title: T cell repertoire in DQ5-positive MuSK-positive myasthenia gravis patients.
abstract: Myasthenia gravis (MG) is a prototypical antibody-mediated disease characterized by muscle weakness and fatigability. Serum antibodies to the acetylcholine receptor and muscle-specific tyrosine kinase receptor (MuSK) are found in about 85% and 8% of patients respectively. We have previously shown that more than 70% of MG patients with MuSK antibodies share the HLA DQ5 allele. The aim of the present study was to analyze the T cell receptor (TCR) repertoire specific for recombinant human MuSK protein. We used the CDR3 TRBV-TRBJ spectratyping (immunoscope) to analyze the T cell response to MuSK from 13 DQ5+ MuSK-MG patients and from 7 controls (six DQ5+ MuSK negative subjects and one DQ5- DQ3+ MuSK positive patient). DQ5+ MuSK-MG patients but not controls used a restricted set of TCR VJ rearrangements in response to MuSK stimulation. One semiprivate (TRBV29-TRBJ2.5) rearrangement was found in 5/13 patients, while 4 other semiprivate (one in TRBV28-TRBJ2.1 and in TRBV3-TRBJ1.2, and two in TRBV28-TRBJ1.2) rearrangements were differently shared by 4/13 patients each and were absent in controls. When we sequenced the TRBV29-TRBJ2.5 rearrangement, we obtained 26 different sequences of the expected 130 bp length from 117 samples of the 5 positive patients: two common motifs GXGQET/TEHQET were shared in 4 patients as semiprivate motifs. Thus, the MuSK-specific T-cell response appears to be restricted in DQ5+ MuSK-MG patients, with a semiprivate repertoire including a common motif of TRBV29. This oligoclonal restriction of T cells will allow the identification of immunodominant epitopes in the antigen, providing therefore new tools for diagnosis and targeted therapy.
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Mariapaola
authors.initials: M
authors.lastname: Marino
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Maiuri
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Scuderi
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: La Carpia
authors.affiliation: Department of Biochemistry, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Trakas
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Provenzano
authors.affiliation: Department of Biochemistry, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Zisimopoulou
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ria
authors.affiliation: Department of Biochemistry, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521 Athens, Greece.
authors.forename: Socrates J
authors.initials: SJ
authors.lastname: Tzartos
authors.affiliation: Department of Neuroscience, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy. Electronic address: a.evoli@rm.unicatt.it.
authors.forename: Amelia
authors.initials: A
authors.lastname: Evoli
authors.affiliation: General Pathology Institute, Università Cattolica del Sacro Cuore, Largo F. Vito, 1, 00168 Rome, Italy. Electronic address: ebartoc@rm.unicatt.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bartoccioni
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D005260:Female; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology; D011950:Receptors, Cholinergic / Q000276:immunology; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; D011950:Receptors, Cholinergic; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: CDR3; Immunoscope; MHC; Repertoire; Spectratyping; T cell receptor