Class Switch Recombination in B Lymphocytes

B 淋巴细胞中的类别转换重组

• 批准号: 10546453
• 负责人: Michel C Nussenzweig
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546453
• 关键词: Affinity; Anatomy; Antibodies; Antibody Affinity; Antibody Response; B-Lymphocytes; Biological; Caspase; Cell Death; Cell Separation; Cells; Clonal Expansion; DNA; DNA Damage; Development; Disease; Event; Funding; Genes; Genetic; Genome; Goals; Homeostasis; Human; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Kinetics; Knock-in; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Microanatomy; Mus; Oncogenes; Plasma Cells; Proteins; Reaction; Reagent; Regulation; Research; Role; Site; Somatic Mutation; Structure of germinal center of lymph node; Vaccines; Work; activation-induced cytidine deaminase; cancer cell; inducible Cre; p53-binding protein 1; prevent; receptor; repaired; response; vaccine development

The proposed research continues to focus on the mechanisms that regulate development of the high affinity antibody responses which are essential to vaccine development. There are several critical aspects to these responses that are entirely B cell specific. First, clonal expansion which occurs in special microanatomic structures called germinal centers (GC). Second, diversification of antibody genes by somatic mutation (SHM) and class switch recombination (CSR), both of which are initiated by activation induced cytidine deaminase (AID). Although AID prefers antibody genes, it is not entirely lg specific and off target activity is the primary cause of B cell cancers in humans. The third B cell specific aspect of high affinity antibody development is selection for clones of B cells that express high affinity receptors. In the first 4 years of the funding period, as part of the original Aims 1 and 2, we examined the mechanisms by which AID targets lg genes and misstargets cancer genes in the germinal center. Moreover, we documented the cellular and cell biological regulation of B cell clonal expansion in the germinal center. We have initiated research on Aim 3 and have made significant progress in understanding how Rif-1 mediates its effects on CSR by studying its interaction partner ZYMD8 which has an important role in AID targeting.

拟议的研究继续关注调节高亲和力的发展的机制， 抗体反应，这对疫苗开发至关重要。其中有几个关键方面 完全是B细胞特异性的反应。首先，发生在特殊显微解剖结构中的克隆扩张， 称为生发中心（GC）。第二，通过体细胞突变（SHM）使抗体基因多样化 和类别转换重组（CSR），这两种重组都是由激活诱导的胞苷脱氨酶启动的 （AID）。尽管AID偏好抗体基因，但它并不完全是Ig特异性的，并且脱靶活性是主要的。 导致人类B细胞癌。高亲和力抗体开发的第三个B细胞特异性方面是 选择表达高亲和力受体的B细胞克隆。在融资期的前4年， 作为最初目标1和2的一部分，我们研究了AID靶向lg基因和错误靶向的机制。 癌基因在生殖中心。此外，我们记录了B的细胞和细胞生物学调节 生发中心细胞克隆性扩增。我们已经开始研究目标3，并取得了重大进展。 通过研究Rif-1的相互作用伙伴ZYMD 8，了解Rif-1如何介导其对CSR的影响 这在艾滋病的目标定位中起着重要作用。

项目成果

Continually recruited naïve T cells contribute to the follicular helper and regulatory T cell pools in germinal centers.

持续募集的幼稚T细胞有助于生发中心的卵泡助手和调节T细胞池。

• DOI: 10.1038/s41467-023-41880-9
• 发表时间: 2023-10-31
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Merkenschlager, Julia;Berz, Riza-Maria;Ramos, Victor;Uhlig, Maximilian;Maclean, Andrew J.;Nowosad, Carla R.;Oliveira, Thiago Y.;Nussenzweig, Michel C.
• 通讯作者: Nussenzweig, Michel C.