RT Journal Article
SR Electronic
T1 Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200093
DO 10.1212/NXI.0000000000200093
VO 10
IS 3
A1 Melissa Sorosina
A1 Silvia Santoro
A1 Laura Ferrè
A1 Elisabetta Mascia
A1 Ferdinando Clarelli
A1 Antonino Giordano
A1 Miryam Cannizzaro
A1 Moiola Lucia
A1 Vittorio Martinelli
A1 Massimo Filippi
A1 Federica Esposito
YR 2023
UL http://nn.neurology.org/content/10/3/e200093.abstract
AB 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.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