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Comprehensive analysis of TCR-beta repertoire in patients with neurological immune-mediated disorders

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Title: Comprehensive analysis of TCR-beta repertoire in patients with neurological immune-mediated disorders
Authors: Sousa, ADPA
Johnson, KR
Ohayon, J
Zhu, J
Muraro, PA
Jacobson, S
Item Type: Journal Article
Abstract: In this study we characterized the TCR repertoire profiles in patients with chronic progressive inflammatory neurological disorders including HAM/TSP, associated with human T-cell lymphotropic virus type I (HTLV-I) infection, and multiple sclerosis (MS), an inflammatory, demyelinating disease of the CNS of unknown etiology. We hypothesized that a T-cell receptor (TCR) clonal repertoire ‘signature’ could distinguish HAM/TSP patients from healthy controls, as well as from patients with a more heterogeneous CNS-reactive inflammatory disease such as MS. In this study, we applied an unbiased molecular technique – unique molecular identifier (UMI) library-based strategy to investigate with high accuracy the TCR clonal repertoire by high throughput sequencing (HTS) technology. cDNA-TCR β-chain libraries were sequenced from 2 million peripheral mononuclear cells (PBMCs) in 14 HAM/TSP patients, 34 MS patients and 20 healthy controls (HC). While HAM/TSP patients showed a higher clonal T-cell expansion compared to MS and HC, increase of the TCR clonal expansion was inversely correlated with the diversity of TCR repertoire in all subjects. In addition, longitudinal analysis of TCR repertoires from HAM/TSP patients demonstrated a correlation of the TCR clonal expansion with HTLV-I proviral load. Surprisingly, MS patients showed a higher diversity of TCR repertoires than other groups. Despite higher TCR clonal expansions in HAM/TSP patients, no disease-specific TCRs were shared among patients. Only non-shared or “private” TCR repertoires was observed. While no clones that shared the same CDR3 amino acid sequences were seen in either HC or MS patients, there was a cluster of related CDR3 amino acid sequences observed for 18 out of 34 MS patients when evaluated by phylogenetic tree analysis. This suggests that a TCR-repertoire signature may be identified in a subset of patients with MS.
Issue Date: 23-Jan-2019
Date of Acceptance: 30-Oct-2018
URI: http://hdl.handle.net/10044/1/66611
DOI: https://dx.doi.org/10.1038/s41598-018-36274-7
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 9
Issue: 1
Copyright Statement: © 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MYELOPATHY/TROPICAL SPASTIC PARAPARESIS
CD8(+) T-CELLS
CEREBROSPINAL-FLUID
MULTIPLE-SCLEROSIS
CLONAL EXPANSIONS
DISEASE
QUANTIFICATION
LYMPHOCYTES
BLOOD
LOAD
Publication Status: Published
Article Number: 344
Online Publication Date: 2019-01-23
Appears in Collections:Department of Medicine (up to 2019)