EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching
EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching
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DOI：
10.4049/jimmunol.171.10.5215
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发表时间：
2003-11-15
影响因子：
4.4
通讯作者：
Cerutti, A
中科院分区：
文献类型：
--
作者：
He, B;Raab-Traub, N;Cerutti, A
通过将IgM的H链C区替换为IgG、IgA或IgE的H链C区，类转换使抗体获得新的效应功能，这对中和入侵病原体至关重要。类转换通过类转换DNA重组（CSR）发生，通常需要CD40配体在ag激活的CD4(+) T细胞上结合B细胞上的CD40。CSR必须严格调控，因为异常的IgG和IgA产生有利于自身免疫的发生，而增加的向IgE的转换会导致特应性。这些炎症性疾病可由eb病毒感染引发或加重。在这项研究中，我们发现EBV通过潜伏膜蛋白1 （latent membrane protein 1, LMP1）诱导从C-mu到下游多个C-gamma、C-alpha和C-epsilon基因的不依赖cd40的CSR， LMP1是一种cd40样病毒蛋白，以不依赖配体的方式发出信号。lmp1诱导的CSR与种系c - γ、c - α和C-epsilon基因的转录激活有关，并触发激活诱导的胞苷脱氨酶的上调，胞苷脱氨酶是CSR机制的重要组成部分。此外，LMP1诱导B细胞表达TNF家族的B细胞活化因子和增殖诱导配体，这两个分子介导B细胞存活和T细胞不依赖的Ab产生。TNF家族的B细胞活化因子和增殖诱导配体与LMP1协同诱导Ig类转换，因为它们被适当的可溶性诱饵受体中和，会减弱表达LMP1的B细胞中的CSR。通过LMP1触发T细胞非依赖性CSR，我们的研究结果表明EBV可能在异常IgG、IgA和/或IgE产生的疾病的发病机制中发挥重要作用。
By substituting the H chain C region of IgM with that of IgG, IgA, or IgE, class switching enables Abs to acquire new effector functions that are crucial for the neutralization of invading pathogens. Class switching occurs through class switch DNA recombination (CSR) and usually requires engagement of CD40 on B cells by CD40 ligand on Ag-activated CD4(+) T cells. CSR must be tightly regulated because abnormal IgG and IgA production favors the onset of autoimmunity, whereas increased switching to IgE leads to atopy. These inflammatory disorders can be triggered or exacerbated by EBV infection. In this study, we show that EBV induces CD40-independent CSR from C-mu to multiple downstream C-gamma, C-alpha, and C-epsilon genes through latent membrane protein 1 (LMP1), a CD40-like viral protein that signals in a ligand-independent fashion. LMP1-induced CSR is associated with transcriptional activation of germline C-gamma, C-alpha, and C-epsilon genes and triggers the up-regulation of activation-induced cytidine deaminase, a crucial component of the CSR machinery. In addition, LMP1 induces B cells to express B cell-activating factor of the TNF family and a proliferation-inducing ligand, two molecules that mediate B cell survival and T cell-independent Ab production. B cell-activating factor of the TNF family and a proliferation-inducing ligand cooperate with LMP1 to induce Ig class switching because their neutralization by appropriate soluble decoy receptors attenuates CSR in LMP1-expressing B cells. By showing that LMP1 triggers T cell-independent CSR, our findings suggest that EBV could play an important role in the pathogenesis of disorders with aberrant IgG, IgA, and/or IgE production.