1. TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood.
- Author
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Amoriello R, Chernigovskaya M, Greiff V, Carnasciali A, Massacesi L, Barilaro A, Repice AM, Biagioli T, Aldinucci A, Muraro PA, Laplaud DA, Lossius A, and Ballerini C
- Subjects
- Adult, Aged, Blood-Brain Barrier, Case-Control Studies, Female, High-Throughput Nucleotide Sequencing, Humans, Italy, Male, Middle Aged, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis genetics, Receptors, Antigen, T-Cell blood, Receptors, Antigen, T-Cell genetics, Sequence Analysis, DNA, Young Adult, Cerebrospinal Fluid immunology, Computational Biology methods, Multiple Sclerosis immunology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology
- Abstract
Background: T cells play a key role in the pathogenesis of multiple sclerosis (MS), a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Although several studies recently investigated the T-cell receptor (TCR) repertoire in cerebrospinal fluid (CSF) of MS patients by high-throughput sequencing (HTS), a deep analysis on repertoire similarities and differences among compartments is still missing., Methods: We performed comprehensive bioinformatics on high-dimensional TCR Vβ sequencing data from published and unpublished MS and healthy donors (HD) studies. We evaluated repertoire polarization, clone distribution, shared CDR3 amino acid sequences (CDR3s-a.a.) across repertoires, clone overlap with public databases, and TCR similarity architecture., Findings: CSF repertoires showed a significantly higher public clones percentage and sequence similarity compared to peripheral blood (PB). On the other hand, we failed to reject the null hypothesis that the repertoire polarization is the same between CSF and PB. One Primary-Progressive MS (PPMS) CSF repertoire differed from the others in terms of TCR similarity architecture. Cluster analysis splits MS from HD., Interpretation: In MS patients, the presence of a physiological barrier, the blood-brain barrier, does not impact clone prevalence and distribution, but impacts public clones, indicating CSF as a more private site. We reported a high Vβ sequence similarity in the CSF-TCR architecture in one PPMS. If confirmed it may be an interesting insight into MS progressive inflammatory mechanisms. The clustering of MS repertoires from HD suggests that disease shapes the TCR Vβ clonal profile., Funding: This study was partly financially supported by the Italian Multiple Sclerosis Foundation (FISM), that contributed to Ballerini-DB data collection (grant #2015 R02)., Competing Interests: Declaration of Competing Interest A.L. reports grants from Sanofi Genzyme, outside the submitted work. D.L. reports grants from EDMUS Foundation, from ARSEP Foundation and from ANR, and personal fees from Biogen, BMS, Alexion, Merck, Sanofi and Roche, outside the submitted work. P.A.M. reports personal fees from Jasper Therapeutics and from Magenta Therapeutics, outside the submitted work. V.G. declares advisory board positions in aiNET GmbH and Enpicom B.V., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
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