Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A
Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A
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DOI：
10.1073/pnas.1514484112
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发表时间：
2015-09-15
影响因子：
11.1
通讯作者：
Kikutani, Hitoshi
中科院分区：
文献类型：
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作者：
Minamitani, Takeharu;Yasui, Teruhito;Kikutani, Hitoshi
EB病毒（Epstein-Barr virus，EBV）感染生发中心（germination center，GC）B细胞，并在记忆B细胞中建立持续感染。EBV感染的B细胞可导致T细胞或天然增殖细胞缺乏的人的B细胞恶性肿瘤。我们现在发现EBV编码的潜伏膜蛋白2A（LMP 2A）模拟小鼠GC B细胞中的B细胞抗原受体（BCR）信号传导，引起体液免疫应答改变和自身免疫性疾病。在GC B细胞或所有B系细胞中条件性表达LMP 2A的小鼠中，研究LMP 2A对B细胞分化的影响发现，LMP 2A表达不仅增强BCR信号，而且增强体外和体内的浆细胞分化。GC B细胞中的条件性LMP 2A表达导致优先选择低亲和力抗体产生B细胞，尽管明显正常的GC形成。GC B细胞特异性LMP 2A表达以年龄依赖性方式导致系统性狼疮样自身免疫表型。LMP 2A B细胞的表观遗传学分析发现，在锌指和bric-a-brac，含tramtrack结构域的蛋白20基因座处，H3 K27 ac和H3 K4 me 1信号增加。我们的结论是，LMP 2A降低了GC B细胞选择的严格性，并可能有助于持久的EBV感染和发病机制，通过提供GC B细胞过度的促生存作用。
Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.