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