Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
Autoři:
Christian Lundtoft aff001; Pascal Pucholt aff001; Juliana Imgenberg-Kreuz aff001; Jonas Carlsson-Almlöf aff002; Maija-Leena Eloranta aff001; Ann-Christine Syvänen aff002; Gunnel Nordmark aff001; Johanna K. Sandling aff001; Ingrid Kockum aff003; Tomas Olsson aff003; Lars Rönnblom aff001; Niklas Hagberg aff001
Působiště autorů:
Rheumatology and Science for Life Laboratories, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
aff001; Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
aff002; Centre for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
aff003
Vyšlo v časopise:
Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling. PLoS Genet 16(10): e1009199. doi:10.1371/journal.pgen.1009199
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009199
Souhrn
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.
Klíčová slova:
B cells – Flow cytometry – Gene expression – Immune cells – Interferons – NK cells – Single nucleotide polymorphisms – T cells
Zdroje
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