权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Interferon Beta Initiated Development of Immunogenic T1 B cells in Lupus

干扰素 Beta 启动狼疮中免疫原性 T1 B 细胞的发育

基本信息

批准号：
10477180
负责人：
John D Mountz
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477180
关键词：
Antibodies Antigens Apoptotic Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Automobile Driving B-Cell Antigen Receptor B-Lymphocyte Subsets B-Lymphocytes Biological Response Modifier Therapy Bone Marrow Caring Cell Compartmentation Cell Maturation Cell Separation Cell Survival Cells Chimera organism Chronic Clinical Cluster Analysis Data Defect Development Disease Elements Environmental Risk Factor Event Exhibits FOXP3 gene Flow Cytometry Funding Gene Expression Gene Expression Profile Gene Expression Profiling Generations Genetic Predisposition to Disease Genetic Transcription Goals Grant IFNAR1 gene IRF3 gene Immunocompetent Immunoglobulin Idiotypes In Vitro Interferon Receptor Interferon Type I Interferon-alpha Interferon-beta Interferons Interleukin-10 Lupus Maintenance Mature B-Lymphocyte Mediating Modeling Molecular Mouse Strains Mus Nuclear Nucleic Acids Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Play Population Process Production Reporter Resolution Role Signal Transduction Specificity Systemic Lupus Erythematosus T-Lymphocyte TLR7 gene Techniques Testing Therapeutic Transitional Cell Up-Regulation Work autocrine autoreactive B cell autoreactivity base cytokine design experimental study immunogenic imprint improved in vivo insight inter-individual variation migration mouse model novel precision medicine receptor-mediated signaling response single cell analysis therapeutic target tool transcription factor

项目摘要

Systemic lupus erythematosus (SLE) is a chronic debilitating disease that is characterized by high titers of autoantibodies with specificity for nuclear autoantigens. It is considered to arise from interactions between underlying genetic susceptibility and environmental factors, with different combinations resulting in inter- individual variations in disease manifestations and therapeutic responsiveness. Directed therapeutic targeting of specific pathways has not proven effective, which suggests that the current understanding of pathogenesis is incomplete. The goal of the proposed project is to test the hypothesis that the survival of immature autoreactive B cells, the preferential development of antinuclear autoreactive B cells and the status of mature autoreactive B cells (immunocompetent vs. anergic/tolerogenic) is decided during the transitional stage 1 (T1) of development and requires constitutive T1 B cell expression of interferon β (IFNβ). This paradigm shifting hypothesis is based on data generated using a combination of mixed-bone marrow chimeras, flow cytometry with tetramer or idiotype antibody selection, and high-throughput single-cell analysis to interrogate type I interferon (IFN) networks in B cell from patients with SLE and lupus-prone BXD2 mice. The data suggest that the currently known molecular and cellular aberrations are preceded by a single primary pathogenic event, i.e., production of IFNβ by T1 B cells. The data suggest that the survival of the very early T1 cells is dependent on endogenous expression of IFNβ. This subset of T1 B cells express endogenous IFNβ, which leads to their development into T1 B cells that produce IFNα. The ability of T1 B cells to escape negative B-cell receptor (BCR)-mediated selection is dictated by the type I IFN-determined responsiveness of this T1 subset to BCR-mediated signaling in combination with stimulation of TLR signaling (TLR7 or TLR9) by apoptotic debris. This preferentially permits escape of nucleic antigen-autoreactive B cells. We have further identified that the T1 B cell compartment contains distinct subsets of cells. As these included subsets with transcriptional profiles that parallel the phenotypes of mature and anergic suppressive regulatory (Breg) cells and their immunogenic counterparts that predominate in SLE, our new data suggest that this phenotypic switch in the mature B cells is imprinted during the T1 stage. These data also suggest that development of type I IFN network associated T1 B cells in BXD2 mice is associated with type I IFN-inducing transcription factors (IRF3 and IRF7) whereas induction of the Foxp3+ regulatory T1 B cells is associated with transcription factor, ID3. Notably, these data not only suggest suppression of precursors of T1-Breg is a novel pathogenic framework in SLE but also provide the tool, i.e., the gene expression signatures in sorted transitional B cells, that enable its analysis. We will test the critical elements of our overall hypothesis through three Specific Aims that will: (1) Distinguish the roles of the constitutive IFNβ signaling and the microenvironmental signals in driving the development of T1 B cells; (2) Identify if the initial T1 B cell transcriptional imprinting is maintained at the T2/MZP-MZ-FO stage of development; and (3) Determine if T1 B-cell endogenous IFNβ promotes a type I IFN network that suppresses the precursors of regulatory B cells at the T1 stage in SLE patients. The scientific premises of the proposed work include the parallels between transcriptional profiles in the T1 B cells and mature B cells and the segregation of type I IFN associated vs Breg associated transcriptional profiles in the T1 B cells. We have acquired reporter mouse strains for IFNβ, IL-10, Foxp3 and Id3 to interrogate discreet developmental stages within and derived from transitional T1 B subsets. The information gained will have a broad-based impact on the field and improve the care of VA patients with SLE by identifying strategies to improve the efficacy of targeted biologic therapies together with non- invasive precision medicine guided-approaches.

