The Role of Canonical and Non-canonical Autophagy in B Cell Immunity

典型和非典型自噬在 B 细胞免疫中的作用

• 批准号: 10349500
• 负责人: Facundo Damian Batista
• 金额: $ 45.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349500
• 关键词: Ablation; Affect; Affinity; Antibodies; Antibody Affinity; Antigen Presentation; Antigens; Autoimmune Diseases; Autophagocytosis; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biology; Cell Survival; Cell physiology; Cells; Cellular biology; Complex; Data; Degradation Pathway; Development; Down-Regulation; Equilibrium; Gene Deletion; Generations; Genes; Genetic; Goals; HIV-1; Health; Homeostasis; Human; Humoral Immunities; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Class Switching; Impairment; Infection; Infectious Agent; Influenza; Knowledge; Lead; Light; Link; Longevity; Maintenance; Memory; Memory B-Lymphocyte; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Outcome Study; Pathway interactions; Phosphotransferases; Physiological; Plasma Cells; Play; Process; Production; Public Health; Regulation; Role; Shapes; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Monoclonal Antibodies; Time; Vaccination; Vaccines; antigen binding; experimental study; fighting; immune function; immunosenescence; improved; in vivo; insight; leukemia; novel; novel therapeutics; novel vaccines; pathogen; protein degradation; response; trafficking; vaccination strategy; Ablation; Affect; Affinity; Antibodies; Antibody Affinity; Antigen Presentation; Antigens; Autoimmune Diseases; Autophagocytosis; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biology; Cell Survival; Cell physiology; Cells; Cellular biology; Complex; Data; Degradation Pathway; Development; Down-Regulation; Equilibrium; Gene Deletion; Generations; Genes; Genetic; Goals; HIV-1; Health; Homeostasis; Human; Humoral Immunities; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Class Switching; Impairment; Infection; Infectious Agent; Influenza; Knowledge; Lead; Light; Link; Longevity; Maintenance; Memory; Memory B-Lymphocyte; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Outcome Study; Pathway interactions; Phosphotransferases; Physiological; Plasma Cells; Play; Process; Production; Public Health; Regulation; Role; Shapes; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Monoclonal Antibodies; Time; Vaccination; Vaccines; antigen binding; experimental study; fighting; immune function; immunosenescence; improved; in vivo; insight; leukemia; novel; novel therapeutics; novel vaccines; pathogen; protein degradation; response; trafficking; vaccination strategy

B cells play a central role in human health by protecting us against infections through their ability to produce high-affinity antibodies and long-lived memory cells capable of antigenic recall. Perturbations in B cell function can not only lead to lowered ability to fight infections and inefficacy of vaccinations, but also to conditions such as leukemia, and autoimmune diseases. Thus, understanding the molecular mechanisms that contribute to optimal B cell function is extremely important for the generation of new therapeutics and vaccination strategies. The major goal of this proposal is to study how autophagy, a lysosomal degradative pathway with numerous physiological and pathophysiological roles, shapes B cell immunoresponses. The induction of canonical autophagy typically requires the downregulation of the biosynthetic kinase, mTORC1. However, in B cells upon BCR stimulation both autophagy and mTORC1 activity are simultaneously upregulated, suggesting that B cell autophagy is likely to be mTORC1 independent. Our lab has recently shown that there is a switch from basal canonical autophagy in naïve, antigen-inexperienced B cells to an unconventional, mTORC1-independent, non- canonical activity in the germinal center (GC) B cells upon antigenic stimulation. GCs are the determinants of high affinity, class switched antibody generation, and therefore the study of the mechanisms that drive these high-quality immunoresponses is vitally important in the development of next-generation vaccines, therapeutic monoclonal antibodies and in the treatment of autoimmune diseases. Our working hypothesis is that non-canonical autophagy is important during B cell proliferation and will be relevant to GC biology affecting antibody quality, while canonical autophagy is important for long-lived memory cells and plasma cells influencing antibody durability. To test this hypothesis, we will evaluate GC and long-term immune responses in mice bearing genetic ablations of novel autophagy genes that we know affect the balance between canonical and non-canonical autophagy, namely Wipi1, Wipi2 and Rubicon. We will also determine the mechanisms by which the deletions of these genes affect antigen presentation and in eliciting T cell help. Finally, because autophagy intersects with mitochondrial integrity and metabolism, we will determine how these gene deletions control the capacity of GC B cells, memory and plasma cells to regulate ROS production, mitochondrial homeostasis and metabolic status and potentially influence B cell fate. We envision that the successful completion of these experimental aims will not only provide a better understanding of B cell function, but also mechanistic insights into how to modulate autophagy to affect humoral immunity – augment it in cases such as immunosenescence, or downregulate it in instances of autoimmune diseases.

B细胞通过通过生产能力来保护我们免受感染的能力来在人类健康中发挥核心作用 高亲和力抗体和能够抗原回忆的长寿命记忆细胞。 B细胞功能的扰动 不仅可以导致降低感染和无效的能力，还可以导致这种情况 作为白血病和自身免疫性疾病。这是理解有助于的分子机制 最佳B细胞功能对于新的治疗和疫苗接种策略的生成极为重要。 该提案的主要目的是研究自噬如何，一种溶酶体降解途径，有许多 生理和病理生理作用，塑造B细胞免疫血液。构成规范 自噬通常需要下调生物合成激酶MTORC1。但是，在B细胞中 BCR刺激自噬和MTORC1活性都简单地更新，这表明B细胞 自噬可能独立于mTORC1。我们的实验室最近表明，基本的转换 幼稚的，抗原抗原的B细胞中的典型自噬，符合非常规，非依赖性，非依赖性，非 - 抗原刺激后，生发中心（GC）B细胞中的规范活性。 GC是 高亲和力，类转换抗体的产生，因此研究了驱动这些机制 高质量的免疫调查在下一代疫苗的开发中至关重要 单克隆抗体和自身免疫性疾病的治疗。 我们的工作假设是，非经典自噬在B细胞增殖中很重要，并且将是 与影响抗体质量的GC生物学相关，而规范自噬对于长寿记忆很重要 细胞和浆细胞会影响抗体耐用性。为了检验这一假设，我们将评估GC和长期 我们知道影响平衡的新型自噬基因的遗传消融的小鼠的免疫反应 在规范和非典型的自噬之间，即WIPI1，WIPI2和Rubicon。我们还将确定 这些基因缺失影响抗原表现并引起T细胞帮助的机制。最后， 因为自噬与线粒体完整性和代谢相交，所以我们将确定这些基因如何 删除控制GC B细胞，记忆和浆细胞调节ROS产生的能力，线粒体 稳态和代谢状态，并可能影响B细胞命运。 我们设想，这些实验目标的成功完成不仅将提供更好的 了解B细胞功能，还了解如何调节自噬以影响体液的机理见解 免疫力 - 在诸如免疫衰老之类的情况下增加或在自身免疫性的情况下下调 疾病。