B cells and humoral immunity in tuberculosis

描述（由申请人提供）：本提案的目标是描述B细胞促进最佳抗结核（TB）免疫发展的机制。T细胞免疫应答对结核分枝杆菌（Mtb）的重要性已经得到了很好的证实。B细胞在结核病中的作用尚不明确。我们和其他人已经表明，B细胞是人类和小鼠肺结核肉芽肿的重要组成部分。它们形成具有生发中心B细胞特征的明显聚集体。利用B细胞缺陷的mMT小鼠，结合B细胞转移研究，我们发现B细胞对抗mtb反应有显著贡献，并且是结核病最佳控制所必需的。与野生型（WT）动物相比，缺乏抑制性Fcg受体IIB （FcgRIIB）的小鼠在急性结核病中表现出增强的Th1反应。mMT小鼠的CD4+ T细胞反应在慢性感染中也发生了改变。总之，这些结果提供了强有力的证据，表明B细胞可以调节结核病中的T细胞免疫，可能部分是通过FcgR与抗原(Ag)-抗体（Ab）复合物的结合。我们最近观察到，卡介苗接种在mMT小鼠中诱导的Th1应答低于在WT小鼠中观察到的应答。最近的一项研究报告了卡介苗不能最佳地保护CBA/xid小鼠（另一种B细胞缺陷菌株）。这些卡介苗研究，连同已发表的B细胞可以调节T细胞记忆和对病原体攻击的二次反应的数据，表明B细胞有助于疫苗的效力。为了严格测试B细胞在调节宿主对结核分枝杆菌免疫中的重要性，我们在食蟹猴（非人类灵长类动物；NHP）模型中研究了B细胞的反应，这种模型可以说是最真实地代表了人类系统。本研究表明，在结核性NHP患者的肺部，如人和小鼠，B细胞可以形成离散的结节，并显示激活标记物的表达增强。我们建议使用小鼠和NHP TB模型来严格检验以下假设：i) B细胞的特定功能对宿主对Mtb的免疫反应有重要贡献；ii) B细胞是结核病中有效T细胞反应的必要条件，包括CD4 T细胞记忆反应；（iii） B细胞对于发展最佳疫苗产生的保护至关重要；Ag-Ab复合物和FcgR可用于增强宿主对Mtb的免疫应答。我们相信这些研究可以揭示B细胞形成宿主对结核分枝杆菌免疫反应的机制，并导致利用体液免疫增强抗结核免疫的新措施。

DESCRIPTION (provided by applicant): The goal of this proposal is to characterize the mechanisms by which B cells contribute to the development of optimal anti-tuberculosis (TB) immunity. The importance of T cell immune response to Mycobacterium tuberculosis (Mtb) has been well established. The role of B cells in TB is not clearly defined. We and others have shown that B cells are a significant component of lung tuberculous granulomas in human and mice. They form conspicuous aggregates with features of germinal center B cells. Using the B cell-deficient mMT mouse, in conjunction with B cell transfer studies, we showed that B cells contribute significantly to anti-Mtb responses and are required for the optimal control of TB. Mice deficient in the inhibitory Fcg receptor IIB (FcgRIIB), relative to wildtype (WT) animals, exhibit an enhanced Th1 response in acute TB. The CD4+ T cells response of mMT mice is also altered in chronic infection. Together, these results provide strong evidence that B cells can regulate T cell immunity in TB, perhaps in part via FcgR engagement with antigen (Ag)-antibody (Ab) complex. We recently observed that BCG vaccination induces a Th1 response in mMT mice that is inferior to that observed in WT's. A recent study reports on the inability of BCG to optimally protect the CBA/xid mouse, another B cell-deficient strain. These BCG studies, together with published data that B cells can regulate T cell memory and secondary response to pathogen challenge, suggests that B cells contribute to vaccine efficacy. To stringently test the significance of B cells in regulating host immunity against Mtb, we initiated studies to examine the B cell response in a cynomolgus macaque (non-human primate; NHP) model, one that arguably most genuinely represents the human system. This study revealed that in the lungs of tuberculous NHP, as in human and mice, B cells can form discreet nodules and display enhanced expression of activation markers. We propose to use both murine and NHP TB models to rigorously test the hypotheses that: i) Specific functions of B cells contribute significantly to the host immune response to Mtb; ii) B cells are required for the development of effective T cell response in TB, including the CD4 T cell memory response; iii) B cells are essential for the development of optimal vaccine-engendered protection; and iv) Ag-Ab complex and FcgR can be exploited to enhance the host immune response to Mtb. We believe the proposed studies can shed light on the mechanisms by which B cells shape the host immune response to Mtb and lead to novel measures for harnessing humoral immunity to augment anti-TB immunity.