A striational muscle antigen and myasthenia gravis-associated thymomas share an acetylcholine-receptor epitope.

Alexander Marx,Socrates Tzartos,Kerstin I Geuder,Mary Osborn,Hans-Konrad Müller-Hermelink,Thomas Kirchner,Wilfried Nix,Berthold Schalke

doi:10.1155/1992/86853

Abstract

The coincidence of autoantibodies against the acetylcholine receptor (AChR) and muscle striational antigens (SA) is a characteristic finding in thymoma-associated myasthenia gravis (MG), but their origins are still unresolved. Some common muscle antigens that were shown to be targets of anti-SA autoantibodies in thymoma-associated MG have also been detected in normal or neoplastic thymic epithelial cells, suggesting that the release of (eventually altered) antigens from the thymic tumors could elicit SA autoimmunity. In contrast to this model, we report here that titin, which is a recently reported target of SA autoimmunity, is not expressed in thymomas. In addition, we show that skeletal muscle type-II fibers exhibit a striational immunoreactivity with monoclonal antibody mAb155, which was previously identified to label a very immunogenic cytoplasmic epitope of the AChR and neoplastic epithelial cells of MGassociated thymomas. We conclude from these findings that titin autoimmunity in thymoma-associated MG is either due to a molecular mimicry mechanism involving tumor antigens (other than titin) or is a secondary phenomenon following release of titin from muscle. Based on the common immunoreactivity of the AChR, a striational antigen and thymoma, we suggest as the pathogenetic mechanism of thymoma-associated MGa "circulus vitiosus" in which SA autoimmunity could help maintain the AChR autoimmunity that is primarily elicited by the thymomas.

Highlights

Myasthenia gravis (MG) is characterized by an abnormal fatiguability of muscle produced in most patients by autoantibodies against the nicotinic acetylcholine receptor (AChR)
We report that titin is not expressed in thymomas, suggesting that this kind of SA autoimmunity is either not due to intratumorous autosensitization or occurs by molecular mimicry mechanisms, that is, by titinrelated antigenic determinants in thymoma proteins that may cross-react with titin-"specific" T
Because the respective epitopemcorresponding to AChR alpha371-378mis the only one so far detected in MG-associated thymomas, we suggest that AChR autoimmunity and part of SA autoimmunity in MG-associated thymomas could be interrelated

Summary

INTRODUCTION

Myasthenia gravis (MG) is characterized by an abnormal fatiguability of muscle produced in most patients by autoantibodies against the nicotinic acetylcholine receptor (AChR). As an important diagnostic feature, only the latter group of MG patients almost invariably has high titers of heterogeneous autoantibodies against striational muscle antigens (SA) in addition to anti-AChR autoantibodies (Peers et al, 1977; Aarli et al, 1990; Connor et al, 1990; Ohta et al, 1990). In thymoma patients without MG anti-SA autoantibodies occur in only 24% (Williams and Lennon, 1987). We report that titin is not expressed in thymomas, suggesting that this kind of SA autoimmunity is either not due to intratumorous autosensitization or occurs by molecular mimicry mechanisms, that is, by titinrelated antigenic determinants in thymoma proteins that may cross-react with titin-"specific" T cells, which could induce an antititin autoantibody response when released to the periphery. Because the respective epitopemcorresponding to AChR alpha371-378mis the only one so far detected in MG-associated thymomas, we suggest that AChR autoimmunity and part of SA autoimmunity in MG-associated thymomas could be interrelated

RESULTS

34 Mixed thymoma

MATERIALS AND METHODS