Selection and Regulation of B Lymphocytes in IDDM

IDDM 中 B 淋巴细胞的选择和调节

基本信息

  • 批准号:
    10316222
  • 负责人:
  • 金额:
    $ 39.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-05-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Summary Type IA or insulin dependent diabetes (T1D) is caused by autoimmune destruction of insulin producing β cells in the pancreatic islets by T lymphocytes. The detection of IgG autoantibodies to insulin and other β cell autoantigens in pre-T1D suggests that T-B lymphocyte interactions are a critical early event in the loss of immune tolerance that leads to T1D. Research in this laboratory is focused on the function of B lymphocytes that recognize the key β cell autoantigen, insulin. By engineering NOD mice to express an insulin autoantibody as a B cell receptor transgene, we discovered that B lymphocytes make unappreciated contributions to the pathogenesis of T1D as antigen presenting cells. Anti-insulin B lymphocytes were found to process and present pathogenic epitopes from insulin B chain to diabetogenic T cells. In all previous studies insulin epitopes were identified by T cell responses to synthetic peptides and natural insulin epitopes on diabetogenic MHCII (IAg7 in NOD and DQ8 in humans) were not know. By combining the novel resource of our anti-insulin B cells with advanced proteomics, we have overcome the barrier to detection of natural insulin epitopes and have discovered an unexpected quantity and quality of insulin-related peptides eluted from IAg7 on anti-insulin B cells. Features of the insulin “immunopeptidome” differ strikingly from synthetic peptides used to mimic epitopes. Pathogenic B chain motifs are in low abundance relative to other insulin-related epitopes and they reside on larger peptides that may support more complex interactions. Surprisingly, a large majority of insulin- related residues from IAg7 reside in multiple epitope clusters encompassing the c-peptide of proinsulin. These findings suggest: i) natural B chain epitopes may reside on larger polypeptides and drive more diverse responses than detected with synthetic peptides (e.g. B9-23); ii) features of c-peptide epitopes eluted from IAg7 indicate anti-insulin B cells capture proinsulin at the site of attack in the islets; iii) properties of proinsulin c-peptide that favor MHCII loading govern thymic education of anti-insulin T cells. These hypotheses will be tested in three aims of the proposal. First, we will identify naturally processed B chain epitopes from IAg7 on B cells that drive unique autoaggressive T cells in T1D. Second, the role of insulitis in loading proinsulin- peptides onto IAg7 in anti-insulin B cells will be determined, and quantitative proteomics will be developed to test this potential biomarker. Third, the functional significance of proinsulin peptides eluted from IAg7 for generation of beneficial T cells that leave the thymus will be assessed. Each of these aims is positioned for rapid translation into human T1D by providing more effective reagents for detection and regulation of autoaggressive T cells, developing a biomarker of early islet invasion, and identifying T cells better suited for maintaining immune tolerance.
总结 IA型或胰岛素依赖型糖尿病(T1 D)是由产生胰岛素的β细胞的自身免疫破坏引起的 通过T淋巴细胞进入胰岛。抗胰岛素等β细胞IgG抗体的检测 T1 D前自身抗原表明,T-B淋巴细胞相互作用是T1 D丧失的关键早期事件。 导致T1 D的免疫耐受本实验室的研究重点是B淋巴细胞的功能 识别关键的β细胞自身抗原胰岛素通过改造NOD小鼠表达胰岛素自身抗体, 作为一种B细胞受体转基因,我们发现B淋巴细胞对细胞凋亡的贡献未被重视。 T1 D作为抗原呈递细胞的发病机制。抗胰岛素B淋巴细胞被发现处理和 将胰岛素B链的致病性表位呈递给致糖尿病T细胞。在所有既往研究中,胰岛素 通过T细胞对合成肽和天然胰岛素表位的反应来鉴定表位, MHCII(NOD中的IAg 7和人类中的DQ 8)未知。通过结合我们的抗胰岛素新资源 B细胞与先进的蛋白质组学,我们已经克服了障碍,检测天然胰岛素表位, 已经发现了从抗胰岛素的IAg 7洗脱的胰岛素相关肽的出乎意料的数量和质量 B细胞。胰岛素“免疫肽组”的特征与用于模拟胰岛素的合成肽有显著不同。 表位致病性B链基序相对于其他胰岛素相关表位的丰度较低, 存在于更大的肽上,可以支持更复杂的相互作用。令人惊讶的是,大多数胰岛素- 来自IAg 7的相关残基存在于包含胰岛素原C肽的多个表位簇中。这些 研究结果表明:i)天然B链表位可能存在于较大的多肽上, ii)与用合成肽(例如B 9 -23)检测到的相比的C-肽表位的特征; IAg 7指示抗胰岛素B细胞在胰岛中的攻击位点捕获胰岛素原; iii)胰岛素原的性质 有利于MHCII负载的C肽控制抗胰岛素T细胞的胸腺教育。这些假设将是 在三个目标的提案测试。首先,我们将从B上的IAg 7鉴定天然加工的B链表位 T1 D中驱动独特的自身攻击性T细胞的细胞。第二,胰岛炎在加载胰岛素原中的作用- 将确定抗胰岛素B细胞中IAg 7上的肽,并将开发定量蛋白质组学, 测试这个潜在的生物标志物第三,从IAg 7洗脱的胰岛素原肽对于胰岛素抵抗的功能意义。 评估离开胸腺的有益T细胞的产生。每一个目标都是为了 通过提供更有效的检测和调节T1 D的试剂, 自身攻击性T细胞,开发早期胰岛侵袭的生物标志物,并鉴定更适合于 维持免疫耐受。

