IgM in the regulation of TB immunity

摘要 T细胞在控制结核分枝杆菌（Mt B）中的作用已被充分确立，对于B细胞和 然而，体液免疫还不太清楚。新的证据表明B细胞和免疫球蛋白 (Igs)可以调节宿主如人、非人灵长类动物（NHP）和 小鼠在人类中，抗体（Ab）已显示出调节疾病结果和/或赋予保护。我们 已经表明，与野生型（WT）相比，缺乏分泌型IgM的Mtb-/-小鼠对Mtb更敏感， C57BL/6。易感性表型表现为增加的死亡率和组织细菌负荷， 感染的慢性阶段。HNS-/-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反应开始于感染的急性期。过敏性和GC相关 表型可以通过用从Mtb感染的WT小鼠获得的免疫血清治疗来改善。我们有 在GC B细胞和滤泡细胞缺陷的两种敲除小鼠品系中观察到Mt B易感性增强 辅助性T细胞（Tfh）是GC的两种主要细胞组分，支持GC在防御Mtb中的作用。 因此，IgM-/-数据表明，在感染的急性期，IgM在免疫应答中起重要作用。 开发最佳GC反应，该反应至少部分地是建立有效的自适应 控制慢性结核病的免疫力。我们最近观察到，肺CD 4 + T细胞和Th 1细胞的水平 在感染期间，相对于WT动物，在高敏感性CNS-/-小鼠中增加。为功能 不同的Th 1亚群（由PD 1和KLRG 1的差异表达定义）可以是保护性的， 对结核宿主有害的研究最近已经被描述，表面上矛盾的CD 45-/- T细胞 表型需要进一步表征，特别是在新描述的Th 1亚群的背景下。IgM 可以通过调节调理作用、树突细胞功能、T细胞免疫和 体液反应天然和免疫IgM都对多种病原体起保护作用 包括细胞内细菌。值得注意的是，我们在两个初治患者的循环中都检测到了Mtb Ag特异性IgM。 感染的老鼠和猕猴。结核分枝杆菌特异性IgM也存在于哮喘患者的支气管肺泡灌洗液（BALF）中。 未感染和感染的猴子，这表明天然和免疫IgM可能都在调节 抗结核免疫，可能开始于结核杆菌-宿主相互作用的早期先天阶段。基于上述情况，我们 结论：（i）IgM在优化对结核分枝杆菌的免疫应答中发挥作用，可能在结核分枝杆菌感染的非常早期阶段。 （ii）IgM是建立最佳GC反应所必需的，这是肺感染所必需的。 发展有效的适应性免疫以控制慢性结核病;（iii）天然IgM可能发挥重要作用， 在调节宿主对Mtb的反应中的作用。本提案将严格测试这些假设， 小鼠和猴TB模型。我们将使用多种缺乏特异性IG的转基因小鼠品系 同种型，连同骨髓嵌合体，血清治疗，和IgM包被的Mtb，以探讨 天然和免疫IgM在调节结核免疫中的作用。我们还将使用离体猕猴感染模型， 能够评价IgM对Mtb与NHP肺泡巨噬细胞相互作用的影响。我们 相信小鼠和猴子的联合方法将揭示IgM在防御Mtb中的作用， 提供机制的见解，这种抗体同种型如何调节抗结核反应，并产生 信息，以指导结核病的体液免疫和天然耐药性的未来工作，并设计新的 对结核杆菌采取干预措施，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.