Virus-like display of a neo-self antigen reverses B cell anergy in a B cell receptor Transgenic mouse model
Virus-like display of a neo-self antigen reverses B cell anergy in a B cell receptor Transgenic mouse model
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DOI：
10.4049/jimmunol.180.9.5816
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Schiller, John T.
中科院分区：
文献类型：
--
作者：
Chackerian, Bryce;Durfee, Marisa R.;Schiller, John T.
区分自身抗原和外来抗原的能力是免疫识别的中心特征。然而，对于B细胞，免疫耐受不是绝对的，并且包括Ag价、T辅助的可用性和多克隆B细胞刺激物的因素可以影响自身抗体应答的诱导。在这里，我们评估了是否多价病毒样颗粒（VLP）为基础的免疫原可以诱导自身抗体反应，在良好表征的转基因（Tg）小鼠，表达可溶性形式的鸡蛋溶菌酶（HEL），其中B细胞耐受HEL是由无能。用多价VLP阵列HEL而不是三价形式的HEL免疫，在可溶性HEL Tg小鼠和双Tg小鼠中诱导针对HEL的高滴度Ab应答，所述双Tg小鼠也表达单克隆HEL特异性BCR。抗HEL自身抗体的诱导不依赖于强佐剂如CFA的共同施用。与之前显示Ab对VLP上的外来表位的T非依赖性诱导的数据相反，HER缀合的VLP在耐受小鼠中诱导抗HEL Ab的能力取决于CD 4（+）Th细胞的存在，并且可以通过存在增强预先存在的同源T细胞。在体外研究中，VLP结合的HEL比三价HEL更有效地上调纯化的无反应性B细胞上的表面活化标志物。此外，在过继转移模型中，用VLP-HEL免疫逆转了体内B细胞无反应性。因此，Ag多价性和T有助于合作逆转B细胞无反应性，这是B细胞耐受性的主要机制。
The ability to distinguish between self and foreign Ags is a central feature of immune recognition. For B cells, however, immune tolerance is not absolute, and factors that include Ag valency, the availability of T help, and polyclonal B cell stimuli can influence the induction of autoantibody responses. Here, we evaluated whether multivalent virus-like particle (VLP)-based immunogens could induce autoantibody responses in well-characterized transgenic (Tg) mice that express a soluble form of hen egg lysozyme (HEL) and in which B cell tolerance to HEL is maintained by anergy. Immunization with multivalent VLP-arrayed HEL, but not a trivalent form of HEL, induced high-titer Ab responses against HEL in both soluble HEL Tg mice and double Tg mice that also express a monoclonal HEL-specific BCR. Induction of autoantibodies against HEL was not dependent on coadministration of strong adjuvants, such as CFA. In contrast to previous data showing the T-independent induction of Abs to foreign epitopes on VLPs, the ability of HEL-conjugated VLPs to induce anti-HEL Abs in tolerant mice was dependent on the presence of CD4(+) Th cells, and could be enhanced by the presence of pre-existing cognate T cells. In in vitro studies, VLP-conjugated HEL was more potent than trivalent HEL in up-regulating surface activation markers on purified anergic B cells. Moreover, immunization with VLP-HEL reversed B cell anergy in vivo in an adoptive transfer model. Thus, Ag multivalency and T help cooperate to reverse B cell anergy, a major mechanism of B cell tolerance.