IgM in the regulation of TB immunity

IgM 在结核免疫调节中的作用

• 批准号: 10551315
• 负责人: John R. Chan
• 金额: $ 73.63万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551315
• 关键词: Acute; Alveolar Macrophages; Animals; Antibodies; Antigens; Antitubercular Agents; B-Lymphocytes; Bacillus; Bacteria; Blood; Bone Marrow; Bronchoalveolar Lavage Fluid; CD4 Positive T Lymphocytes; Carbohydrates; Cell physiology; Cells; Characteristics; Chimera organism; Chronic; Chronic Phase; Circulation; Communicable Diseases; Containment; Data; Defect; Dendritic Cells; Development; Disease; Disease Outcome; Evaluation; Exhibits; Experimental Designs; Future; Goals; Granuloma; Granulomatous; Helper-Inducer T-Lymphocyte; Histologic; Human; Humoral Immunities; Immune; Immune Sera; Immune response; Immunity; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulins; Immunologic Factors; Impairment; Infection; Inflammation; Intervention; Investigation; Irrigation; Knockout Mice; Learning; Liquid substance; Lung; Macaca; Macrophage; Mediating; Microbe; Modeling; Monkeys; Mouse Strains; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Natural Resistance; Outcome; Pathogenesis; Phase; Phenotype; Plasma Cells; Plasmablast; Play; Predisposition; Publications; Reaction; Regulation; Reporting; Research Proposals; Role; Serum; Shapes; Structure of germinal center of lymph node; System; T-Lymphocyte; Testing; Th1 Cells; Thymus Gland; Tissues; Tuberculosis; Vaccines; Wild Type Mouse; Work; acute infection; adaptive immunity; antimicrobial; chronic infection; design; differential expression; experimental study; immunoregulation; in vivo; insight; mortality; mouse model; nonhuman primate; novel; pathogen; programmed cell death protein 1; protective effect; response; tuberculosis immunity

Abstract A role for T cells in the control of Mycobacterium tuberculosis (Mtb) is well established, that for B cells and humoral immunity, however, is less well understood. Emerging evidence indicate B cells and immunoglobulins (Igs) can modulate the immune response to Mtb in hosts such as humans, non-human primates (NHP), and mice. In humans, antibodies (Ab) has been shown to modulate disease outcome and/or confer protection. We have shown that S-/- mice, which lack secreted IgM, are more susceptible to Mtb compared to wild-type (WT) C57BL/6. The susceptibility phenotype manifests as enhanced mortality and tissue bacterial loads in the chronic phase of infection. S-/- mice also exhibit germinal center (GC) defects characterized by histological abnormality, decreased levels of plasma cells/plasmablasts, and an impaired GC B cell and antigen (Ag)- specific IgG response beginning in the acute phase of infection. The hypersusceptibility and GC-related phenotypes can be ameliorated by therapy with immune serum procured from Mtb-infected WT mice. We have observed enhanced Mtb susceptibility in two knockout mouse strains defective in GC B cells and follicular helper T cells (Tfh), two major cellular components of GC, supporting a role for GC in defense against Mtb. The S-/- data thus suggest that in the acute phase of infection, IgM plays an important role in the development of an optimal GC reaction that is required, at least in part, for establishing effective adaptive immunity for the control of chronic TB. We recently observed that the levels of lung CD4+ T cells and Th1 cells are increased in the hypersusceptible S-/- mice relative to WT animals during infection. As functionally distinct Th1 subsets (defined by differential expression of PD1 and KLRG1) that can be protective or detrimental to a tuberculous host have recently been described, the seemingly paradoxical S-/- T cell phenotype warrants further characterization, particularly in the context of the newly described Th1 subsets. IgM can mediate antimicrobial activities by modulating opsonization, dendritic cell functions, T cell immunity and humoral responses. Both natural and immune IgMs play a protective role against a variety of pathogens including intracellular bacteria. Of note, we have detected Mtb Ag-specific IgM in the circulation of both naϊve and infected mice and macaques. Mtb-specific IgM is also present in brochoalveolar lavage fluids (BALF) of uninfected and infected monkeys, suggesting that natural and immune IgM may both play a role in regulating anti-TB immunity, possible beginning in the early innate phase of Mtb-host interaction. Based on the above, we posit that: (i) IgM plays a role in optimizing the immune response to Mtb, possibly at the very early phase of infection in the lungs; (ii) IgM is required for establishing an optimal GC reaction that is required for the development of effective adaptive immunity for the control of chronic TB; (iii) natural IgM may play an important role in modulating the host response to Mtb. This proposal will rigorously test these hypotheses using both mouse and monkey TB models. We will use a variety of genetically altered mouse strains which lack specific Ig isotypes, together with bone marrow chimeras, serum therapy, and IgM-coated Mtb to probe the significance of natural and immune IgM in regulating TB immunity. We will also use an ex vivo macaque infection model that enables the evaluation of the effect of IgM on the interaction of Mtb with NHP alveolar macrophages. We believe the combined mouse and monkey approach will shed light on the role of IgM in defense against Mtb, provide mechanistic insights into how this Ab isotype regulates anti-tuberculous responses, and yield information to guide future work on the humoral immunity and natural resistance in TB and the design of novel interventions against the tubercle bacillus, including vaccines.

