Muscle autoantigens in thyroid associated ophthalmopathy: the limits of molecular genetics

Unlike autoimmune thyroid disease (AITD) in which a number of autoantigens have been identified and characterized, the situation in thyroid associated ophthalmopathy (TAO) is far from clear. A number of candidate antigens have been identified by probing Western blots of orbital tissue (OT) with sera from TAO patients, the most frequently cited being proteins of molecular weight 23, 28, 55, 64, 78 and 120 kilodaltons. In an attempt to identify autoantigens in TAO we have produced a lambda gt11 human eye muscle expression library. This has been screened with sera from four patients with severe TAO whose antibodies bind to one or more of the aforementioned candidate antigens or to a thyroglobulin/acetylcholinesterase (Tg/Ache) shared epitope. Four clones were isolated and characterized; clone R14 encodes the carboxyl terminal 193 amino acids of an IgE binding protein, clones R10 and R13 encode unknown proteins having significant similarity with heat shock protein 27 and the U1 small nuclear ribonucleoprotein respectively. Clone R1 encodes an unknown peptide of 347 amino acids having no similarity with proteins in available data banks. R1 clone affinity purified autoantibodies bind to a protein of Mr 78 kD in a Western blot of porcine eye muscle tissue. Autoantibodies to the R1 recombinant lysogen were clearly demonstrated in 5 of 20 sera from Graves disease patients, its role merits further investigation. The possible relevance of these clones to the pathogenesis of TAO is discussed as well as the limitations of this type of approach in the identification of unknown autoantigens.