Regulation of B cell function in demyelinating disease by N-glycan branching

N-聚糖分支调节脱髓鞘疾病中的 B 细胞功能

基本信息

  • 批准号:
    10535482
  • 负责人:
  • 金额:
    $ 50.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-14 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

Abstract Our published work has revealed that deficiencies in Asn (N)-linked protein glycosylation reduce inflammatory demyelination in mice and are associated with Multiple Sclerosis (MS). Deficiency in the branching of N-glycan's attached to proteins, either induced experimentally in mice or via natural genetic variation in humans, promotes T-cell mediated inflammatory demyelination and neurodegeneration. For example, branching deficiency induces a spontaneous and slowly progressive MS-like disease in PL/J mice, characterized by inflammatory demyelination, axonal damage and neuronal death. Mechanistically, the branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins, a 14- member family of sugar binding proteins. Galectin binding to cell surface glycoproteins, via their attached N- glycans, forms a macro-molecular lattice at the cell surface that controls the distribution, clustering and endocytosis of surface glycoproteins in a coordinated and predictable manner. N-glycan branching markedly inhibits T cell activity in mice and humans by reducing T cell receptor clustering/signaling at the immune synapse, promoting surface retention of the growth inhibitor CTLA-4 and inhibiting differentiation into pro- inflammatory TH1 and TH17 cells while promoting anti-inflammatory iTreg and TH2 cell differentiation. Although these T cell phenotypes are important regulators of inflammatory demyelination, it has become increasing clear that B cells also play a critical role in MS. This is best exemplified by the potent activity of B cell depleting therapies in MS, such as the anti-CD20 monoclonal antibody ocrelizumab. B cells are unique in the immune system by having both innate and adaptive immune activity; the former exemplified by activation via Toll-like receptors (TLR) and antigen-presenting cell (APC) functions that trigger T cell responses. The mechanism of action of ocrelizumab appears to primarily result from reduced innate immune activity rather than altering antibody production, as ocrelizumab reduces T cell number but not antibody or plasma cell levels in the cerebral spinal fluid of treated MS patients. Here we test the hypothesis that N-glycan branching serves as a critical negative regulator of pro-inflammatory innate immune activity in B cells to suppress pro- inflammatory T cell responses and inflammatory demyelination. To evaluate this hypothesis, the following Aims are proposed. Aim 1 examines regulation of TLR4 and TLR2 responses by N-glycan branching in B cells. Aim 2 examines regulation of B cell receptor signaling by N-glycan branching. Aim 3 examines whether N- glycan branching in B cells suppresses inflammatory demyelination. Positive results will identify N-glycan branching as a major contributor to B cell mediated regulation of inflammatory demyelination and has implications for understanding the mechanism of action of B cell depleting therapies in MS.
摘要 我们已发表的工作表明,Asn(N)连接蛋白糖基化的缺陷 减少小鼠的炎性脱髓鞘,并与多发性硬化症(MS)有关。缺乏 在连接到蛋白质的N-聚糖的分支中,无论是在小鼠中实验诱导还是通过天然遗传 在人类中的变异,促进T细胞介导的炎性脱髓鞘和神经变性。为 例如,分支缺乏会诱导PL/J小鼠自发且缓慢进展的MS样疾病, 其特征在于炎性脱髓鞘、轴突损伤和神经元死亡。机械地, 每个蛋白质分子的N-聚糖的分支和数量协同调节与半乳糖凝集素的结合,半乳糖凝集素是一种14- 糖结合蛋白家族成员。半乳糖凝集素结合细胞表面糖蛋白,通过其连接的N- 聚糖,在细胞表面形成大分子晶格,控制分布,聚集和 细胞以协调和可预测的方式内吞表面糖蛋白。N-聚糖分支明显 通过减少免疫系统中的T细胞受体聚集/信号传导来抑制小鼠和人类中的T细胞活性 突触,促进生长抑制剂CTLA-4的表面保留,并抑制分化为前 在一些实施方案中,本发明的组合物可抑制炎性TH 1和TH 17细胞,同时促进抗炎性iTreg和TH 2细胞分化。虽然 这些T细胞表型是炎性脱髓鞘的重要调节因子, B细胞也在MS中起关键作用。这最好地由B细胞消耗的有效活性来例证。 MS治疗,如抗CD 20单克隆抗体ocrelizumab。B细胞在免疫系统中是独一无二的。 系统具有先天性和适应性免疫活性;前者的例子是通过Toll样激活 受体(TLR)和抗原呈递细胞(APC)的功能,触发T细胞反应。的机理 ocrelizumab的作用似乎主要是由于先天性免疫活性降低而不是改变 抗体产生,因为ocrelizumab减少T细胞数量,但不减少抗体或浆细胞水平。 治疗的MS患者的脑脊液。在这里,我们测试的假设,N-聚糖分支作为 在B细胞中促炎性先天免疫活性的关键负调节剂,以抑制促炎性先天免疫活性。 炎性T细胞反应和炎性脱髓鞘。为了评估这一假设, 提出了目标。目的1检测B细胞中N-聚糖分支对TLR 4和TLR 2应答的调节。 目的2研究N-聚糖分支对B细胞受体信号传导的调节。目标3考察N- B细胞中的聚糖分支抑制炎性脱髓鞘。阳性结果将识别N-聚糖 分支作为B细胞介导的炎症性脱髓鞘调节的主要贡献者, 对理解MS中B细胞耗竭疗法的作用机制的意义。

