新規クラスタリング法による多発性硬化症に特徴的なT細胞受容体の同定

Résumé

Objective: To characterize T-cell receptors (TCRs) and identify target epitopes in multiple sclerosis (MS).Methods: Peripheral blood mononuclear cells were obtained from 39 MS patients and 19 healthy controls (HCs).TCR repertoires for a/b/d/c chains, TCR diversity, and V/J usage were determined by next-generation sequencing.TCR b chain repertoires were compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH).Cytomegalovirus (CMV)-IgG was measured in an additional 113 MS patients and 93 HCs.Regulatory T cells (Tregs) were measured by flow cytometry.Results: TCR diversity for all four chains decreased with age.TCRa and TCRb diversity was higher in MS patients (P = 0.0015 and 0.024, respectively), even after age correction.TRAJ56 and TRBV4-3 were more prevalent in MS patients than in HCs (p corr = 0.027 and 0.040, respectively).GLIPH consolidated 208,674 TCR clones from MS patients into 1,294 clusters, among which two candidate clusters were identified.The TRBV4-3 cluster was shared by HLA-DRB1*04:05-positive patients (87.5%) and predicted to recognize CMV peptides (CMV-TCR).MS Severity Score (MSSS) was lower in patients with CMV-TCR than in those without (P = 0.037).CMV-IgG-positivity was associated with lower MSSS in HLA-DRB1*04:05 carriers (P = 0.0053).HLA-DRB1*04:05-positive individuals demonstrated higher CMV-IgG titers than HLA-DRB1*04:05-negative individuals (P = 0.017).CMV-IgG-positive patients had more Tregs than CMV-IgG-negative patients (P = 0.054).Interpretation: High TCRa/TCRb diversity, regardless of age, is characteristic of MS.Association of a CMV-recognizing TCR with mild disability indicates CMV's protective role in HLA-DRB1*04:05-positive MS.

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