Perturbation of B cell anergy in T1D

T1D 中 B 细胞无反应性的扰动

基本信息

  • 批准号:
    9121223
  • 负责人:
  • 金额:
    $ 23.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-02-16 至 2018-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease characterized by immune system attack and destruction of insulin-producing islet beta cells in the pancreas. The disease affects an estimated three million Americans and 30 million people worldwide, and continues to increase in frequency. Given the impact of this disease on world health and the absence of a cure, there is critical need for studies directed at understanding its etiology and pathophysiology. Although it is well accepted that T cells function as the beta cell executioners, it is unclear what events precede and precipitate their activity in disease. The studies proposed here will extend our recently published findings suggesting a role for insulin-reactive B cells in T1D development. Studies in the Non-Obese Diabetic (NOD) mouse model demonstrate that islet antigen-reactive B cells are required for development of T1D, and further indicate that these B cells are necessary for activation and proliferation of diabetogenic T cells in the pancreas. The function of B cells in human disease is less well understood. However, a role for these cells is supported by the success of B cell depleting therapy (Rituximab) in T1D. We have recently shown that in healthy subjects B cells bearing high affinity insulin-binding antigen receptors reside in the anergic, so-called BND, compartment, but leave this compartment in all new onset diabetic and prediabetic patients, and, perhaps most importantly, in a proportion of their healthy but "at risk" first degree relatives (FDRs). These findings suggest that B cell anergy can be lost in healthy individuals with similar environmental exposure and genotype as type 1 diabetics, and thus may be a predisposing or initiating event in T1D driven by these factors. We have further shown that insulin-reactive antigen receptors expressed by BND B cells are crossreactive with chromatin and lipopolysaccharide. Thus, in the context of disease development, BNDs may be activated by chromatin aggregates carrying co-stimulatory TLR ligands, rather than insulin. In this R21 application we propose to extend these findings in three aims. In Aim 1 we will determine whether escape of BNDs occurs only in FDRs carrying particular genetic alleles that confer risk of autoimmunity. Might certain risk alleles compromise B cell anergy? In Aim 2 we will analyze B cells derived from pancreatic islets of new-onset diabetic patients, determining whether they are activated and express high insulin affinity, polyreactive antigen receptors, consistent with BND origin. Could these cells be activated BNDs that have lodged in islets? In Aim 3 we will assess whether early escape of BND cells is peculiar to T1D, or also occurs in other autoimmune diseases, i.e. lupus or autoimmune thyroid disease. Is this a generalized event in autoimmunity?


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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John C Cambier其他文献

Src-family kinases in B-cell development and signaling
B 细胞发育和信号转导中的 Src 家族激酶
  • DOI:
    10.1038/sj.onc.1208075
  • 发表时间:
    2004-10-18
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Stephen B Gauld;John C Cambier
  • 通讯作者:
    John C Cambier

John C Cambier的其他文献

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{{ truncateString('John C Cambier', 18)}}的其他基金

Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
  • 批准号:
    9568080
  • 财政年份:
    2016
  • 资助金额:
    $ 23.33万
  • 项目类别:
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
  • 批准号:
    9121221
  • 财政年份:
    2016
  • 资助金额:
    $ 23.33万
  • 项目类别:
Insulin Specific T and B cells in Type 1 Diabetes
1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞
  • 批准号:
    9180031
  • 财政年份:
    2016
  • 资助金额:
    $ 23.33万
  • 项目类别:
Perturbation of B cell anergy in T1D
T1D 中 B 细胞无反应性的扰动
  • 批准号:
    9225164
  • 财政年份:
    2016
  • 资助金额:
    $ 23.33万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8372067
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    9104150
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8690052
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
  • 批准号:
    8282484
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
  • 批准号:
    8519291
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:
B Cells and Type 1 Diabetes
B 细胞和 1 型糖尿病
  • 批准号:
    8534115
  • 财政年份:
    2012
  • 资助金额:
    $ 23.33万
  • 项目类别:

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