In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 16, No. 10 ( 2020-10-26), p. e1009199-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009199
DOI:
10.1371/journal.pgen.1009199.g001
DOI:
10.1371/journal.pgen.1009199.g002
DOI:
10.1371/journal.pgen.1009199.g003
DOI:
10.1371/journal.pgen.1009199.g004
DOI:
10.1371/journal.pgen.1009199.g005
DOI:
10.1371/journal.pgen.1009199.g006
DOI:
10.1371/journal.pgen.1009199.t001
DOI:
10.1371/journal.pgen.1009199.s001
DOI:
10.1371/journal.pgen.1009199.s002
DOI:
10.1371/journal.pgen.1009199.s003
DOI:
10.1371/journal.pgen.1009199.s004
DOI:
10.1371/journal.pgen.1009199.s005
DOI:
10.1371/journal.pgen.1009199.s006
DOI:
10.1371/journal.pgen.1009199.s007
DOI:
10.1371/journal.pgen.1009199.s008
DOI:
10.1371/journal.pgen.1009199.s009
DOI:
10.1371/journal.pgen.1009199.s010
DOI:
10.1371/journal.pgen.1009199.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2186725-2
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