Autoimmunity risk- and protection-associated IL7RA genetic variants differentially affect soluble and membrane IL-7Rα expression

被引：8

作者：

Lundtoft, Christian ^{[1
]}

Seyfarth, Julia ^{[1
,2
]}

Oberstrass, Sonja ^{[1
]}

Rosenbauer, Joachim ^{[2
,3
]}

Baechle, Christina ^{[2
,3
]}

Roden, Michael ^{[4
,5
]}

Holl, Reinhard W. ^{[2
,6
]}

Mayatepek, Ertan ^{[1
]}

Kummer, Sebastian ^{[1
]}

Meissner, Thomas ^{[1
,2
]}

Jacobsen, Marc ^{[1
]}

机构：

[1] Univ Childrens Hosp, Dept Gen Pediat Neonatol & Pediat Cardiol, Fac Med, D-40225 Dusseldorf, Germany

[2] German Ctr Diabet Res DZD, D-8576 Munich, Germany

[3] Heinrich Heine Univ Dusseldorf, Inst Biometr & Epidemiol, German Diabet Ctr, Leibniz Ctr, D-40225 Dusseldorf, Germany

[4] Heinrich Heine Univ Dusseldorf, Div Endocrinol & Diabetol, Fac Med, D-40225 Dusseldorf, Germany

[5] Heinrich Heine Univ Dusseldorf, Inst Clin Diabetol, German Diabet Ctr, Leibniz Ctr, D-40225 Dusseldorf, Germany

[6] Univ Ulm, Inst Epidemiol & Med Biometry, ZIBMT, D-89081 Ulm, Germany

来源：

JOURNAL OF AUTOIMMUNITY | 2019年 / 97卷

关键词：

T cells; IL-7; IL-7 receptor alpha-chain; rs1494558; rs6897932; CD8; T-CELLS; INTERLEUKIN-7; RECEPTOR; WSXWS MOTIF; IL-7; CHAIN; IL-21R; ALPHA;

D O I：

10.1016/j.jaut.2018.10.003

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Interleukin-7 receptor alpha-chain (IL7RA) haplotypes are associated with susceptibility to autoimmune diseases including type 1 diabetes (T1D). Previous studies found lower soluble IL-7R alpha (sIL-7R alpha) 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-7R alpha 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-7R alpha was analyzed. The risk-associated Ile66 variant affected gel mobility and impaired secretion of the sIL-7R alpha as well as expression of the membrane-associated (m)IL-7R alpha in HEK293T cells. Serum sIL-7R alpha analyses confirmed differential gel mobility of the Ile66 variant and found decreased sIL-7R alpha 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 m1L-7R alpha expression, whereas the risk haplotype mainly affected the sIL-7R alpha. This study identified novel functional effects of the Ile66 IL7RA variant and characterized features of auto-immunity risk- and protection-associated haplotypes. The findings add to our understanding of how these haplotypes regulate sIL-7R alpha and mIL-7R alpha expression in T cells causing differential susceptibility to autoimmune diseases.

引用

页码：40 / 47

页数：8

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