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首页> 外文期刊>MBio >Human Herpesvirus 8 Induces Polyfunctional B Lymphocytes That Drive Kaposi’s Sarcoma
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Human Herpesvirus 8 Induces Polyfunctional B Lymphocytes That Drive Kaposi’s Sarcoma

机译：人类疱疹病毒8诱导多功能的B淋巴细胞驱动卡波西氏肉瘤

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Kaposi’s sarcoma (KS) is an unusual neoplasia wherein the tumor consists primarily of endothelial cells infected with human herpesvirus 8 (HHV-8; Kaposi’s sarcoma-associated herpesvirus) that are not fully transformed but are instead driven to excess proliferation by inflammatory and angiogenic factors. This oncogenic process has been postulated but unproven to depend on a paracrine effect of an abnormal excess of host cytokines and chemokines produced by HHV-8-infected B lymphocytes. Using newly developed measures for intracellular detection of lytic cycle proteins and expression of cytokines and chemokines, we show that HHV-8 targets a range of naive B cell, IgM memory B cell, and plasma cell-like populations for infection and induction of interleukin-6, tumor necrosis factor alpha, macrophage inhibitory protein 1α, macrophage inhibitory protein 1β, and interleukin-8 in vitro and in the blood of HHV-8/HIV-1-coinfected subjects with KS. These B cell lineage subsets that support HHV-8 infection are highly polyfunctional, producing combinations of 2 to 5 of these cytokines and chemokines, with greater numbers in the blood of subjects with KS than in those without KS. Our study provides a new paradigm of B cell polyfunctionality and supports a key role for B cell-derived cytokines and chemokines produced during HHV-8 infection in the development of KS. >IMPORTANCE Kaposi’s sarcoma (KS) is the most common cancer in HIV-1-infected persons and is caused by one of only 7 human cancer viruses, i.e., human herpesvirus 8 (HHV-8). It is unclear how this virus causes neoplastic transformation. Development and outgrowth of endothelial cell lesions characteristic of KS are hypothesized to be dependent on virus replication and multiple immune mediators produced by the KS cells and inflammatory cells, yet the roles of these viral and cell factors have not been defined. The present study advances our understanding of KS in that it supports a central role for HHV-8 infection of B cells inducing multiple cytokines and chemokines that can drive development of the cancer. Notably, HIV-1-infected individuals who developed KS had greater numbers of such HHV-8-infected, polyfunctional B cells across a range of B cell phenotypic lineages than did HHV-8-infected persons without KS. This intriguing production of polyfunctional immune mediators by B cells serves as a new paradigm for B cell function and classification.
机译：卡波西氏肉瘤（KS）是一种不寻常的肿瘤，其中的肿瘤主要由感染了人类疱疹病毒8（HHV-8;卡波西氏肉瘤相关疱疹病毒）的内皮细胞组成，该内皮细胞尚未完全转化，而是被炎症和血管生成因子驱动而过度增殖。该致癌过程已被假定，但未经证实取决于由HHV-8感染的B淋巴细胞产生的异常过量的宿主细胞因子和趋化因子的旁分泌作用。使用新开发的用于细胞内溶胞周期蛋白检测以及细胞因子和趋化因子表达的检测手段，我们显示HHV-8靶向一系列幼稚B细胞，IgM记忆B细胞和浆细胞样人群，用于感染和诱导白介素-在图6中，在患有KS的HHV-8 / HIV-1感染的受试者中，在体外和血液中，肿瘤坏死因子α，巨噬细胞抑制蛋白1α，巨噬细胞抑制蛋白1β和白细胞介素8 。这些支持HHV-8感染的B细胞谱系亚型具有高度的多功能性，可产生2至5种这些细胞因子和趋化因子的组合，患有KS的受试者的血液中的数量要多于没有KS的受试者。我们的研究提供了B细胞多功能性的新范式，并支持在KS的发展过程中HHV-8感染过程中产生的B细胞衍生的细胞因子和趋化因子的关键作用。 >重要性卡波西氏肉瘤（KS）是HIV-1感染者中最常见的癌症，仅由7种人类癌症病毒之一，即人类疱疹病毒8（HHV-8）引起。目前尚不清楚该病毒如何引起肿瘤转化。假设KS的内皮细胞损伤的发生和生长依赖于病毒复制和KS细胞和炎性细胞产生的多种免疫介体，但尚未确定这些病毒和细胞因子的作用。本研究提高了我们对KS的理解，因为它支持B细胞HHV-8感染的中心作用，诱导BHV的多种细胞因子和趋化因子可以驱动癌症的发展。值得注意的是，与没有KS的HHV-8感染者相比，发生KS的HIV-1感染者在一系列B细胞表型谱系中具有更多的此类HHV-8感染的多功能B细胞。 B细胞产生的这种有趣的多功能免疫介体可作为B细胞功能和分类的新范例。

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