抽象的 T 细胞在控制结核分枝杆菌 (Mtb) 中的作用已得到充分证实，而 B 细胞和 然而，对体液免疫的了解还不太清楚。新证据表明 B 细胞和免疫球蛋白 (Igs) 可以调节人类、非人灵长类动物 (NHP) 等宿主对 Mtb 的免疫反应， 老鼠。在人类中，抗体 (Ab) 已被证明可以调节疾病结果和/或提供保护。我们 研究表明，与野生型 (WT) 相比，缺乏分泌型 IgM 的 S-/- 小鼠对 Mtb 更敏感 C57BL/6。易感性表型表现为死亡率和组织细菌负荷的增加 感染的慢性期。 S-/- 小鼠还表现出以组织学特征为特征的生发中心（GC）缺陷 异常、浆细胞/浆母细胞水平降低以及 GC B 细胞和抗原 (Ag) 受损 - 特异性 IgG 反应在感染急性期开始。高敏感性与GC相关 使用从 Mtb 感染的 WT 小鼠中获得的免疫血清进行治疗可以改善表型。我们有 观察到 GC B 细胞和滤泡缺陷的两种基因敲除小鼠品系的 Mtb 易感性增强 辅助 T 细胞 (Tfh) 是 GC 的两个主要细胞成分，支持 GC 在防御 Mtb 中发挥作用。 因此，S-/- 数据表明，在感染急性期，IgM 在感染过程中发挥着重要作用。 开发最佳的 GC 反应，至少部分地需要建立有效的适应性 免疫控制慢性结核病。我们最近观察到肺 CD4+ T 细胞和 Th1 细胞的水平 在感染过程中，与 WT 动物相比，高度敏感的 S-/- 小鼠中的表达增加。从功能上来说 不同的 Th1 子集（由 PD1 和 KLRG1 的差异表达定义）可以具有保护性或 最近描述了对结核宿主有害的现象，看似矛盾的S-/- T 细胞 表型需要进一步表征，特别是在新描述的 Th1 亚群的背景下。免疫球蛋白M 可通过调节调理作用、树突状细胞功能、T 细胞免疫和 体液反应。天然 IgM 和免疫 IgM 均对多种病原体发挥保护作用 包括细胞内细菌。值得注意的是，我们在两种幼稚小鼠的循环中都检测到了 Mtb Ag 特异性 IgM。 以及受感染的老鼠和猕猴。 Mtb 特异性 IgM 也存在于支气管肺泡灌洗液 (BALF) 中 未感染和感染的猴子，表明天然 IgM 和免疫 IgM 可能都在调节中发挥作用 抗结核免疫，可能始于结核分枝杆菌与宿主相互作用的早期先天阶段。基于以上情况，我们 假设： (i) IgM 在优化针对 Mtb 的免疫反应中发挥着作用，可能是在 Mtb 的早期阶段 肺部感染； (ii) IgM 是建立最佳 GC 反应所必需的，该反应是 发展有效的适应性免疫来控制慢性结核病； (iii) 天然 IgM 可能发挥重要作用 调节宿主对 Mtb 的反应。该提案将使用以下两种方法严格检验这些假设 小鼠和猴结核病模型。我们将使用多种缺乏特定 Ig 的转基因小鼠品系 同种型，连同骨髓嵌合体、血清疗法和 IgM 包被的 Mtb 来探讨 天然和免疫 IgM 调节结核免疫。我们还将使用离体猕猴感染模型 能够评估 IgM 对 Mtb 与 NHP 肺泡巨噬细胞相互作用的影响。我们 相信小鼠和猴子相结合的方法将阐明 IgM 在防御 Mtb 中的作用， 提供有关该抗体同种型如何调节抗结核反应的机制见解，并产生 指导结核病体液免疫和自然抵抗的未来工作以及新型药物设计的信息 针对结核杆菌的干预措施，包括疫苗。