APOε4 is associated with enhanced in vivo innate immune responses in human subjects.
APOε4 is associated with enhanced in vivo innate immune responses in human subjects.
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DOI：
10.1016/j.jaci.2014.01.032
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发表时间：
2014-07
影响因子：
14.2
通讯作者：
Fessler, Michael B.
中科院分区：
文献类型：
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作者：
Gale, Stephen C.;Gao, Li;Mikacenic, Carmen;Coyle, Susette M.;Rafaels, Nicholas;Dudenkov, Tanda Murray;Madenspacher, Jennifer H.;Draper, David W.;Ge, William;Aloor, Jim J.;Azzam, Kathleen M.;Lai, Lihua;Blackshear, Perry J.;Calvano, Steven E.;Barnes, Kathleen C.;Lowry, Stephen F.;Corbett, Siobhan;Wurfel, Mark M.;Fessler, Michael B.
人类先天免疫反应的遗传决定因素知之甚少。载脂蛋白（apo）E是一种影响炎症的脂质运输蛋白，具有良好描述的“野生型”（ε3）和疾病相关（ε2，ε4）等位基因，但其与人类先天免疫的关系尚不明确。目的探讨载脂蛋白ε4（APOε4）与人先天免疫应答的关系。我们在几种人类先天免疫应答的功能模型中评估了载脂蛋白ε4，包括在人类受试者中的静脉内脂多糖激发，并评估了载脂蛋白ε4与人类严重脓毒症（一种由先天免疫失调驱动的疾病）中器官损伤的相关性。在用Toll样受体（TLR）2、TLR 4或TLR 5配体离体刺激后，来自健康APO ε 3/APOε4志愿者的全血诱导的细胞因子高于来自APOε3/APOε3受试者的血液，而TLR 7/8应答相似。这与APOε3/APOε4单核细胞中脂筏增加有关。相比之下，APOε3/APOε3和APOε3/APOε4血清中和脂多糖的能力相当，并支持ApoE缺陷型巨噬细胞中相似的脂多糖反应，这与分泌型APOE 4蛋白的差异作用相反。静脉注射脂多糖后，APOε3/APOε4受试者的体温升高和血浆TNFα水平高于APOε3/APOε3受试者，血浆IL-6水平也高于APOε3/APOε3受试者。与APOE 3对应物相比，APOE 4靶向替代小鼠在全身性脂多糖后显示出增强的低温、血浆细胞因子和肝损伤，并改变了脾淋巴细胞凋亡。在828例严重脓毒症患者队列中，载脂蛋白ε4与欧洲裔美国受试者凝血系统衰竭增加相关。APOε4是人类对多种TLR配体的先天性免疫应答的决定因素，并与人类脓毒症中器官损伤模式的改变相关。
The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (apo)E, a lipid-trafficking protein that impacts inflammation, has well-described ‘wild type’ (ε3) and disease-associated (ε2, ε4) alleles, but its connection to human innate immunity is undefined. To define the relationship of APOε4 to the human innate immune response. We evaluated APOε4 in several functional models of the human innate immune response including intravenous lipopolysaccharide challenge in human subjects, and assessed APOε4 association to organ injury in human severe sepsis, a disease driven by dysregulated innate immunity. Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokines upon ex vivo stimulation with Toll like Receptor (TLR)2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 subjects, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized lipopolysaccharide equivalently and supported similar lipopolysaccharide responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous lipopolysaccharide, APOε3/APOε4 human subjects had higher hyperthermia and plasma TNFα and earlier plasma IL-6 than APOε3/APOε3 subjects. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury, and altered splenic lymphocyte apoptosis after systemic lipopolysaccharide compared with APOE3 counterparts. In a cohort of 828 severe sepsis patients, APOε4 was associated with increased coagulation system failure among European American subjects. APOε4 is a determinant of the human innate immune response to multiple TLR ligands, and associates with altered patterns of organ injury in human sepsis.
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影响因子：
--
作者：
Chang, Man-huei;Yesupriya, Ajay;Ned, Renee M.;Mueller, Patricia W.;Dowling, Nicole F.
通讯作者：
Dowling, Nicole F.
影响因子：
7.5
作者：
Dong, Anping;Caicedo, Jessica;Gairola, C. Gary
通讯作者：
Gairola, C. Gary
DOI：
10.1165/rcmb.2005-0404oc
发表时间：
2006-04-01
影响因子：
6.4
作者：
Gao, L;Grant, A;Garcia, JGN
通讯作者：
Garcia, JGN
影响因子：
4.8
作者：
Chow, JC;Young, DW;Gusovsky, F
通讯作者：
Gusovsky, F
DOI：
10.4049/jimmunol.1100253
发表时间：
2011-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fessler MB;Parks JS
通讯作者：
Parks JS