Epigenetic Regulation of Memory B Cell Differentiation and Reactivation

记忆 B 细胞分化和再激活的表观遗传调控

• 批准号: 9761825
• 负责人: Madeline Joan Price
• 金额: $ 2.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-01-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761825
• 关键词: Acute; Affinity; Antibodies; Antibody Formation; Antibody Response; Antigens; Architecture; Autoimmune Diseases; Autoimmune Process; B cell differentiation; B-Lymphocytes; Binding; Biochemical; Biological Markers; C57BL/6 Mouse; CD80 gene; CD8B1 gene; Cell Differentiation process; Cell Maintenance; Cell division; Cells; Chromatin; Coupled; DNA Methylation; Disease; Effector Cell; Enhancers; Epigenetic Process; Epitopes; Exhibits; Flow Cytometry; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Health; Human; Humoral Immunities; Immune; Immunize; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Isotopes; Kinetics; Label; Mediating; Memory; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; Methods; Methylation; Microbe; Modification; Nucleoproteins; Oxidative Phosphorylation; Pathogenicity; Pathology; Pattern; Plasma Cells; Population; Process; Production; Proteins; Receptors, Antigen, B-Cell; Repression; Role; Systemic Lupus Erythematosus; T memory cell; Translations; Up-Regulation; Vaccination; Viola; Virus; Work; XBP1 gene; XCL1 gene; differentiated B cell; epigenetic regulation; epigenome; experimental study; genomic data; human DNA; human pathogen; insight; metabolic profile; plasma cell differentiation; programs; promoter; response; transcriptome; transcriptome sequencing

Project Summary Humoral immunity relies on B cells to differentiate into plasma cells, which then secrete antibodies. These antibodies bind to antigen to facilitate neutralization and clearance of microbes. Natural infection and vaccination induce differentiation of naïve B cells to plasma cells or to memory B cells. Memory B cells, unlike plasma cells, maintain responsiveness to antigen, and can be stimulated by subsequent challenge, similar to a naïve B cell. However, upon secondary stimulation, memory B cells differentiate faster to plasma cells and produce higher affinity, more class-switched antibody. Memory B cells can be IgM+ or isotype-switched. It is now appreciated that IgM+ memory B cells are key players in the reactivation response. IgM+ memory B cells respond in a quantitatively and qualitatively more efficient manner than naïve B cells, similar to class-switched memory B cells. This suggests that the differences in memory B cell responses are not simply due to class-switched B cell receptors. We propose that memory B cells have an altered chromatin architecture that facilitates their enhanced ability to respond to subsequent infection. These changes are likely in the promoter or enhancer regions of key genes involved in metabolism and plasma cell differentiation, such as Pdhx and Xbp1, respectively. Our genomics data shows that plasma cells rely on more oxidative phosphorylation than naïve and activated B cells. Because memory B cells differentiate to plasma cells faster, it suggests that memory B cells will be able to perform oxidative phosphorylation more effectively upon stimulation than naïve B cells. We have also shown that naive B cell differentiation to plasma cells is coupled to cell division and to specific epigenetic changes that occur during each division. We do not know whether memory B cells follow the same or similar epigenetic patterns. The overall goal of this proposal is to identify genetic factors that contribute to enhanced reactivation by memory B cells. To accomplish this, Aim 1 will use a variety of infection / inoculation methods to determine the biochemical and epigenetic programs that define metabolism of memory B cells. Aim 2 will characterize the differentiation programs of naïve, IgM+ and class-switched memory B cells to plasma cells by seeking to understand the number of divisions required for memory cell differentiation to a plasma cell and how the transcriptome changes during secondary challenge. Thus, the work proposed will define the changes in metabolic gene programming that are mediated by epigenetic changes and enhance our understanding of how memory B cells respond to immune challenge.

项目摘要 体液免疫依赖于B细胞分化为浆细胞，然后将其分化为秘密抗体。这些 抗体与抗原结合以促进微生物的神经刺激和清除率。自然感染和疫苗接种 诱导幼稚的B细胞分化为浆细胞或记忆B细胞。与浆细胞不同的记忆B细胞， 保持对抗原的反应，可以通过随后的挑战来刺激，类似于幼稚的B细胞。 但是，在次级刺激后，记忆B细胞将更快地分化为浆细胞，并产生更高的 亲和力，更多的类切换抗体。内存B单元可以是IgM+或同种型切换。现在值得赞赏 IgM+内存B细胞是重新激活响应中的关键参与者。 IgM+内存B细胞在A中响应 与幼稚的B细胞相比，定量和定性上的效率更高，类似于类切换的记忆b 细胞。这表明记忆B细胞响应的差异不仅是由于类切换的B细胞引起的 接收者。我们建议记忆B细胞具有变化的染色质结构，从而有助于其增强 能够应对随后的感染。这些变化很可能在密钥的发起人或增强子区域中 分别参与代谢和浆细胞分化的基因，例如PDHX和XBP1。我们的 基因组学数据表明，浆细胞比幼稚和活化的B细胞更依赖更多的氧化磷酸化。 由于内存B单元格更快地与浆细胞区分开，因此表明内存B细胞将能够 与幼稚的B细胞相比，在刺激时更有效地执行氧化磷酸化。我们还表明 天真的B细胞与浆细胞的分化与细胞分裂耦合，并与发生的特定表观遗传变化耦合 在每个分区期间。我们不知道记忆B细胞是遵循相同还是相似的表观遗传模式。 该提案的总体目标是确定有助于通过记忆增强重新激活的遗传因素 B细胞。为此，AIM 1将使用各种感染 /接种方法来确定 定义记忆B细胞代谢的生化和表观遗传程序。 AIM 2将表征 幼稚，IgM+和类切换的记忆B细胞的分化程序通过寻求寻求 了解记忆细胞分化为等离子体细胞所需的划分数量以及如何 次要挑战期间的转录组变化。那就是提出的工作将定义 由表观遗传变化介导的代谢基因编程，并增强我们对 记忆B细胞应对免疫挑战。