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

• 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
• 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

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被认为是由之间的相互作用产生的。 潜在的遗传易感性和环境因素，不同的组合会导致相互影响 疾病表现和治疗反应的个体差异。 特定途径的研究尚未被证明有效，这表明目前对发病机制的理解 所提出的项目的目标是检验不成熟的生存的假设。 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状态 自身反应性 B 细胞（免疫活性与无能/耐受性）在过渡阶段 1 (T1) 期间决定 发育过程中需要 T1 B 细胞组成型表达干扰素 β (IFNβ)。 这种范式转变假设基于使用混合骨髓组合生成的数据 嵌合体、四聚体或独特型抗体选择的流式细胞术以及高通量单细胞分析 研究 SLE 患者和易患狼疮的 BXD2 小鼠 B 细胞中的 I 型干扰素 (IFN) 网络。 数据表明，目前已知的分子和细胞畸变之前有一个单一的主要畸变 致病事件，即 T1 B 细胞产生 IFNβ。数据表明，非常早期的 T1 细胞能够存活。 T1 B 细胞依赖于内源性 IFNβ 的表达。 这导致它们发育成产生 IFNα 的 T1 B 细胞 T1 B 细胞逃避阴性的能力。 B 细胞受体 (BCR) 介导的选择由该 T1 的 I 型 IFN 决定的反应性决定 BCR 介导的信号传导的子集与 TLR 信号传导（TLR7 或 TLR9）的刺激相结合 凋亡碎片优先允许核酸抗原自身反应性 B 细胞逃逸。 确定 T1 B 细胞区室包含不同的细胞子集，因为这些细胞子集包含 与成熟和无能抑制调节 (Breg) 细胞表型相似的转录谱 及其在 SLE 中占主导地位的免疫原性供体，我们的新数据表明这种表型转变 这些数据还表明，I 型干扰素的发育在成熟 B 细胞中被印记。 BXD2 小鼠中网络相关的 T1 B 细胞与 I 型 IFN 诱导转录因子 (IRF3 和 IRF7），而 Foxp3+ 调节性 T1 B 细胞的诱导与转录因子 ID3 相关。 值得注意的是，这些数据不仅表明抑制 T1-Breg 前体是一种新的致病性 SLE 中的框架，还提供了工具，即分选的移行 B 细胞中的基因表达特征， 我们将通过三个具体目标来测试我们总体假设的关键要素。 这将：（1）区分组成型 IFNβ 信号和微环境信号在 驱动T1 B细胞的发育；(2)确定初始T1 B细胞转录印记是否得以维持 在 T2/MZP-MZ-FO 发育阶段；以及 (3) 确定 T1 B 细胞内源性 IFNβ 是否促进某种类型 I IFN 网络可抑制 SLE 患者 T1 阶段调节性 B 细胞的前体细胞。 拟议工作的科学前提包括 T1 B 细胞转录谱之间的相似性 和成熟 B 细胞以及 I 型 IFN 相关与 Breg 相关转录谱的分离 我们已经获得了 IFNβ、IL-10、Foxp3 和 Id3 的报告小鼠品系，以进行谨慎的询问。 过渡性 T1 B 子集内或衍生自过渡性 T1 B 子集的发育阶段。 获得的信息将对该领域产生广泛的影响，并改善退伍军人事务部患者的护理 通过确定提高靶向生物疗法与非药物疗法疗效的策略来治疗 SLE 侵入性精准医学引导方法。

项目成果

The Dynamic Duo-Inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases.

风湿病中的动态双炎症 M1 巨噬细胞和 Th17 细胞。

• DOI: 10.13188/2334-2846.1000002
• 发表时间: 2013-11-01
• 期刊: Journal of orthopedics & rheumatology
• 作者: Li J;Hsu HC;Mountz JD
• 通讯作者: Mountz JD

Identification of follicular T helper cells in tissue sections.

组织切片中滤泡 T 辅助细胞的鉴定。

• 发表时间: 2015
• 作者: Ding, Yanna;Mountz, John D;Hsu, Hui
• 通讯作者: Hsu, Hui

Editorial: STATus of STAT3 in Psoriatic Arthritis.

社论：STAT3 在银屑病关节炎中的现状。

• 发表时间: 2018-06
• 作者: Mountz; John D
• 通讯作者: John D

Interrelation of T cell cytokines and autoantibodies in systemic lupus erythematosus: A cross-sectional study.

系统性红斑狼疮中 T 细胞细胞因子和自身抗体的相互关系：一项横断面研究。

• DOI: 10.1016/j.clim.2023.109239
• 发表时间: 2023-01-01
• 期刊: Clinical immunology
• 影响因子: 8.6
• 作者: Fatima Alduraibi;K. Sullivan;W. Chatham;H. Hsu;J. Mountz
• 通讯作者: J. Mountz

IL-23 Promotes a Coordinated B Cell Germinal Center Program for Class-Switch Recombination to IgG2b in BXD2 Mice.

IL-23 促进 BXD2 小鼠中协调的 B 细胞生发中心程序，实现类别转换重组为 IgG2b。

• 发表时间: 2020
• 作者: Hong, Huixian;Gao, Min;Wu, Qi;Yang, PingAr;Liu, Shanrun;Li, Hao;Burrows, Peter D;Cua, Daniel;Chen, Jake Y;Hsu, Hui;Mountz, John D
• 通讯作者: Mountz, John D