BCAP regulation of TLR7/9 signaling in Lupus

BCAP 对狼疮中 TLR7/9 信号传导的调节

基本信息

项目摘要

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the nucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling. pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9 signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE and in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter for PI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that in macrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. We recently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine how BCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is a key regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease in proliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP- deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an important role of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given the importance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is that BCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease. Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production in pDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine the relative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.
项目总结

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jessica A Hamerman其他文献

The path ahead for understanding Toll-like receptor-driven systemic autoimmunity
理解 Toll 样受体驱动的全身性自身免疫的未来之路
  • DOI:
    10.1016/j.coi.2024.102482
  • 发表时间:
    2024-12-01
  • 期刊:
  • 影响因子:
    5.800
  • 作者:
    Jessica A Hamerman;Gregory M Barton
  • 通讯作者:
    Gregory M Barton

Jessica A Hamerman的其他文献

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{{ truncateString('Jessica A Hamerman', 18)}}的其他基金

Identifying autoimmune associated genes in patrolling monocytes that promote lupus nephritis
识别巡逻单核细胞中促进狼疮肾炎的自身免疫相关基因
  • 批准号:
    10726991
  • 财政年份:
    2023
  • 资助金额:
    $ 35.48万
  • 项目类别:
IgA-containing immune complexes in plasmacytoid dendritic cell activation in SLE
含 IgA 的免疫复合物在 SLE 浆细胞样树突细胞激活中的作用
  • 批准号:
    10170270
  • 财政年份:
    2020
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP regulation of TLR7/9 signaling in Lupus
BCAP 对狼疮中 TLR7/9 信号传导的调节
  • 批准号:
    10531202
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP regulation of TLR7/9 signaling in Lupus
BCAP 对狼疮中 TLR7/9 信号传导的调节
  • 批准号:
    10306342
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP regulation of TLR7/9 signaling in Lupus
BCAP 对狼疮中 TLR7/9 信号传导的调节
  • 批准号:
    9917228
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP regulation of TLR7/9 signaling in Lupus
BCAP 对狼疮中 TLR7/9 信号传导的调节
  • 批准号:
    10062474
  • 财政年份:
    2019
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP regulation of pDC IFNa production in lupus
BCAP 对狼疮 pDC IFNa 产生的调节
  • 批准号:
    9245545
  • 财政年份:
    2017
  • 资助金额:
    $ 35.48万
  • 项目类别:
Function of the TREM2 R47H variant associated with risk of Alzheimer's disease
TREM2 R47H 变异的功能与阿尔茨海默病风险相关
  • 批准号:
    8824172
  • 财政年份:
    2015
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP/PI3K regulation of innate immunity to Listeria monocytogenes
BCAP/PI3K 对单核细胞增生李斯特氏菌先天免疫的调节
  • 批准号:
    9124703
  • 财政年份:
    2015
  • 资助金额:
    $ 35.48万
  • 项目类别:
BCAP/PI3K regulation of innate immunity to Listeria monocytogenes
BCAP/PI3K 对单核细胞增生李斯特氏菌先天免疫的调节
  • 批准号:
    9214306
  • 财政年份:
    2015
  • 资助金额:
    $ 35.48万
  • 项目类别:

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