The T-cell repertoire in myasthenia gravis involves multiple cholinergic receptor epitopes

Antibodies against the alpha-subunit of the acetylcholine receptor (AChR) are found in most patients with myasthenia gravis and are considered to contribute to the receptor damage which leads to the characteristic signs and symptoms of the disease. This B-cell response is T-cell driven. Elevated T-cell reactivities to AChR and its alpha-subunit have been described in myasthenia gravis, and AChR alpha-subunit peptide reactive T-cell lines and clones preferentially recognizing certain defined sequence segments have been reported, thereby disclosing the possibility of specific immunotherapy. We have defined the T-cell repertoire to AChR, its alpha-subunit and the synthetic peptide sequences 100-117, 113-130, 143-163, 161-179, 207-225, 221-240, and 235-255 of the alpha-subunit in an immunospot assay which is based on secretion of interferon-gamma (IFN-gamma) by individual memory T cells upon stimulation with specific antigen in short-term cultures. Most patients with myasthenia gravis displayed T-cell reactivities to 1 to 6 different peptides. The mean numbers of T cells recognizing individual peptides varied in the myasthenia gravis patients between 1 per 77,000 and 1 per 167,000 peripheral blood mononuclear cells. None of the seven peptides evaluated could be identified as an immunodominant T-cell epitope, and any of them was found to dominate in individual patients. The numbers of T cells reacting with AChR and recombinant human AChR alpha-subunit were slightly higher (mean numbers 1 per 26,000 and 1 per 50,000 mononuclear cells, respectively). Such cells, as well as AChR alpha-subunit peptide reactive T cells, were also found in patients with other neurological diseases and in healthy subjects, but at lower frequencies and numbers. In myasthenia gravis, the elevated numbers of memory T cells recognizing multiple AChR alpha-subunit peptides may be crucial for the development of the disease, and the IFN-gamma released by such T cells might be important for its perpetuation.