PMID- 36792371
OWN - NLM
STAT- MEDLINE
DCOM- 20230223
LR  - 20230226
IS  - 2332-7812 (Electronic)
IS  - 2332-7812 (Linking)
VI  - 10
IP  - 3
DP  - 2023 May
TI  - Risk HLA Variants Affect the T-Cell Repertoire in Multiple Sclerosis.
LID - 10.1212/NXI.0000000000200093 [doi]
LID - e200093
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 x 10(-3)), rs9271366 (1.96 x 10(-3)), 
      rs766848979 A (1.89 x 10(-2)), rs9277626 (2.95 x 10(-2)), and rs11751659 (1.92 x 
      10(-2)), with evidence of expanded clonotypes in carriers of risk alleles. 
      Moreover, HLA-DRB1*15:01 (4.99 x 10(-3)), rs9271366 (6.54 x 10(-3)), rs1049079 C 
      (4.37 x 10(-2)), AA DQBeta1 position -5 L (1.05 x 10(-3)), and AA DQBeta1 position 221 
      Q (9.39 x 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.
CI  - Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on 
      behalf of the American Academy of Neurology.
FAU - Sorosina, Melissa
AU  - Sorosina M
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Santoro, Silvia
AU  - Santoro S
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Ferre, Laura
AU  - Ferre L
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Mascia, Elisabetta
AU  - Mascia E
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Clarelli, Ferdinando
AU  - Clarelli F
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Giordano, Antonino
AU  - Giordano A
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Cannizzaro, Miryam
AU  - Cannizzaro M
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Lucia, Moiola
AU  - Lucia M
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Martinelli, Vittorio
AU  - Martinelli V
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Filippi, Massimo
AU  - Filippi M
AUID- ORCID: 0000-0002-5485-0479
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy.
FAU - Esposito, Federica
AU  - Esposito F
AD  - From the Laboratory of Neurological Complex Disorders (M.S., S.S., L.F., E.M., 
      F.C., A.G., M.C., F.E.), Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE), IRCCS San Raffaele Scientific Institute; Neurology and 
      Neurorehabilitation Unit (L.F., A.G., M.C., M.L., V.M., M.F., F.E.), IRCCS San 
      Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University 
      (M.F.); Neurophysiology Unit (M.F.), IRCCS San Raffaele Scientific Institute; and 
      Neuroimaging Research Unit, Division of Neuroscience, Institute of Experimental 
      Neurology (INSPE) (P.F.), IRCCS San Raffaele Scientific Institute, Milan, Italy. 
      esposito.federica@hsr.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230215
PL  - United States
TA  - Neurol Neuroimmunol Neuroinflamm
JT  - Neurology(R) neuroimmunology & neuroinflammation
JID - 101636388
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (HLA Antigens)
SB  - IM
MH  - Humans
MH  - *Epstein-Barr Virus Infections
MH  - Herpesvirus 4, Human
MH  - HLA-DRB1 Chains/genetics
MH  - *Multiple Sclerosis/genetics
MH  - Receptors, Antigen, T-Cell/genetics
MH  - T-Lymphocytes
MH  - HLA Antigens/genetics
PMC - PMC9931183
EDAT- 2023/02/16 06:00
MHDA- 2023/02/18 06:00
PMCR- 2023/02/15
CRDT- 2023/02/15 21:42
PHST- 2022/08/02 00:00 [received]
PHST- 2022/12/14 00:00 [accepted]
PHST- 2023/02/15 21:42 [entrez]
PHST- 2023/02/16 06:00 [pubmed]
PHST- 2023/02/18 06:00 [medline]
PHST- 2023/02/15 00:00 [pmc-release]
AID - 10/3/e200093 [pii]
AID - NXI-2022-200100 [pii]
AID - 10.1212/NXI.0000000000200093 [doi]
PST - epublish
SO  - Neurol Neuroimmunol Neuroinflamm. 2023 Feb 15;10(3):e200093. doi: 
      10.1212/NXI.0000000000200093. Print 2023 May.