The Rabbit Genome, Immune System and Ig Genetics

兔是几种传染病的唯一或最佳动物模型。7倍覆盖率的兔子基因组序列于2008年7月在博德研究所、麻省理工学院和哈佛大学完成。深度报道汇编已于2009年8月3日提交给GenBank(登录号：AAGW02000000)。我们能够在不完整的2x轨迹档案和组装中找到并使用的序列，以及7x轨迹档案，已经被证明对各种研究有用。现在有两个网站可用：第一个是由NIAID在免疫学和感染性Disease(http://www3.niaid.nih.gov/research/resources/ri/.中对兔进行的该网站提供了NIAID于2005年举办的关于人类传染病兔模型的研讨会的摘要。第二个站点是由国家生物技术信息中心维护的，b9异型http://www.ncbi.nlm.nih.gov/projects/genome/guide/rabbit/.Rabbits已被用于各种需要高特异性高亲和力抗体的免疫项目。HIV-1 gp41保守的N-七肽重复序列(NHR)形成一个螺旋线圈，是融合反应的前体。用gp41 NHR区模拟NHR卷曲线圈(N35CCG-N13)免疫同种异型兔，从免疫噬菌体展示文库中分离到HIV-1中和单抗。从1只兔中回收的3株中和单链抗体的VDJ序列是克隆性相关的，其重链可变区(VH)由一个很少表达的VH基因(X32)编码(Nelson等人)。免疫b9兔还产生了针对NgR1和NgR2的单抗，用于表征一种新的中枢神经系统髓鞘抑制拮抗剂(Robak等人，2009年)。我们发表的开发SLE兔模型的工作(Puliyath等人，2008年，以及其中的参考文献)提高了人们对使用选择性培育的兔来产生自身抗体的兴趣，该抗体用于旨在开发新的疫苗以引起广泛的中和抗HIV反应的研究。有人假设，编码能够广泛中和不同HIV毒株的抗体的B细胞是由于潜在的自身抗体活性而在B细胞发育过程中被选中的。BAFF介导的未成熟B细胞的存活也有助于自身反应性B细胞的存活和成熟。几个小组将或目前正在使用我们先前研究中报告的纯种兔子的近亲来研究对各种抗原的反应，这些抗原可能会引起对艾滋病毒的广泛中和抗体，因为它们更有可能产生自身抗体。正在进行的一项研究的计划还包括使用我们所描述的重组兔BAFF(Yang等人。2009年)。在最近的研究中，从免疫的兔中筛选出b9同种异型的兔/人嵌合Fab文库，以鉴定对HIV-1 Rev蛋白的天然表位具有高亲和力和特异性的嵌合兔/人Fab。我们假设兔/人嵌合Fab可以促进共结晶。通过与一个独特的表位结合，Fab被证明能够有效地溶解REV聚合物。对FAB/REV络合物进行了提纯、表征和结晶。作为晶体伴侣的能力是兔/人嵌合Fab具有广泛用途的新应用。从b9兔免疫中选择的单抗也有一个由不寻常的VH基因编码的重链可变区。(MS in preparation S.Stahl，N.Watts，P.Wingfield，et al.佩比。NIAMS，R MAGE，NIAID，C.Rader NCI)。

Rabbits are the only or best animal model for several infectious diseases. The sequence of the rabbit genome at 7x coverage was completed in July 2008 at Broad Institute MIT and Harvard. Assembly of the deep coverage was submitted to GenBank (accession AAGW02000000) on August 3, 2009. The sequences we have been able to find and use in the incomplete 2x trace archive and assembly along with the 7x trace archive have already proven useful for various studies. Two websites are now available:the first is by NIAID on Rabbit in Immunology & Infectious Disease(http://www3.niaid.nih.gov/research/resources/ri/. This site offers a summary of an NIAID workshop on Rabbit Models of Human Infectious diseases held in 2005. The second site is one maintained by the National Center for Biotechnology Information (NCBI), http://www.ncbi.nlm.nih.gov/projects/genome/guide/rabbit/.Rabbits of the b9 allotype have been used in a variety of immunization projects where highly specific high affinity antibodies are desired. The conserved N-heptad repeat (NHR) region of gp41of HIV-1 forms a coiled-coil that is a precursor to the fusion reaction. HIV-1-neutralizing monoclonal antibodies were isolated from immune phage display libraries from rabbits of b9 allotype immunized with a mimetic of the NHR coiled-coil, (N35CCG-N13) of the NHR region of gp41. The VDJ sequences of the three recovered neutralizing scFv from one rabbit were clonally related and had a heavy chain variable region (VH) encoded by a rarely expressed VH gene (x32) (Nelson et al. 2008).Immunization of b9 rabbits also led to mAbs specific for NgR1 and NgR2 that were used for characterization of a novel antagonist of CNS myelin inhibition (Robak et al, 2009). Our published work to develop a rabbit model of SLE (Puliyath et al, 2008, and reference therein) has a raised interest in the use of rabbits selectively bred to produce autoantibodies for studies aimed at development of new vaccines to elicit broadly neutralizing anti-HIV responses. It has been hypothesized that B-cells encoding antibodies capable of broadly neutralizing different HIV strains are selected against during B-cell development due to potential autoantibody activity. It is also known that BAFF-mediated survival of immature B cells contributes to the survival and maturation of autoreactive B cells. The responses to various antigens that may elicit broadly neutralizing antibodies to HIV will be or are currently being investigated by several groups using relatives of the pedigreed rabbits reported in our previous studies because they are more likely to produce autoantibodies. The plan of one study in progress also includes use of recombinant rabbit BAFF that we described (Yang et al. 2009). In more recent studies, a chimeric rabbit/human Fab library generated from immunized rabbits, of b9 allotype was screened to identify chimeric rabbit/human Fab of high affinity and specificity for a native epitope of the Rev protein of HIV-1. We hypothesized that chimeric rabbit/human Fab could facilitate co-crystallization. By binding to a unique epitope, the Fab was shown to potently dissolve Rev polymers. Fab/Rev complexes were purified, characterized and crystallized. The ability to serve as crystal chaperones is a new application of broad utility for chimeric rabbit/human Fab. The selected mAb from b9 rabbit immunization also had a heavy chain variable region encoded by an unusual VH gene. (Ms in preparation S. Stahl, N.Watts, P.Wingfield, et al. PEB. NIAMS, R Mage, NIAID, C. Rader NCI).