Abstract
Background and Objectives The major histocompatibility complex (MHC) locus has a predominant role in the genetic predisposition to multiple sclerosis (MS), with 32 associations found to be involved. We aimed to investigate the impact of MHC MS-risk alleles on T-cell repertoire in patients with MS.
Methods We studied 161 untreated patients with relapsing-remitting MS for whom Class I and II human leukocyte antigen (HLA) alleles were inferred from whole-genome genotyping data, and T-cell receptor (TCR) CDR3 sequences were obtained through next-generation sequencing. T-cell repertoire features including diversity, public clones, and architecture were evaluated.
Results We identified 5 MS-risk loci associated with TCR diversity: HLA-DRB1*15:01 (7.65 × 10−3), rs9271366 (1.96 × 10−3), rs766848979 A (1.89 × 10−2), rs9277626 (2.95 × 10−2), and rs11751659 (1.92 × 10−2), with evidence of expanded clonotypes in carriers of risk alleles. Moreover, HLA-DRB1*15:01 (4.99 × 10−3), rs9271366 (6.54 × 10−3), rs1049079 C (4.37 × 10−2), AA DQΒ1 position −5 L (1.05 × 10−3), and AA DQΒ1 position 221 Q (9.39 × 10−4) showed an association with the CDR3 aminoacidic sequence architecture, suggesting an impact on the antigen recognition breadth as well. Evaluating the sharing of clones across MS-risk allele carrier individuals revealed the presence of highly shared clonotypes predicted to target viral antigens, including Epstein-Barr virus.
Discussion Our study supports the association between MHC-risk alleles and macrofeatures of the T-cell repertoire in the context of MS. Further studies are needed to understand the underlying molecular mechanisms.
Glossary
- CDR=
- complementarity-determining region;
- CMV=
- cytomegalovirus;
- EBV=
- Epstein-Barr virus;
- EDSS=
- Expanded Disability Status Scale;
- gDNA=
- genomic DNA;
- HLA=
- human leukocyte antigen;
- HLAGB=
- HLA genetic burden;
- LevD=
- Levenshtein distance;
- MAF=
- minor allele frequency;
- MHC=
- major histocompatibility complex;
- MS=
- multiple sclerosis;
- PCA=
- principal component analysis;
- SNP=
- single nucleotide polymorphism;
- RRMS=
- relapsing-remitting MS;
- TCR=
- T-cell receptor
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
Submitted and externally peer reviewed. The handling editor was Deputy Editor Scott S. Zamvil, MD, PhD, FAAN.
- Received August 2, 2022.
- Accepted in final form December 14, 2022.
- Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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