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Comprehensive Analysis of TCR-β Repertoire in Patients with Neurological Immune-mediated Disorders

Authors
  • Alves Sousa, Alessandra de Paula1
  • Johnson, Kory R.2
  • Ohayon, Joan3
  • Zhu, Jun4
  • Muraro, Paolo A.5
  • Jacobson, Steven1
  • 1 National Institute of Neurological Disorder and Stroke, NIH, Neuroimmunology Branch, Viral Immunology Section, Bethesda, Maryland, United States , Bethesda (United States)
  • 2 National Institute of Neurological Disorder and Stroke, NIH, Bioinformatics Section, Bethesda, Maryland, United States , Bethesda (United States)
  • 3 National Institute of Neurological Disorder and Stroke, NIH, Clinical Neuroimmunology Unit, Bethesda, Maryland, United States , Bethesda (United States)
  • 4 National Heart Lung and Blood Institute, NIH, Systems Biology Center, Bethesda, Maryland, United States , Bethesda (United States)
  • 5 Faculty of Medicine, Imperial College London, Division of Brain Sciences, London, United Kingdom , London (United Kingdom)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Jan 23, 2019
Volume
9
Issue
1
Identifiers
DOI: 10.1038/s41598-018-36274-7
Source
Springer Nature
License
Green

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.

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