PT  - JOURNAL ARTICLE
AU  - Melissa Sorosina
AU  - Silvia Santoro
AU  - Laura Ferrè
AU  - Elisabetta Mascia
AU  - Ferdinando Clarelli
AU  - Antonino Giordano
AU  - Miryam Cannizzaro
AU  - Moiola Lucia
AU  - Vittorio Martinelli
AU  - Massimo Filippi
AU  - Federica Esposito
TI  - Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis
AID  - 10.1212/NXI.0000000000200093
DP  - 2023 May 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e200093
VI  - 10
IP  - 3
4099  - http://nn.neurology.org/content/10/3/e200093.short
4100  - http://nn.neurology.org/content/10/3/e200093.full
SO  - Neurol Neuroimmunol Neuroinflamm2023 May 01; 10
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