IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation
IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation
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DOI：
10.4049/jimmunol.1001392
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Olsson, Tomas
中科院分区：
文献类型：
--
作者：
Beyeen, Amennai D.;Adzemovic, Milena Z.;Olsson, Tomas
多发性硬化（MS）是中枢神经系统的炎性神经退行性疾病。全基因组筛选工具的最新进展已经发现了几个MS风险基因，其中大多数具有已知的免疫相关功能。然而，疾病异质性和低组织可及性阻碍了已建立的MS风险基因的功能研究。由于这个原因，MS模型实验性自身免疫性脑脊髓炎（EAE）经常被用来研究神经炎症性疾病的机制。在这项研究中，我们进行了高分辨率的连锁分析，在大鼠先进的互交线，以确定一个EAE调节数量性状位点，Eae 29，在大鼠1号染色体上。来自耐药菌株的Eae 29等位基因均赋予较轻的EAE和巨噬细胞中促炎分子的较低产生，如同源系DA. PVG-Eae 29（Dc 1 P）所证明的。可溶性IL-22 R α 2基因（IL-22 ra 2）位于Eae 29位点内，其表达在Dc 1 P中减少，无论是在活化的巨噬细胞和免疫大鼠的脾细胞中。此外，位于IL-22 RA 2末端的单核苷酸多态性与5019例瑞典和挪威受试者的MS风险相关，显示比值比为1.26（p = 8.0 x 10（-4））。IL-22及其受体与慢性炎症有关，表明IL-22 RA 2调节中枢免疫途径。通过包括在动物模型中的遗传学和免疫学调查以及MS患者的大规模关联研究的组合方法，我们确定IL-22 RA 2为MS风险基因。免疫学杂志，2010，185：6883-6890。
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the CNS. Recent advances in whole-genome screening tools have enabled discovery of several MS risk genes, the majority of which have known immune-related functions. However, disease heterogeneity and low tissue accessibility hinder functional studies of established MS risk genes. For this reason, the MS model experimental autoimmune encephalomyelitis (EAE) is often used to study neuroinflammatory disease mechanisms. In this study, we performed high-resolution linkage analysis in a rat advanced intercross line to identify an EAE-regulating quantitative trait locus, Eae29, on rat chromosome 1. Eae29 alleles from the resistant strain both conferred milder EAE and lower production of proinflammatory molecules in macrophages, as demonstrated by the congenic line, DA. PVG-Eae29 (Dc1P). The soluble IL-22R alpha 2 gene (Il-22ra2) lies within the Eae29 locus, and its expression was reduced in Dc1P, both in activated macrophages and splenocytes from immunized rats. Moreover, a single nucleotide polymorphism located at the end of IL-22RA2 associated with MS risk in a combined Swedish and Norwegian cohort comprising 5019 subjects, displaying an odds ratio of 1.26 (p = 8.0 x 10(-4)). IL-22 and its receptors have been implicated in chronic inflammation, suggesting that IL-22RA2 regulates a central immune pathway. Through a combined approach including genetic and immunological investigation in an animal model and large-scale association studies of MS patients, we establish IL-22RA2 as an MS risk gene. The Journal of Immunology, 2010, 185: 6883-6890.