Lysosome Defects and the Accumulation of Immune Complexes in Human Lupus

人类狼疮中溶酶体缺陷和免疫复合物的积累

基本信息

批准号：
9890988
负责人：
BARBARA J VILEN
金额：
$ 47.19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-03-11 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890988
关键词：
Antigen-Antibody Complex Apoptotic Attenuated Autoantibodies Autoantigens B-Cell Activation B-Lymphocytes Back Biological Bone Marrow Cell Death Cell Membrane Permeability Cell membrane Cell surface Cells Chronic Consequentialism Coupled Cross-Sectional Studies Cytosol Data Defect Dendritic Cells Disease Enrollment Event Exhibits FRAP1 gene Functional disorder Genes Hematopoietic Human Immunoglobulin G In Vitro Inbred MRL lpr Mice Individual Inflammatory Interferon-alpha Interferons Kidney Diseases Lead Longitudinal Studies Lupus Lysosomes Measures Modeling Molecular Mus Myeloid Cells Necrosis Nuclear Nuclear Antigens PIK3CG gene Pathology Patients Phagosomes Phosphotransferases Production Publishing Recurrent disease Recycling Relapse Research Serum Signal Transduction Surface Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Intervention Visit cell motility cell type crosslink cytokine human disease immune activation longitudinal analysis macrophage monocyte neutrophil peripheral blood phosphoinositide-3,4,5-triphosphate prevent receptor sensor targeted treatment therapy design

项目摘要

Although multiple genes, molecular events, and cell types are implicated in systemic lupus erythematosus (SLE), apoptotic debris and its formation into immune complexes (IgG-ICs) is thought to be important in onset and/or perpetuation of disease. Our published studies show that high levels of IgG-ICs accumulate on the surface of human and murine hematopoietic cells in SLE. On murine myeloid cells, this is a consequence of diminished lysosome acidification that prevents degradation of FcgR-bound IgG-ICs. Undegraded IgG-ICs recycle to the cell surface where they accumulate and promote chronic FcgR signaling. Accumulation of undegraded IgG-ICs in the phagosome induces phagosomal membrane permeability, which allows IgG and nuclear antigens to leak into the cytosol, subsequently activating cytosolic sensors and inducing IFNa production. Using FcgRI-deficient MRL/lpr mice we found reduced accumulation of nuclear self-antigen, reduced activation of signaling effectors, reduced autoantibody production (95%), reduced BAFF levels (90%), and FcgRI-/-/MRL/lpr mice do not develop renal disease. These findings implicate lysosome defects and dysregulated FcgRI signaling as important events in SLE that lie upstream of multiple pathologies. Preliminary data show that diminished lysosome acidification is induced by events at, or upstream of, PI3k/mTOR identifying a feedforward loop between chronic PI3k activation and diminished lysosome acidification. We show that SHIP1 is integral in lysosome dysfunction, and that crosslinking FcgRI with FcgRIIb (a SHIP1 coupled receptor) on murine macrophages restores lysosome acidification and diminishes PI3k signaling. Preliminary human studies of monocytes and B cells show that lysosome dysfunction is evident in active, but not inactive, SLE. We hypothesize that lysosome dysfunction and a feedforward loop involving FcgRI/RIIa activation underlie human SLE, with the level of lysosome degradation reflecting disease activity. Thus, we propose that defects in lysosome function lead to the accumulation of surface IgG-ICs, which triggers active disease. In aims 1 and 2, cross-sectional studies will assess whether the state of lysosome function reflects disease activity, and whether the mechanisms underlying lysosome defects in human SLE are similar to those in mice. In aim 3, a longitudinal study will analyze individual SLE patients through active and inactive disease to assess whether lysosome dysfunction increases and decreases as disease relapses and remits. If successful, this study will define whether lysosome defects underlie human SLE, and whether attenuating the feedforward loop restores lysosome function in cells from patients with active disease.

尽管多个基因，分子事件和细胞类型与全身性红斑狼疮（SLE）有关，但凋亡碎片及其在免疫复合物（IgG-ICS）中的形成在发作和/或疾病的延续。我们发表的研究表明，高水平的IgG-ICS积累在表面 SLE中的人和鼠造血细胞。在鼠髓样细胞上，这是减少的结果溶酶体酸化可防止FCGR结合的IgG-ICS降解。未基因的IgG-ICS回收到它们积聚并促进慢性FCGR信号传导的细胞表面。积累了未依据的IgG-ICS 在吞噬体中，诱导吞噬膜渗透性，这使IgG和核抗原泄漏进入细胞质，随后激活胞质传感器并诱导IFNA产生。使用FCGRI缺陷 MRL/LPR小鼠我们发现核自我抗原的积累减少，信号效应子的激活降低，自身抗体产生降低（95％），BAFF水平降低（90％）和FCGRI - / - /MRL/LPR小鼠不发展肾脏疾病。这些发现暗示溶酶体缺陷和失调的FCGRI信号作为重要事件在多种病理上游的SLE中。初步数据表明，溶酶体酸化减少是由PI3K/mTOR的事件或上游诱导的鉴定慢性PI3K激活与溶酶体酸化减少之间的前进环。我们显示该Ship1在溶酶体功能障碍中是不可或缺的，并且与FCGRIIB交联的FCGRI（Ship1耦合受体）在鼠巨噬细胞上恢复溶酶体酸化并减少PI3K信号传导。初步的人类对单核细胞和B细胞的研究表明，溶酶体功能障碍在活动中显而易见，但不是活性， sle。我们假设溶酶体功能障碍和涉及FCGRI/RIIA激活基础的前馈回路人SLE，溶酶体降解水平反映了疾病活性。因此，我们提出了在溶酶体功能导致表面IgG-IS的积累，这会触发活性疾病。在目标1和2中横断面研究将评估溶酶体功能的状态是否反映了疾病活动，以及是否反映人SLE中溶酶体缺陷的基础机制与小鼠相似。在AIM 3中，纵向研究将通过主动疾病和非活性疾病分析单个SLE患者，以评估是否溶酶体功能障碍随着疾病复发和汇率而增加和减少。如果成功，这项研究将定义是否溶酶体缺陷是人类SLE的基础，以及衰减前馈环还原溶酶体功能在患有活性疾病患者的细胞中。