Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), remains a global health burden. While Mtb is primarily a respiratory pathogen, it can spread to other organs, including the brain and meninges, causing TB meningitis (TBM). However, little is known about the immunological mechanisms that leads to differential disease across organs. Attention has focused on differences in T cell responses in the control of Mtb in the lungs, but emerging data point to a role for antibodies, as both biomarkers of disease control and as antimicrobial molecules. Given an increasing appreciation for compartmentalized antibody responses across the blood brain barrier, here we characterized the antibody profiles across the blood and brain compartments during TBM, and determined whether Mtb-specific humoral immune responses differed between Mtb infection of the lung (pulmonary TB) and TBM. Using a high throughput systems serology approach, we deeply profiled the antibody responses against 10 different Mtb antigens, including lipoarabinomannan (LAM) and purified protein derivative (PPD), in HIV-negative adults with pulmonary TB (n=10) vs TBM (n=60). Antibody studies included analysis of immunoglobulin isotypes (IgG, IgM, IgA) and subclass levels (IgG1-4), the capacity of Mtb-specific antibodies to bind to Fc receptors or C1q, and to activate innate immune effectors functions (complement and NK cells activation, monocyte or neutrophil phagocytosis). Machine learning methods were applied to characterize serum and CSF responses in TBM, identify prognostic factors associated with disease severity, and define the key antibody features that distinguish TBM from pulmonary TB. In individuals with TBM, we identified CSF-specific antibody profiles that marked a unique and compartmentalized humoral response against Mtb, characterized by an enrichment of Mtb-specific antibodies able to robustly activate complement and drive phagocytosis by monocytes and neutrophils, all of which were associated with milder TBM severity at presentation. Moreover, individuals with TBM exhibited Mtb-specific antibodies in the serum with an increased capacity to activate phagocytosis by monocytes, compared to individuals with pulmonary TB, despite having lower IgG titers and Fcγ receptors (FcγR)-binding capacity. Collectively, these data point to functionally divergent humoral responses depending on the site of infection (i.e. lungs vs brain), and demonstrate a highly compartmentalized Mtb-specific antibody response within the CSF during TBM. Moreover, our results suggest that phagocytosis- and complement-mediating antibodies may promote attenuated neuropathology and milder TBM disease.

中文翻译：

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肺部和脑部感染中结核分枝杆菌的独特抗体反应

结核分枝杆菌 (Mtb) 是结核病 (TB) 的病原体，仍然是全球健康负担。虽然结核分枝杆菌主要是一种呼吸道病原体，但它可以传播到其他器官，包括大脑和脑膜，引起结核性脑膜炎 (TBM)。然而，人们对导致跨器官差异性疾病的免疫机制知之甚少。人们的注意力集中在控制肺部结核分枝杆菌方面 T 细胞反应的差异，但新出现的数据表明抗体的作用，既可以作为疾病控制的生物标志物，也可以作为抗菌分子。鉴于人们对跨血脑屏障的区室化抗体反应的日益认识，我们在此描述了 TBM 期间跨血液和脑区室的抗体谱，并确定了 Mtb 特异性体液免疫反应在肺部（肺结核）和 Mtb 感染之间是否存在差异。隧道掘进机。使用高通量系统血清学方法，我们深入分析了 HIV 阴性成人肺结核 (n=10) 与 TBM (n =60）。抗体研究包括分析免疫球蛋白同种型（IgG、IgM、IgA）和亚类水平（IgG1-4）、Mtb 特异性抗体与 Fc 受体或 C1q 结合的能力，以及激活先天免疫效应器功能（补体和 NK 细胞）的能力。激活、单核细胞或中性粒细胞吞噬作用）。应用机器学习方法来表征 TBM 中的血清和脑脊液反应，识别与疾病严重程度相关的预后因素，并定义区分 TBM 与肺结核的关键抗体特征。在患有 TBM 的个体中，我们鉴定了脑脊液特异性抗体谱，这些抗体谱标志着针对 Mtb 的独特且区室化的体液反应，其特征是 Mtb 特异性抗体的富集，能够强力激活补体并驱动单核细胞和中性粒细胞的吞噬作用，所有这些都与就诊时 TBM 严重程度较轻。此外，尽管 IgG 滴度和 Fcγ 受体 (FcγR) 结合能力较低，但与肺结核患者相比，TBM 患者血清中表现出 Mtb 特异性抗体，且激活单核细胞吞噬作用的能力增强。总的来说，这些数据表明，根据感染部位（即肺与脑）的不同，体液反应的功能也有所不同，并证明了 TBM 期间 CSF 内存在高度区分开的 Mtb 特异性抗体反应。此外，我们的结果表明吞噬作用和补体介导的抗体可能会促进神经病理学减弱和 TBM 疾病减轻。