Antibody-mediated immunity to Borrelia burgdorferi

抗体介导的伯氏疏螺旋体免疫 摘要 迫切需要更好地了解伯氏疏螺旋体的免疫保护机制和致病机制。 (Bb)，莱姆病的病原体。这一建议旨在增进对抗BB免疫及其临床应用的认识。 未能清除其天然水库宿主中的BB感染。抗体控制BB感染，尽管它们不能清除 感染。免疫球蛋白通过激活FCG受体(FcgR)和补体受体(CR1/2)与宿主细胞结合支持先天 细胞介导的病原体破坏和抗原提呈以诱导适应性免疫反应。相比之下， 抑制FcgRIIb的结合会抑制免疫细胞的激活。它提高了B细胞受体信号的阈值， 导致B细胞凋亡增强，GC和浆细胞发育减少，但也支持体细胞 超突变。卵泡外浆母细胞产生对BB感染的定量强抗体反应 而GC反应是短暂的和非功能性的。它们不能产生长寿的浆细胞和记忆B 细胞，并维持抗体亲和力成熟的BB和联合注射的抗原。这背后的机制 体液免疫缺陷是未知的，这是这项提案旨在填补的一个关键知识空白。最近的数据表明 BB感染小鼠的免疫球蛋白与B细胞和其他APC结合能力的变化，部分是通过抑制FcgRIIb AS 以及在BB感染过程中收集的血清免疫球蛋白的糖链图谱的变化。FcgRIIb缺陷小鼠有 BB感染后GC反应延长，而BB感染小鼠的血清转移但不引起非感染小鼠的血清转移 受者中的GC崩溃。该提案的目的是定义关键的免疫球蛋白与免疫细胞的相互作用及其影响 关于BB感染的研究，并确定其调节机制。这一假设将被检验为无效和/或 免疫球蛋白与FcgRs相互作用的改变降低了对BB的有效免疫。目的1是确定免疫球蛋白的作用机制。 通过研究调节B细胞反应的FcgR-Ig G相互作用来调节BB感染中的B细胞反应，评估 在存在和不存在的情况下进行体液免疫，并测量其对BB感染过程的影响。目标2是 评估免疫球蛋白B细胞相互作用对抗原呈递和T-B相互作用的有效性。目标3是确定 BB-Ig G改变FcgR结合、探测免疫复合体形成和Ig G糖链修饰的机制 它们对抗BB-Ig G被动保护能力和/或BB感染病程的影响。预期结果将 确定免疫球蛋白-B细胞相互作用的变化，作为次优抗BB免疫球蛋白免疫的原因，加强对 BB的发病机制和莱姆病的潜在治疗靶点。

Antibody-Mediated Immunity to Borrelia burgdorferi Summary There is an urgent need to better understand mechanisms of immune protection and pathogenesis of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. This proposal aims to advances understanding of anti-Bb immunity and its failure to clear Bb infections in its natural reservoir hosts. Antibodies control Bb infection, although they cannot clear the infection. Binding of IgG to host cells via activating Fcg receptors (FcgR) and complement receptors (CR1/2) supports innate cell-mediated destruction of pathogens and antigen presentation for adaptive immune response induction. In contrast, engagement of the inhibitory FcgRIIb suppresses immune cell activation. It heightens B cell receptor-signaling thresholds, causing enhanced B cell apoptosis and reduced GC and plasma cell development, but also supporting somatic hypermutations. Quantitatively strong antibody responses to Bb infection are generated by plasmablasts in extrafollicular foci, while GC responses are short-lived and non-functional. They fail to generate long-lived plasma cell and memory B cells, and to sustain antibody affinity maturation to Bb and to co-administered antigens. The mechanisms underlying this humoral immune deficiency are unknown, a key gap in knowledge this proposal aims to fill. Recent data demonstrated changes to the ability of IgG from Bb-infected mice to bind to B cells and other APC, in part via the inhibitory FcgRIIb as well as changes to the glycan profile of serum IgG collected over the course of Bb infection. FcgRIIb-deficient mice had prolonged GC responses after Bb infection, while transfer of serum from Bb-infected, but not non-infected mice, induced GC collapse in recipients. The objective of the proposal is to define critical IgG-immune cell interactions and their effects on Bb infection, and to identify mechanisms of their regulation. The hypothesis will be tested that ineffective and/or altered interactions of IgG with FcgRs reduce effective immunity to Bb. Aim 1 is to identify the mechanisms of IgG- mediated B cell response regulation in Bb infection by studying FcgR-IgG interactions that regulate B cell responses, assess humoral immunity in their presence and absence, and measure their effects on the course of Bb infection. Aim 2 is to assess the effectiveness of IgG-B cell interaction for antigen-presentation and T-B interaction. Aim 3 is to identify the mechanisms of altered FcgR binding by Bb-IgG, probing immune complex formation and IgG glycans modifications and their effects on the passive protective capacity of anti-Bb IgG and/or the course of Bb-infection. Expected results would identify changes to IgG-B cell interactions, as causes of suboptimal anti-Bb IgG immunity, enhancing understanding of the pathogenesis of Bb and providing potential therapeutic targets for Lyme disease.