B cells and humoral immunity in tuberculosis

描述（由申请方提供）：本提案的目的是表征B细胞促进最佳抗结核（TB）免疫力形成的机制。T细胞免疫应答对结核分枝杆菌（Mtb）的重要性已经得到充分证实。B细胞在TB中的作用尚未明确。我们和其他人已经证明B细胞是人和小鼠肺结核性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。使用B细胞缺陷型mMT小鼠，结合B细胞转移研究，我们表明B细胞显著促进抗MT B应答，并且是TB的最佳控制所需的。相对于野生型（WT）动物，抑制性Fcg受体IIB（FcgRIIB）缺陷的小鼠在急性TB中表现出增强的Th 1应答。mMT小鼠的CD 4 + T细胞应答在慢性感染中也发生改变。总之，这些结果提供了强有力的证据，即B细胞可以调节TB中的T细胞免疫，可能部分地通过FcgR与抗原（Ag）-抗体（Ab）复合物的接合。我们最近观察到，BCG疫苗接种诱导的Th 1反应在mMT小鼠中，这是劣于在WT中观察到的。最近的一项研究报告说，BCG不能最佳地保护CBA/xid小鼠，另一种B细胞缺陷株。这些BCG研究，连同B细胞可以调节T细胞记忆和对病原体攻击的次级应答的已发表数据，表明B细胞有助于疫苗效力。为了严格测试B细胞在调节针对Mt B的宿主免疫中的意义，我们开始研究以检查食蟹猴（非人灵长类动物; NHP）模型中的B细胞应答，该模型可以说是最真实地代表人类系统的模型。本研究揭示，在结核性NHP的肺中，与在人和小鼠中一样，B细胞可以形成不连续的结节并显示活化标记物的增强表达。我们建议使用小鼠和NHP TB模型来严格检验以下假设：i）B细胞的特异性功能显著地促进宿主对Mt B的免疫应答; ii）B细胞是TB中有效T细胞应答（包括CD 4 T细胞记忆应答）的发展所必需的; iii）B细胞是最佳疫苗产生的保护的发展所必需的;和iv）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，拟议的研究可以阐明B细胞塑造宿主对结核分枝杆菌B的免疫应答的机制，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.