系统性红斑狼疮（SLE）是一种慢性衰弱性疾病，其特征是高滴度的对核自身抗原具有特异性的自身抗体。它被认为是由以下因素之间的相互作用引起的：潜在的遗传易感性和环境因素，不同的组合会导致疾病表现和治疗反应的个体差异。定向治疗靶向尚未证明有效，这表明目前对发病机制的理解不完整该项目的目标是检验不成熟的生存假设，自身反应性B细胞、抗核自身反应性B细胞的优先发育和成熟的自身反应性B细胞（免疫活性与无反应性/耐受性）在过渡期1（T1）决定的发展，并需要组成型T1 B细胞表达干扰素β（IFNβ）。这一范式转变假说是基于使用混合骨髓组合产生的数据，嵌合体、流式细胞术与四聚体或独特型抗体选择以及高通量单细胞分析探讨SLE患者和狼疮易感BXD 2小鼠B细胞中I型干扰素（IFN）网络。的数据表明，目前已知的分子和细胞畸变之前，致病事件，即，T1 B细胞产生IFNβ。这些数据表明，非常早期的T1 细胞依赖于IFNβ的内源性表达。该T1 B细胞亚群表达内源性IFNβ，这导致它们发育成产生IFNα的T1 B细胞。T1 B细胞逃避阴性反应的能力 B细胞受体（BCR）介导的选择是由I型IFN-决定的反应，这种T1 BCR介导的信号传导的子集与TLR信号传导（TLR 7或TLR 9）的刺激的组合，凋亡碎片。这优先允许核酸抗原自身反应性B细胞逃逸。我们进一步鉴定了T1 B细胞区室包含不同的细胞亚群。因为这些包括子集，与成熟和无反应性抑制性调节（布雷格）细胞的表型平行的转录谱以及它们在SLE中占主导地位的免疫原性对应物，我们的新数据表明，这种表型转换成熟B细胞中的DNA在T1阶段被印记。这些数据还表明，I型干扰素的发展 BXD 2小鼠中的网络相关T1 B细胞与I型IFN诱导转录因子（IRF 3）相关和IRF 7），而Foxp 3+调节性T1 B细胞的诱导与转录因子ID 3相关。值得注意的是，这些数据不仅表明T1-布雷格前体的抑制是一种新的致病性疾病，框架，但也提供了工具，即，分选的过渡性B细胞中的基因表达特征，使其能够进行分析。我们将通过三个具体目标来检验我们总体假设的关键要素这将：（1）区分组成性IFNβ信号和微环境信号在IFN β诱导的细胞凋亡中的作用。驱动T1 B细胞的发育;（2）鉴定初始T1 B细胞转录印记是否维持在发育的T2/MZP-MZ-FO阶段;和（3）确定T1 B细胞内源性IFNβ是否促进一种类型的IFN β，在SLE患者T1期抑制调节性B细胞前体的I IFN网络。的这项工作的科学前提包括T1 B细胞中转录谱的相似性和成熟B细胞中I型IFN相关与布雷格相关转录谱的分离。 T1 B细胞。我们已经获得了IFNβ、IL-10、Foxp 3和Id 3的报告小鼠品系，以询问谨慎的过渡T1 B亚群内的和衍生自过渡T1 B亚群的发育阶段。所获得的信息将对该领域产生广泛的影响，并改善VA患者的护理通过确定改善靶向生物治疗与非靶向生物治疗的疗效的策略，侵入性精确医学引导方法。