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细胞对最佳抗结核(TB)免疫的发展作出贡献的机制。结核分枝杆菌(Mtb)的T细胞免疫应答的重要性已经得到了充分的证实。B细胞在结核病中的作用还没有明确的定义。我们和其他人已经证明，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细胞对抗结核分枝杆菌反应有显著贡献，是最佳控制结核病所必需的。与野生型(WT)动物相比，抑制FCG受体IIB(FcgRIIB)缺陷的小鼠在急性结核病中表现出增强的Th1反应。慢性感染时，MMT小鼠的CD4T细胞应答也会发生改变。总之，这些结果提供了强有力的证据，表明B细胞可以调节TB的T细胞免疫，可能部分是通过FcgR与抗原(Ag)-抗体(Ab)复合体的结合。这些BCG研究，连同发表的B细胞可以调节T细胞记忆和对病原体攻击的次级反应的数据，表明B细胞对疫苗效力有贡献。这项研究表明，在结核NHP的肺中，就像在人类和小鼠中一样，B细胞可以形成离散的结节，并显示激活标记的增强表达。我们相信，所提出的研究可以阐明B细胞塑造宿主对结核分枝杆菌的免疫反应的机制，并导致利用体液免疫来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.