IgM in the regulation of TB immunity

摘要 T细胞在控制结核分枝杆菌(Mtb)中的作用是公认的，B细胞和 然而，体液免疫却鲜为人知。新的证据表明B细胞和免疫球蛋白 (Ig)可以调节宿主如人类、非人灵长类(NHP)对结核分枝杆菌的免疫反应，以及 老鼠。在人类中，抗体(Ab)已被证明可调节疾病结局和/或提供保护。我们 研究表明，缺乏分泌型免疫球蛋白的S-/-小鼠比野生型(WT)更容易感染结核分枝杆菌。 C57BL/6。敏感性表型表现为死亡率和组织细菌负荷增加。 感染的慢性期。S-/-小鼠也表现出生发中心(GC)缺陷，其组织学特征为 异常，浆细胞/浆母细胞水平下降，GC B细胞和抗原(Ag)受损- 在感染的急性期开始的特异性免疫球蛋白应答。过敏性与GC相关 从结核杆菌感染的WT小鼠获得的免疫血清可以通过治疗来改善表型。我们有 观察到两个GC B细胞和卵泡缺陷基因敲除小鼠的结核分枝杆菌敏感性增强 辅助性T细胞(TFH)是GC的两个主要细胞成分，支持GC对结核分枝杆菌的防御作用。 因此，S的数据表明，在感染的急性期，免疫球蛋白M在 发展最佳的GC反应，至少部分地是建立有效适应性所必需的 控制慢性结核病的免疫力。我们最近观察到肺内CD4T细胞和Th1细胞水平 在感染期间，超敏S-/-小鼠相对于WT动物增加。AS在功能上 不同的Th1亚群(由PD1和KLRG1的差异表达定义)可以是保护性的或 对结核宿主有害的最近被描述，看似矛盾的S-/-T细胞 表型需要进一步的表征，特别是在新描述的Th1亚群的背景下。IGM 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。天然和免疫的免疫球蛋白对多种病原体都有保护作用。 包括胞内细菌。值得注意的是，我们在两个NAϊVE的循环中都检测到了结核分枝杆菌抗原特异性免疫球蛋白 以及受感染的老鼠和猕猴。结核分枝杆菌特异性IgM也存在于慢性支气管炎患者的支气管肺泡灌洗液中。 未感染和感染的猴子，表明自然和免疫的IgM都可能在调节中发挥作用 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。基于以上原因，我们 假设：(I)IgM在优化对结核分枝杆菌的免疫反应中发挥作用，可能在Mtb的非常早期阶段 肺部感染；(Ii)IgM是建立最佳GC反应所必需的，这是 发展有效的获得性免疫以控制慢性结核病；(Iii)天然免疫球蛋白M可能发挥重要作用 在调节宿主对结核分枝杆菌的反应中的作用。这项提案将使用两种方法严格测试这些假设 小鼠和猴结核病模型。我们将使用各种缺乏特异性免疫球蛋白的转基因小鼠品系 结合骨髓嵌合体、血清治疗和IgM包被的结核分枝杆菌，探讨其意义。 天然免疫IgM在结核病免疫调节中的作用。我们还将使用体外猕猴感染模型， 能够评估IgM对结核分枝杆菌与NHP肺泡巨噬细胞相互作用的影响。我们 相信老鼠和猴子的结合方法将揭示IgM在防御结核分枝杆菌中的作用， 提供了关于这种抗体同种类型如何调节抗结核反应和产量的机械性见解 指导未来结核病体液免疫和自然耐药工作的信息以及新的设计 针对结核杆菌的干预措施，包括疫苗。

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.