Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
Mast Cell Activation and KSHV Infection in Kaposi Sarcoma
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DOI：
10.1158/1078-0432.ccr-18-0873
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发表时间：
2018-10-15
影响因子：
11.5
通讯作者：
King, Christine A.
中科院分区：
文献类型：
--
作者：
Ayers, Leona W.;Barbachano-Guerrero, Arturo;King, Christine A.
目的：卡波西肉瘤（Kaposi sarcoma，KS）是一种由KS相关疱疹病毒（KSHV）感染内皮细胞而引起的血管性肿瘤。KS依赖于由病灶内白细胞和新EC的持续感染提供的持续促炎信号。然而，这些细胞因子和感染性病毒在病变中的来源并不完全清楚。在这里，肥大细胞（MC）被确定为KS病变内的促炎细胞，是允许的，并激活，感染KSHV.Experimental设计：三个验证的MC线被用来评估perperadenance的MC感染KSHV和评估MC激活感染后。通过免疫组化方法对31例AIDS-KS病例和11例AIDS对照的活检组织进行评估，以确定KS病变中MC的存在，并评估MC活化状态和KSHV感染。从26个艾滋病-KS，13个经典KS，和13个健康成人的血浆样本进行了评价MC颗粒含量类胰蛋白酶和histamin.Results的水平：在文化，MC支持潜伏和溶解KSHV感染，感染诱导MC脱粒。KS病变内，MC与梭形细胞密切相关。此外，MC激活广泛的KS患者，反映了类胰蛋白酶和组胺代谢物的循环水平升高。一个病人的广泛MC激活的临床症状与MC促炎介质，这导致在一个快速和持久的回归AIDS-KS lesions.Conclusions的拮抗剂治疗：使用免费的体外和体内研究，我们确定MC作为一个潜在的长寿水库KSHV和KS病变微环境内的促炎介质的来源。此外，我们确定MC拮抗剂作为一个有前途的新的治疗方法KS。(C)2018年AACR。
Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV.Experimental Design: Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine.Results: In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MCactivation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions.Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. (C) 2018 AACR.