项目成果

期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells.
  • DOI:
    10.1016/j.molimm.2014.01.003
  • 发表时间:
    2014-12
  • 期刊:
  • 影响因子:
    3.6
  • 作者:
    Bonami RH;Wolfle WT;Thomas JW;Kendall PL
  • 通讯作者:
    Kendall PL
Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.
  • DOI:
    10.2337/db11-1746
  • 发表时间:
    2012-08
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Henry RA;Kendall PL;Thomas JW
  • 通讯作者:
    Thomas JW
Follicular B cell trafficking within the spleen actively restricts humoral immune responses.
  • DOI:
    10.1016/j.immuni.2010.07.016
  • 发表时间:
    2010-08-27
  • 期刊:
  • 影响因子:
    32.4
  • 作者:
    Hoek KL;Gordy LE;Collins PL;Parekh VV;Aune TM;Joyce S;Thomas JW;Van Kaer L;Sebzda E
  • 通讯作者:
    Sebzda E
Therapeutic targeting of Syk in autoimmune diabetes.
  • DOI:
    10.4049/jimmunol.1000983
  • 发表时间:
    2010-08-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Colonna L;Catalano G;Chew C;D'Agati V;Thomas JW;Wong FS;Schmitz J;Masuda ES;Reizis B;Tarakhovsky A;Clynes R
  • 通讯作者:
    Clynes R
Reduced diabetes in btk-deficient nonobese diabetic mice and restoration of diabetes with provision of an anti-insulin IgH chain transgene.
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Rachel H Bonami其他文献

Rachel H Bonami的其他文献

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{{ truncateString('Rachel H Bonami', 18)}}的其他基金

Molecular Characterization of Autoreactive B Cells in Immune Checkpoint Inhibitor-Induced Autoimmune Sicca
免疫检查点抑制剂诱导的自身免疫性干燥症中自身反应性 B 细胞的分子特征
  • 批准号:
    10287167
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
Molecular Characterization of Autoreactive B Cells in Immune Checkpoint Inhibitor-Induced Autoimmune Sicca
免疫检查点抑制剂诱导的自身免疫性干燥症中自身反应性 B 细胞的分子特征
  • 批准号:
    10427436
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
The Origins of Human Anti-Insulin B Lymphocytes in Type 1 Diabetes
1 型糖尿病中人类抗胰岛素 B 淋巴细胞的起源
  • 批准号:
    10532164
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:
The Origins of Human Anti-Insulin B Lymphocytes in Type 1 Diabetes
1 型糖尿病中人类抗胰岛素 B 淋巴细胞的起源
  • 批准号:
    10343084
  • 财政年份:
    2021
  • 资助金额:
    $ 39.48万
  • 项目类别:

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Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes
针对胰岛细胞表面抗原的自身抗体及其在 1 型糖尿病中的病理作用
  • 批准号:
    10161015
  • 财政年份:
    2020
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神经免疫疾病中两种脂质分子形成的复合抗原自身抗体的研究
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肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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    2011
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
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  • 财政年份:
    2011
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    $ 39.48万
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
  • 批准号:
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  • 财政年份:
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Autoantibodies to tumor-associated antigens as diagnostic biomarkers in liver can
肿瘤相关抗原的自身抗体作为肝脏的诊断生物标志物可以
  • 批准号:
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  • 财政年份:
    2011
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Follicular Exclusion of Self Antigens Prevents Development of Autoantibodies
滤泡排除自身抗原可防止自身抗体的产生
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    8795154
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Follicular Exclusion of Self Antigens Prevents Development of Autoantibodies
滤泡排除自身抗原可防止自身抗体的产生
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Identifications of non-Hodgkin's lymphoma (NHL)-specific antigens bounded with autoantibodies in plasma derived from patients with NHL by an autoantibodiomics
通过自身抗体组学鉴定 NHL 患者血浆中与自身抗体结合的非霍奇金淋巴瘤 (NHL) 特异性抗原
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    2007
  • 资助金额:
    $ 39.48万
  • 项目类别:
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