. Anti-FAD antibodies were detected in all 11 patients (78%) in which 6 patients with GH who developed ocular myopathy after beginning anti-thyroid drug therapy and in 5 out of the 6 who developed congestive ophthalmopathy.

Discussion: Because of the wide distribution of mitochondrial enzymes in nature there are likely to be many opportunities for developing cross reactive antibodies (“molecular mimicry”) in tests for anti-Fp antibodies, especially in patients with organ specific or multisystem autoimmunity.

Conclusion: Because antibodies targeting mitochondrial enzymes, Fp and FAD are unlikely to be pathogenic, as the antigens are intracellular, future studies should focus on their clinical utility as a marker of ophthalmopathy in patients with Graves’ hyperthyroidism.