Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling.
Adult
Aged
Aged, 80 and over
Alleles
B-Lymphocytes
/ immunology
Female
Flow Cytometry
Genetic Predisposition to Disease
HLA-A2 Antigen
/ genetics
Humans
Interferon Type I
/ genetics
Interferon-gamma
/ genetics
Killer Cells, Natural
/ immunology
Male
Middle Aged
Multiple Sclerosis
/ epidemiology
Polymorphism, Single Nucleotide
/ genetics
Quantitative Trait Loci
/ genetics
Receptor, Interferon alpha-beta
/ genetics
Receptors, Interferon
/ genetics
T-Lymphocytes
/ immunology
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
25
06
2020
accepted:
15
10
2020
revised:
05
11
2020
pubmed:
27
10
2020
medline:
1
1
2021
entrez:
26
10
2020
Statut:
epublish
Résumé
Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD-CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.
Identifiants
pubmed: 33104735
doi: 10.1371/journal.pgen.1009199
pii: PGENETICS-D-20-01001
pmc: PMC7644105
doi:
Substances chimiques
HLA-A*02 antigen
0
HLA-A2 Antigen
0
Interferon Type I
0
Receptors, Interferon
0
interferon receptor, type II
0
Receptor, Interferon alpha-beta
156986-95-7
Interferon-gamma
82115-62-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009199Déclaration de conflit d'intérêts
I have read the journal's policy and the authors of this manuscript have the following competing interests: Tomas Olsson has received unrestricted MS research grants, and/or advisory board/lecture honoraria from AstraZeneca, Biogen, Novartis, Merck, Sanofi and Roche, none of which has been related to this work.
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