IgM in the regulation of TB immunity

IgM 在结核免疫调节中的作用

• 批准号: 10531746
• 负责人: John R. Chan
• 金额: $ 4.48万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531746
• 关键词: IgM; regulation; TB; 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）中的作用已经确立了B细胞和 然而，体液免疫学的理解率不高。新的证据表明B细胞和免疫球蛋白 （IG）可以调节人类，非人类灵长类动物（NHP）等宿主中对MTB的免疫反应，并且 老鼠。在人类中，已显示抗体（AB）调节疾病结果和/或赋予保护。我们 已经表明，与野生型（WT）相比 C57BL/6。敏感性表型表现为增强的死亡率和组织细菌的负荷 慢性感染期。 S - / - 小鼠还表现出以组织学为特征的生发中心（GC）缺陷 异常，浆细胞/浆液水平降低，GC B细胞和抗原（Ag） - 特定的IgG反应从感染的急性阶段开始。超出能力和与GC相关的性能 可以通过从MTB感染的WT小鼠中获得的免疫血清来改善表型。我们有 观察到在两个基因敲除小鼠菌株中，在GC B细胞和滤泡中有缺陷的MTB敏感性增强 GC的两个主要细胞成分，支持GC在防御MTB中的作用。 因此，S - / - 数据表明，在感染的急性阶段，IGM在 开发最佳的GC反应至少部分需要建立有效的适应性 控制慢性结核病的免疫力。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，相对于WT动物，高爆发的s/ - 小鼠的增加。在功能上 可以保护或 最近描述了对结节宿主的不利，看似悖论的S/ - T细胞 表型值得进一步表征，特别是在新描述的Th1子集的背景下。 Igm 可以通过调节调子化，树突状细胞功能，T细胞免疫和 体液反应。天然和免疫IGM都针对多种病原体起着受保护的作用 包括细胞内细菌。值得注意的是，我们在Naϊve的循环中检测到MTB Ag特异性IgM 并感染了小鼠和猕猴。 MTB特异性IgM也存在 未感染和感染的猴子，表明自然和免疫IgM可能都在调节中发挥作用 抗TB免疫，可能从MTB宿主相互作用的先天阶段开始。基于上述，我们 认为：（i）IGM在优化对MTB的免疫反应中起作用，这是可能的早期阶段 肺部感染； （ii）建立最佳GC反应所必需的IgM是必需的 开发有效的适应性免疫来控制慢性结核病； （iii）自然IgM可能发挥重要作用 在调节宿主对MTB的响应中的作用。该建议将使用两者都严格检验这些假设 鼠标和猴子结核病模型。我们将使用各种缺乏特定IG的一般改变的小鼠菌株 同种型以及骨髓嵌合体，血清疗法和IgM涂层MTB，以探测 调节结核病免疫中的天然和免疫IgM。我们还将使用一个离体猕猴感染模型 可以评估IgM对MTB与NHP肺泡巨噬细胞相互作用的影响。我们 相信鼠标和猴子的合并方法将阐明IgM在防御MTB中的作用， 提供机械洞察力，以了解该AB同种型如何调节反联反应和产量 指导未来关于结核病的体液免疫和自然抵抗和新颖设计的工作的信息 针对结核菌的干预措施，包括疫苗。