项目成果

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MICHAEL DEMETRIOU其他文献

MICHAEL DEMETRIOU的其他文献

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{{ truncateString('MICHAEL DEMETRIOU', 18)}}的其他基金

Extended half-life GlyTR1 combined with checkpoint blockade for Cancer Immunotherapy
延长半衰期的 GlyTR1 与检查点阻断相结合用于癌症免疫治疗
  • 批准号:
    10766646
  • 财政年份:
    2023
  • 资助金额:
    $ 50.05万
  • 项目类别:
Cancer Immunotherapy Targeting Tn Antigen
针对 Tn 抗原的癌症免疫疗法
  • 批准号:
    10326021
  • 财政年份:
    2021
  • 资助金额:
    $ 50.05万
  • 项目类别:
Regulation of B cell function in demyelinating disease by N-glycan branching
N-聚糖分支调节脱髓鞘疾病中的 B 细胞功能
  • 批准号:
    10311524
  • 财政年份:
    2019
  • 资助金额:
    $ 50.05万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10465041
  • 财政年份:
    2018
  • 资助金额:
    $ 50.05万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10229448
  • 财政年份:
    2018
  • 资助金额:
    $ 50.05万
  • 项目类别:
O-Glycan-dependent Immunotherapy for Cancer
O-聚糖依赖性癌症免疫疗法
  • 批准号:
    9988594
  • 财政年份:
    2018
  • 资助金额:
    $ 50.05万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    9789858
  • 财政年份:
    2018
  • 资助金额:
    $ 50.05万
  • 项目类别:
N-glycosylation and Immunotherapy for cancer
N-糖基化和癌症免疫治疗
  • 批准号:
    10005189
  • 财政年份:
    2018
  • 资助金额:
    $ 50.05万
  • 项目类别:
Mechanisms of human immune modulation by oral N-acetylglucosamine
口服N-乙酰氨基葡萄糖调节人体免疫的机制
  • 批准号:
    9272357
  • 财政年份:
    2014
  • 资助金额:
    $ 50.05万
  • 项目类别:
Mechanisms of human immune modulation by oral N-acetylglucosamine
口服N-乙酰氨基葡萄糖调节人体免疫的机制
  • 批准号:
    8851521
  • 财政年份:
    2014
  • 资助金额:
    $ 50.05万
  • 项目类别:

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