TCR repertoire diversity in Multiple Sclerosis: High-dimensional bioinformatics analysis of sequences from brain, cerebrospinal fluid and peripheral blood

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 Methods: We performed comprehensive bioinformatics on high-dimensional TCR Vb sequencing data from published and unpublished MS and healthy donors (HD) studies.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 Vb 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 Vb 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).

Serial Analysis of the T-Cell Receptor β-Chain Repertoire in People Living With HIV Reveals Incomplete Recovery After Long-Term Antiretroviral Therapy

“…We calculated the degree of each node in the network and plotted the degree distribution for all the repertoires in each of the three groups (pre-ART, post-ART, control). Previous studies have shown that naïve TRB repertoires exhibit an exponential degree distribution curve dominated by many-to-many interactions in the T-cell network ( 34 , 35 ). This has been attributed to the increased diversity typically observed in naïve repertoires, which results in a higher likelihood of finding sequences with an edit distance of one.…”

Relevance of Pathogenetic Mechanisms to Clinical Effectiveness of B-Cell-Depleting Monoclonal Antibodies in Multiple Sclerosis

“…MS was traditionally considered a T-cell-mediated autoimmune disorder, based on preclinical data from animal models of the disease (experimental autoimmune encephalomyelitis—EAE) and evidence for T-cell infiltration in inflammatory lesions and normal-appearing white matter of autoptic and biopsy CNS specimens from affected individuals, with an association between CD8+ T cells number and axonal damage [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Furthermore, the identification of expanded T-cell clones in the brain parenchyma, cerebrospinal fluid (CSF), and peripheral blood of MS patients detected using T-cell receptor (TCR) analyses reinforced the hypothesis that inflammatory infiltrates were constituted by pathogenetic expanded T-cell clones reactive to myelin antigens [ 13 , 14 , 15 , 16 ]. Circulating CD4+ T cells from MS patients were indeed demonstrated to recognise myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG), even if the same phenomenon was also observed in healthy individuals; evidence regarding potential differences between these groups in frequency and avidity of cell interactions is conflicting [ 17 , 18 ].…”

Haematopoietic Stem Cell Transplantation Results in Extensive Remodelling of the Clonal T Cell Repertoire in Multiple Sclerosis

“…These modelling algorithms have the potential to scrutinize TCR repertoires of patients with autoimmune disease for autoreactive clones. Recently, highdimensional TCR sequencing analysis has assessed clusters of clones in the CSF and peripheral blood of MS patients, confirming the effect of MS on the TCR clonal profile (41). MS is presumed to arise as a result of auto-reactive T-cells (42), which are likely to escape negative selection in the thymus and then become activated following interaction with undefined environmental factors.…”