Integrative approaches defining the ontogeny, maintenance, and immune response dynamics of marginal-zone B cells

定义边缘区 B 细胞个体发育、维持和免疫反应动力学的综合方法

• 批准号: 10660534
• 负责人: Sanket Rane
• 金额: $ 47.78万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660534
• 关键词: Adopted; Adult; Age; Antibodies; Antibody-mediated protection; Antigens; Autoimmune; Autoimmunity; B cell differentiation; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bacterial Infections; Bayesian Analysis; Blood-Borne Pathogens; Bone Marrow; Cell Compartmentation; Cell Count; Cell Maintenance; Cell Ontogeny; Cell division; Cells; Cessation of life; Chimera organism; Circulation; Clinical; Complex; Coupled; Data; Dedications; Development; Elderly; Emigrant; Encapsulated; Environment; Frequencies; Gatekeeping; Generations; Growth; Health; Heterogeneity; Homeostasis; Human; Immune; Immune response; Immune system; Immunoglobulin M; Immunologic Deficiency Syndromes; Impairment; Infant; Infiltration; Kinetics; Life; Link; Lipids; Longevity; Lymphatic; Lymphocyte; Maintenance; Malignant - descriptor; Maps; Mathematics; Mature B-Lymphocyte; Measures; Mediating; Modeling; Mouse Strains; Mus; Mutation; Natural Immunity; Pathology; Pathway interactions; Patients; Peripheral; Phylogenetic Analysis; Play; Population; Positioning Attribute; Predisposition; Process; Proliferating; Proteins; Regulation; Reporter; Reporter Genes; Sepsis; Shapes; Signal Transduction; System; Systemic infection; T-Independent Antigens; Testing; Time; Trees; Variant; Virus; adaptive immunity; cell age; computational pipelines; congenic; density; experimental study; humoral immunity deficiency; immune activation; immunogenic; insight; kinetic model; mathematical model; mortality; neonate; novel; pathogen; permissiveness; quorum sensing; residence; response; restoration; self-renewal; therapeutic development; therapeutic target; therapy development; tool; transcriptomics; vaccine efficacy

Project Summary Strategically positioned as the gatekeepers between the circulation and the immune system, splenic marginal zone (MZ) B cells form a frontline of defense against blood-borne pathogens. They mediate early protective responses against diverse T-dependent and T-independent antigens, by employing strategies that blur the boundary between innate and adaptive immunity. In humans, MZ B cell deficiency is linked to reduced IgM titers and heightened susceptibility to sepsis and mortality related to encapsulated bacterial infections. In addition, impairment in their function and localization is associated with several autoimmune pathologies. Despite their importance, many aspects of the ontogeny and homeostasis of MZ B cells remain obscure. The establishment and maintenance of MZ B cells in their splenic niche are determined by a complex set of rules that regulate cell division, the influx of new bone marrow (BM) derived cells, death, and onward differentiation. We hypothesize that the rules governing MZ B cell dynamics evolve as we age, and are modulated significantly during immunogenic encounters, resulting in a profound variation in their niche size and clonal composition. Here, we propose a unique integrative approach that synthesizes mathematical and experimental strategies to quantitatively map the developmental trajectories of MZ B cells and dissect the mechanisms that maintain their numbers and clonal diversity, across the lifespan. Specifically, we will develop mechanistic mathematical models to describe the data derived from a validated experimental system in which one can track the constitutive replacement within the MZ B cell compartment, over long timescales in healthy mice. This approach will allow us to measure turnover, reveal any heterogeneity within the MZ B cell pool, and define their developmental trajectories. Further, we will adopt and extend these deterministic models to identify the rules governing the establishment of MZ B cell niche in early life and formulate them as PDE systems to quantify the dynamic transitions in cells’ ability to persist, as a function of time since their compartmental entry. Next, we will develop a dynamical modeling strategy to map B cell differentiation pathways during immune responses, using novel mouse strains expressing an antigen-inducible reporter gene and B cell-specific mutations in Notch2. Lastly, we will employ a computational pipeline to study the single-cell immune repertoire and transcriptomic profiles of activated B cells and to generate phylogenetic trees of antigen-specific clones as they diversify during immune responses.

项目概要 脾边缘作为循环系统和免疫系统之间的看门人 B 区 (MZ) B 细胞构成对抗血源性病原体的前线。他们调解早期保护 通过采用模糊 T 依赖性和 T 非依赖性抗原的策略， 先天免疫和适应性免疫之间的界限。在人类中，MZ B 细胞缺陷与 IgM 减少有关 滴度以及与封装细菌感染相关的败血症和死亡率的易感性增加。在 此外，其功能和定位受损与多种自身免疫性疾病有关。 尽管 MZ B 细胞很重要，但其个体发育和稳态的许多方面仍然不清楚。 MZ B 细胞在脾脏生态位中的建立和维持由一组复杂的因素决定 调节细胞分裂、新骨髓 (BM) 衍生细胞的流入、死亡等的规则 差异化。我们假设控制 MZ B 细胞动力学的规则随着年龄的增长而演变，并且是 在免疫原性遭遇期间显着调节，导致其生态位大小发生深刻变化 和克隆组成。在这里，我们提出了一种独特的综合方法，综合了数学和 定量绘制 MZ B 细胞发育轨迹并剖析的实验策略 在整个生命周期中维持其数量和克隆多样性的机制。 具体来说，我们将开发机械数学模型来描述从经过验证的数据中得出的数据 实验系统，其中可以追踪 MZ B 细胞室内的组成型替换， 在健康小鼠中进行长时间的实验。这种方法将使我们能够衡量营业额，揭示任何 MZ B 细胞池内的异质性，并定义其发育轨迹。此外，我们将采用 并扩展这些确定性模型来确定管理 MZ B 细胞生态位建立的规则 早期生命并将它们制定为偏微分方程系统，以量化细胞持续能力的动态转变， 作为自他们进入隔间以来的时间的函数。接下来，我们将制定动态建模策略 使用表达 B 细胞分化途径的新型小鼠品系来绘制免疫反应期间的 B 细胞分化途径 Notch2 中抗原诱导的报告基因和 B 细胞特异性突变。最后，我们将雇佣一个 研究激活 B 的单细胞免疫库和转录组谱的计算流程 细胞并在免疫反应期间多样化时生成抗原特异性克隆的系统发育树。