Antibody-mediated immunity to Borrelia burgdorferi
抗体介导的伯氏疏螺旋体免疫
基本信息
- 批准号:10731568
- 负责人:
- 金额:$ 43.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-08 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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.
抗体介导的抗伯氏疏螺旋体免疫
总结
目前迫切需要更好地了解伯氏疏螺旋体的免疫保护机制和发病机制
(Bb)莱姆病的病原体。该建议旨在促进对抗Bb免疫及其
未能清除其天然储存宿主中的Bb感染。抗体控制Bb感染,尽管它们不能清除Bb感染。
感染IgG通过激活Fcg受体(FcgR)和补体受体(CR 1/2)与宿主细胞的结合支持先天免疫应答。
细胞介导的病原体破坏和抗原呈递以诱导适应性免疫应答。与此相反,
抑制性FcgRIIb的参与抑制免疫细胞活化。它提高了B细胞受体信号阈值,
导致增强的B细胞凋亡和减少的GC和浆细胞发育,但也支持体细胞
超突变对Bb感染的强抗体应答是由滤泡外淋巴细胞中的浆母细胞产生的。
病灶,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,并维持对Bb和共施用抗原的抗体亲和力成熟。这背后的机制
体液免疫缺陷是未知的,这是该提案旨在填补的知识空白。最近的数据显示,
B b感染小鼠的IgG与B细胞和其他APC结合的能力的改变,部分是通过抑制性FcgRIIb,
以及在Bb感染过程中收集的血清IgG聚糖谱的变化。FcgRIIb缺陷小鼠具有
Bb感染后GC反应延长,而从Bb感染的小鼠而不是非感染的小鼠转移血清,诱导
接收者中的GC崩溃。该提案的目的是确定关键的IgG-免疫细胞相互作用及其影响
对Bb感染,并确定其调节机制。将检验假设,即无效和/或
IgG与FcgR的改变的相互作用降低了对Bb的有效免疫。目的1是确定IgG-
通过研究调节B细胞应答的FcgR-IgG相互作用,评估BB感染中介导的B细胞应答调节,
体液免疫在他们的存在和不存在,并测量其对Bb感染的过程中的影响。目标二是
评估IgG-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
通过Bb-IgG改变FcgR结合的机制,探测免疫复合物形成和IgG聚糖修饰,
它们对抗Bb IgG的被动保护能力和/或Bb感染过程的影响。以预期成果
确定IgG-B细胞相互作用的变化,作为次优抗Bb IgG免疫的原因,增强对
Bb的发病机制,并为莱姆病提供潜在的治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nicole Baumgarth其他文献
Nicole Baumgarth的其他文献
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{{ truncateString('Nicole Baumgarth', 18)}}的其他基金
Antibody-mediated immunity to Borrelia burgdorferi
抗体介导的伯氏疏螺旋体免疫
- 批准号:
10368140 - 财政年份:2021
- 资助金额:
$ 43.3万 - 项目类别:
Antibody-mediated immunity to Borrelia burgdorferi
抗体介导的伯氏疏螺旋体免疫
- 批准号:
10559504 - 财政年份:2021
- 资助金额:
$ 43.3万 - 项目类别:
B-1 cells, IgM and Protective Humoral Immunity to Influenza
B-1 细胞、IgM 和流感保护性体液免疫
- 批准号:
10681028 - 财政年份:2019
- 资助金额:
$ 43.3万 - 项目类别:
B-1 cells, IgM and Protective Humoral Immunity to Influenza
B-1 细胞、IgM 和流感保护性体液免疫
- 批准号:
10023157 - 财政年份:2019
- 资助金额:
$ 43.3万 - 项目类别:
Protective humoral immunity to influenza infection
对流感感染的保护性体液免疫
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9196008 - 财政年份:2016
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Long-lived B cell Immunity in the Respiratory Tract
呼吸道中的长寿命 B 细胞免疫
- 批准号:
8521064 - 财政年份:2010
- 资助金额:
$ 43.3万 - 项目类别:
Long-lived B cell Immunity in the Respiratory Tract
呼吸道中的长寿命 B 细胞免疫
- 批准号:
8316175 - 财政年份:2010
- 资助金额:
$ 43.3万 - 项目类别:
Long-lived B cell Immunity in the Respiratory Tract
呼吸道中的长寿命 B 细胞免疫
- 批准号:
8134252 - 财政年份:2010
- 资助金额:
$ 43.3万 - 项目类别:
Long-lived B cell Immunity in the Respiratory Tract
呼吸道中的长寿命 B 细胞免疫
- 批准号:
8009552 - 财政年份:2010
- 资助金额:
$ 43.3万 - 项目类别:
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