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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells
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Endocytic sequestration of the B cell antigen receptor and toll-like receptor 9 in anergic cells

机译：B细胞抗原受体和toll样受体9在细胞内的内吞隔离

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摘要

In autoimmune prone murine strains, sequential engagement of the B cell antigen receptor (BCR) on the cell surface and toll-like receptors (TLRs) in late endosomes is necessary and sufficient for secretion of autoantibodies. However, ubiquitous nucleoprotein self-antigens fail to elicit productive TLR activation, and break self-tolerance in anergic DNA-reactive B cells. The mechanisms limiting TLR activation in these cells are largely unknown. Here, we demonstrate that in anergic 3H9/Vκ8 and Ars/A1 B cells the normal endocytic transit of both the ligated BCR and TLR9 into late endosomes is abrogated. The BCR and TLR9 arrest together just outside late endosomes, indicating that they enter this compartment along a single, regulated endocytic route. Access to late endosomes could be restored by reversing anergy through several methods, including conferring genetic susceptibility to autoimmu-nity, complementing proximal BCR signaling or by preventing BCR binding to self-antigen. Downstream of the BCR, JNK, which is activated in na?ve but not anergic B cells, regulated entry into late endosomes. Restoration of BCR and TLR9 endocytic trafficking rescued TLR9 activation by BCR-captured ligands. These results indicate that B cell anergy is reinforced by the exclusion of both TLRs and their BCR captured ligands from subcellular environments necessary for TLR activation.
机译：在易自身免疫的鼠毒株中，细胞内B细胞抗原受体（BCR）和晚期内体中的Toll样受体（TLR）的顺序结合对于分泌自身抗体是必要和充分的。但是，无处不在的核蛋白自身抗原无法引起生产性TLR激活，并破坏了无反应性DNA反应性B细胞的自我耐受性。限制这些细胞中TLR激活的机制尚不清楚。在这里，我们证明在无能的3H9 /Vκ8和Ars / A1 B细胞中，已连接的BCR和TLR9进入晚期内体的正常内吞转运被消除了。 BCR和TLR9刚好在晚期内体外面停滞，表明它们是通过一条受调节的内吞途径进入该区室的。晚期内体的获取可以通过几种方法逆转无反应性来恢复，包括赋予对自身免疫的遗传易感性，补充近端BCR信号传导或通过防止BCR与自身抗原结合。在幼稚但未激活B细胞中被激活的JNK在BCR的下游，调节进入晚期内体的过程。 BCR和TLR9内吞运输的恢复挽救了BCR捕获的配体对TLR9的激活。这些结果表明，从TLR激活所必需的亚细胞环境中排除了TLR及其BCR捕获的配体，从而增强了B细胞的无反应性。

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  • 作者

    Shannon K. ONeill; Margaret L. Veselits; Miao Zhang; Christine Labno; Yanxia Cao; Alison Finnegan; Melissa Uccellini; Maria-Luisa Alegre; John C. Cambier; Marcus R. Clark;

  • 作者单位

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637 Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206;

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637;

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637;

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637;

    Department of Immunology and Microbiology and Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL 60612;

    Department of Immunology and Microbiology and Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Chicago, IL 60612;

    Department of Microbiology, Boston University School of Medicine, Boston, MA 02118;

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637;

    Integrated Department of Immunology, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206;

    Department of Medicine, Section of Rheumatology, and The Knapp Center for Lupus Research, University of Chicago, Chicago, IL 60637;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    endocytic trafficking; anergy;

    机译：内吞运输;无能;

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