Autoimmunity risk- and protection-associated IL7RA genetic variants differentially affect soluble and membrane IL-7Rα expression.
Alleles
Amino Acid Substitution
Autoimmunity
/ genetics
Diabetes Mellitus, Type 1
/ genetics
Gene Expression
Genetic Variation
Glycosylation
HEK293 Cells
Haplotypes
Humans
Models, Molecular
Multiple Sclerosis
/ genetics
Mutation
Polymorphism, Single Nucleotide
Protein Conformation
Receptors, Interleukin-7
/ blood
Structure-Activity Relationship
T-Lymphocyte Subsets
/ immunology
IL-7
IL-7 receptor α-chain
T cells
rs1494558
rs6897932
Journal
Journal of autoimmunity
ISSN: 1095-9157
Titre abrégé: J Autoimmun
Pays: England
ID NLM: 8812164
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
10
10
2018
accepted:
11
10
2018
pubmed:
22
10
2018
medline:
27
5
2020
entrez:
22
10
2018
Statut:
ppublish
Résumé
Interleukin-7 receptor α-chain (IL7RA) haplotypes are associated with susceptibility to autoimmune diseases including type 1 diabetes (T1D). Previous studies found lower soluble IL-7Rα (sIL-7Rα) serum levels of the protection-associated IL7RA haplotype assumed to reduce IL-7 availability for self-reactive T cells. Also, a risk-associated IL7RA haplotype is accompanied by lower sIL-7Rα serum concentrations but no underlying mechanisms have been described and the causative polymorphism remains unknown. Here, we characterized functional implications of the nonsynonymous rs1494558 (Thr66Ile), which tags the protection-associated IL7RA haplotype, in HEK293T cells and serum samples of T1D patients with different haplotype carriers. Influence of risk- and protection-associated haplotypes on IL-7Rα was analyzed. The risk-associated Ile66 variant affected gel mobility and impaired secretion of the sIL-7Rα as well as expression of the membrane-associated (m)IL-7Rα in HEK293T cells. Serum sIL-7Rα analyses confirmed differential gel mobility of the Ile66 variant and found decreased sIL-7Rα serum levels of T1D patients carrying the Ile66-tagged haplotype. Differences in glycosylation were not causative for differential mobility but enhanced the effects on impaired secretion. Comparison of protection- and risk-associated haplotypes in a cell line-based in vitro model identified dominant effects of the protective haplotype tagged by rs6897932 (Ile244) on mIL-7Rα expression, whereas the risk haplotype mainly affected the sIL-7Rα. This study identified novel functional effects of the Ile66 IL7RA variant and characterized features of autoimmunity risk- and protection-associated haplotypes. The findings add to our understanding of how these haplotypes regulate sIL-7Rα and mIL-7Rα expression in T cells causing differential susceptibility to autoimmune diseases.
Identifiants
pubmed: 30342817
pii: S0896-8411(18)30588-2
doi: 10.1016/j.jaut.2018.10.003
pii:
doi:
Substances chimiques
Receptors, Interleukin-7
0
interleukin-7 receptor, alpha chain
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
40-47Informations de copyright
Copyright © 2018 Elsevier Ltd. All rights reserved.