TCR SPECIFICITY IN MuSK-POSITIVE MYASTHENIA GRAVIS

Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease characterized by muscle weakness and excessive fatigability. Anti- acetylcholine receptor or anti muscle-specific receptor tyrosine kinase (MuSK) pathogenic autoantibodies are found in about 80% and 10% of patients respectively. We have previously shown that more than 70% of MuSK+ MG patients have HLA - DQ5 allele. The aim of the present study was to analyse the T-cell receptor (TCR) repertoire after in vitro stimulation with recombinant human MuSK protein. We used the CDR3 BV-BJ spectratyping (immunoscope) to study the response to MuSK of T cells from ten DQ5+ MuSK positive MG patients and from four DQ5+ MuSK negative subjects. MuSK positive but not MuSK negative controls showed a restricted set of TCR VJ rearrangements in response to MuSK stimulation. One public (Vβ4 - Jβ 2.5) rearrangement has been found in seven out of ten patients, while three semiprivate (one Vβ4-Jβ1.5 and two Vβ4-Jβ1.2) rearrangements were variously shared by a smaller number of patients. Thus, the MuSK-specific T-cell repertoire is restricted in DQ5+MuSK+ patients and involves approximately 4 rearrangements, all of them in Vbeta 4 region, whose specific sequence is currently being determined. This observation supports the hypothesis that a limited number of peptides are involved in the pathogenesis of the disease. The identification of these immunodominant epitopes will provide new tools for diagnosis and targeted therapy.