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Autoimmunity risk- and protection-associated IL7RA genetic variants differentially affect soluble and membrane IL-7Rα expression.
Journal of Autoimmunity ( IF 7.9 ) Pub Date : 2018-10-17 , DOI: 10.1016/j.jaut.2018.10.003
Christian Lundtoft 1 , Julia Seyfarth 2 , Sonja Oberstrass 1 , Joachim Rosenbauer 3 , Christina Baechle 3 , Michael Roden 4 , Reinhard W Holl 5 , Ertan Mayatepek 1 , Sebastian Kummer 1 , Thomas Meissner 2 , Marc Jacobsen 1
Journal of Autoimmunity ( IF 7.9 ) Pub Date : 2018-10-17 , DOI: 10.1016/j.jaut.2018.10.003
Christian Lundtoft 1 , Julia Seyfarth 2 , Sonja Oberstrass 1 , Joachim Rosenbauer 3 , Christina Baechle 3 , Michael Roden 4 , Reinhard W Holl 5 , Ertan Mayatepek 1 , Sebastian Kummer 1 , Thomas Meissner 2 , Marc Jacobsen 1
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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.
中文翻译：
自身免疫风险和保护相关的IL7RA基因变异差异影响可溶性和膜IL-7Rα表达。
白细胞介素7受体α链（IL7RA）单倍型与包括1型糖尿病（T1D）在内的自身免疫性疾病易感性相关。先前的研究发现，与保护相关的IL7RA单倍型的可溶性IL-7Rα（sIL-7Rα）血清水平较低，被认为可降低IL-7对自反应性T细胞的利用度。同样，与风险相关的IL7RA单倍型伴随着较低的sIL-7Rα血清浓度，但尚未描述任何潜在机制，并且致病多态性仍然未知。在这里，我们表征了非同义rs1494558（Thr66Ile）的功能含义，该标签标记了与保护相关的IL7RA单倍型，在具有不同单倍型携带者的T1D患者的HEK293T细胞和血清样品中。分析了与风险和保护相关的单体型对IL-7Rα的影响。风险相关的Ile66变体影响HEK293T细胞中的凝胶迁移率和sIL-7Rα的分泌以及膜相关（m）IL-7Rα的表达受损。血清sIL-7Rα分析证实了Ile66变体的差异凝胶流动性，并发现携带Ile66标签单倍型的T1D患者的sIL-7Rα血清水平降低。糖基化的差异不是导致差异性迁移的原因，而是增强了对分泌受损的影响。在基于细胞系的体外模型中比较保护型和风险型单倍型，发现rs6897932（Ile244）标记的保护型单倍型对mIL-7Rα表达的显性作用，而风险型单倍型主要影响sIL-7Rα。这项研究确定了Ile66 IL7RA变体的新型功能作用，并表征了自身免疫风险和保护相关单倍型的特征。这些发现增加了我们对这些单倍型如何调节T细胞中sIL-7Rα和mIL-7Rα表达的认识，从而引起了对自身免疫性疾病的易感性差异。
更新日期：2018-10-17
中文翻译：
自身免疫风险和保护相关的IL7RA基因变异差异影响可溶性和膜IL-7Rα表达。
白细胞介素7受体α链（IL7RA）单倍型与包括1型糖尿病（T1D）在内的自身免疫性疾病易感性相关。先前的研究发现，与保护相关的IL7RA单倍型的可溶性IL-7Rα（sIL-7Rα）血清水平较低，被认为可降低IL-7对自反应性T细胞的利用度。同样，与风险相关的IL7RA单倍型伴随着较低的sIL-7Rα血清浓度，但尚未描述任何潜在机制，并且致病多态性仍然未知。在这里，我们表征了非同义rs1494558（Thr66Ile）的功能含义，该标签标记了与保护相关的IL7RA单倍型，在具有不同单倍型携带者的T1D患者的HEK293T细胞和血清样品中。分析了与风险和保护相关的单体型对IL-7Rα的影响。风险相关的Ile66变体影响HEK293T细胞中的凝胶迁移率和sIL-7Rα的分泌以及膜相关（m）IL-7Rα的表达受损。血清sIL-7Rα分析证实了Ile66变体的差异凝胶流动性，并发现携带Ile66标签单倍型的T1D患者的sIL-7Rα血清水平降低。糖基化的差异不是导致差异性迁移的原因，而是增强了对分泌受损的影响。在基于细胞系的体外模型中比较保护型和风险型单倍型，发现rs6897932（Ile244）标记的保护型单倍型对mIL-7Rα表达的显性作用，而风险型单倍型主要影响sIL-7Rα。这项研究确定了Ile66 IL7RA变体的新型功能作用，并表征了自身免疫风险和保护相关单倍型的特征。这些发现增加了我们对这些单倍型如何调节T细胞中sIL-7Rα和mIL-7Rα表达的认识，从而引起了对自身免疫性疾病的易感性差异。
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