Unraveling the role of B cells in the pathogenesis of an oncogenic avian herpesvirus
Unraveling the role of B cells in the pathogenesis of an oncogenic avian herpesvirus
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DOI：
10.1073/pnas.1813964115
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发表时间：
2018-11-06
影响因子：
11.1
通讯作者：
Kaufer, Benedikt B.
中科院分区：
文献类型：
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作者：
Bertzbach, Luca D.;Laparidou, Maria;Kaufer, Benedikt B.
马立克氏病病毒(MDV)是一种高度致癌的甲型疱疹病毒，会导致鸡的免疫抑制、瘫痪和致命的淋巴瘤。在受感染的动物中，B细胞被有效地感染，并被认为能放大病毒并将其转移到T细胞。MDV随后在T细胞中建立潜伏期，并转化CD4(+)T细胞，导致致命的淋巴瘤。尽管多年来的研究，但不同的B和T细胞亚群在MDV致病中的确切作用仍然知之甚少，主要是因为在鸡身上缺乏反向遗传学。近年来，缺乏成熟B细胞和外周B细胞的免疫球蛋白重链J基因片段敲除(JH-KO)鸡相继产生。为了确定这些B细胞在MDV致病中的作用，我们用MDV超强毒株RB1B感染JH-KO鸡。令人惊讶的是，在没有B细胞的情况下，感染动物血液中的病毒载量没有改变。更重要的是，JH-KO鸡的疾病和肿瘤发病率与野生型相当，这表明成熟B细胞和外周B细胞在MDV的致病过程中都是必不可少的。有趣的是，MDV在JH-KO动物的法氏囊中有效复制，而病毒传播到脾和胸腺的时间被推迟。在没有B细胞的情况下，MDV很容易感染CD4(+)和CD8(+)T细胞，允许病毒在淋巴器官中有效复制和转化T细胞。综上所述，我们的数据改变了B细胞发挥中心作用的教条，从而为MDV的发病机制提供了重要的见解。
Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes immunosuppression, paralysis, and deadly lymphomas in chickens. In infected animals, B cells are efficiently infected and are thought to amplify the virus and transfer it to T cells. MDV subsequently establishes latency in T cells and transforms CD4(+) T cells, resulting in fatal lymphomas. Despite many years of research, the exact role of the different B and T cell subsets in MDV pathogenesis remains poorly understood, mostly due to the lack of reverse genetics in chickens. Recently, Ig heavy chain J gene segment knockout (JH-KO) chickens lacking mature and peripheral B cells have been generated. To determine the role of these B cells in MDV pathogenesis, we infected JH-KO chickens with the very virulent MDV RB1B strain. Surprisingly, viral load in the blood of infected animals was not altered in the absence of B cells. More importantly, disease and tumor incidence in JH-KO chickens was comparable to wild-type animals, suggesting that both mature and peripheral B cells are dispensable for MDV pathogenesis. Intriguingly, MDV efficiently replicated in the bursa of Fabricius in JH-KO animals, while spread of the virus to the spleen and thymus was delayed. In the absence of B cells, MDV readily infected CD4(+) and CD8(+) T cells, allowing efficient virus replication in the lymphoid organs and transformation of T cells. Taken together, our data change the dogma of the central role of B cells, and thereby provide important insights into MDV pathogenesis.