B cell TLRs and germinal centers

B 细胞 TLR 和生发中心

• 批准号: 9097649
• 负责人: Anthony L Defranco
• 金额: $ 19.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097649
• 关键词: Address; Affinity; Antibodies; Antibody Response; Antigens; Autoimmunity; B-Lymphocytes; Binding; Bone Marrow; CD4 Positive T Lymphocytes; Cell Separation; Cells; Dendritic Cells; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; IgG1; Immune; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Inflammatory; Ligands; Measures; Memory; Messenger RNA; MicroRNAs; Microfluidics; Modeling; Molecular; Molecular Profiling; Mus; Nuclear; Nucleic Acids; Oligonucleotides; Pathway interactions; Process; Production; Proteins; Receptor Signaling; Regulation; Reporter; Signal Transduction; Source; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Therapeutic; Toll-like receptors; Transgenic Mice; Vaccine Design; Variant; Virus; Virus Diseases; Virus-like particle; Wild Type Mouse; base; cytokine; design; experience; insight; mouse model; novel; research study; response; single cell analysis; therapy development; transcriptome sequencing; virus development; Address; Affinity; Antibodies; Antibody Response; Antigens; Autoimmunity; B-Lymphocytes; Binding; Bone Marrow; CD4 Positive T Lymphocytes; Cell Separation; Cells; Dendritic Cells; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; IgG1; Immune; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Individual; Inflammatory; Ligands; Measures; Memory; Messenger RNA; MicroRNAs; Microfluidics; Modeling; Molecular; Molecular Profiling; Mus; Nuclear; Nucleic Acids; Oligonucleotides; Pathway interactions; Process; Production; Proteins; Receptor Signaling; Regulation; Reporter; Signal Transduction; Source; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Therapeutic; Toll-like receptors; Transgenic Mice; Vaccine Design; Variant; Virus; Virus Diseases; Virus-like particle; Wild Type Mouse; base; cytokine; design; experience; insight; mouse model; novel; research study; response; single cell analysis; therapy development; transcriptome sequencing; virus development

 DESCRIPTION (provided by applicant): Determinants of the quality of a humoral immune response, including the magnitude and isotype of antibody produced, and the extent of affinity maturation, remain poorly defined, limiting efforts of rational vaccine design. Whereas earlier studies had implicated innate immune recognition by Toll-like receptors (TLRs) of B cells in rapid lower affinity antibody responses, our recent studies have shown that innate recognition by TLR9 or TLR7 of B cells strongly enhances the magnitude and the efficacy of the germinal center (GC) response, which generates high quality antibodies. Moreover, this novel function of TLRs has been shown to be required for immune defense against several virus infections in mouse models. In addition, accumulating evidence has indicated that TLR7 and TLR9 are critical components required for the production of anti-nuclear antibodies in mouse models of systemic lupus erythematosus (SLE). Thus, a new pathway whereby TLRs promote high affinity GC antibody responses is likely to be important for immune defense against many viruses and for development of SLE. Recent studies have begun to define the cellular basis by which TLR recognition enhances the magnitude and quality of the IgG response, but the molecular mechanisms underlying this regulation are unknown, which is the topic of this application. Specific Aim 1 is designed to define the changes in mRNA and microRNA expression in GC B cells experiencing stimulation via their TLR9 compared to GC B cells responding to the same immunization but lacking a functional version of the TLR signaling component MyD88. Specific Aim 2 will address the hypothesis that key changes in gene expression are concentrated in subsets of GC B cells, namely GC B cells that are receiving selection signals from follicular helper T cells (TFH) and/or have a higher affinity for antigen. This issue will be assessed by microfluidic single cell analysis of gene expression profiles from GC B cells expressing a Myc-GFP reporter (resulting from productive interaction with TFH cells) or from GC B cells of defined affinity for antigen. Understanding the molecular mechanisms of this process will be useful for rational vaccine design and also many provide new targets for development of therapies to treat SLE.

 描述（由适用提供）：体液免疫响应质量的决定因素，包括产生的抗体的大小和同型，以及亲和力成熟的程度，保持不当定义，这是理性疫苗设计的限制努力。尽管早期的研究已经通过快速较低的亲和力抗体反应中B细胞的TOLL样受体（TLR）实施了先天的免疫认知，但我们最近的研究表明，B细胞的TLR9或TLR7的先天识别强烈增强了发芽中心（GC）反应的幅度和效率，从而产生高质量的抗体抗体。此外，已经证明，这种新型TLR的新功能是针对小鼠模型中多种病毒感染的免疫反应所必需的。此外，积累的证据表明，TLR7和TLR9是在全身性红斑狼疮的小鼠模型中生产抗核抗体所需的关键成分（SLE）。这是一种新的途径，TLR促进高亲和力GC抗体反应对于许多病毒和SLE的发育可能很重要。最近的研究已经开始定义细胞基础，通过该基础，TLR识别增强了IgG响应的大小和质量，但是该调节的分子机制尚不清楚，这是该应用的主题。设计的特定目标1旨在定义与对相同免疫抑制的GC B细胞相比，通过其TLR9刺激的GC B细胞中mRNA和microRNA表达的变化，但缺乏TLR信号传导成分MYD88的功能性版本。具体目标2将解决以下假设：基因表达的关键变化集中在GC B细胞的子集中，即从卵泡辅助T细胞（TFH）接收选择信号的GC B细胞（TFH）和/或对抗原具有较高的亲和力。该问题将通过表达MYC-GFP报告基因的GC B细胞的基因表达谱的微流体单细胞分析来评估（由产物与TFH细胞相互作用）或来自定义抗原亲和力的GC B细胞产生。了解该过程的分子机制将对理性疫苗设计有用，并且许多人为开发治疗SLE的疗法提供了新的靶标。