Evolution of autoreactive GC and epitope spreading in lupus

狼疮自身反应性GC和表位扩散的演变

• 批准号: 10399632
• 负责人: Michael Craig Carroll
• 金额: $ 46.17万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-13 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399632
• 关键词: Address; Affinity; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Back; Bone Marrow; Cell Cycle; Cells; Chimera organism; Chronic Disease; Clone Cells; Complement 3d Receptors; Development; Disease; Effector Cell; Environment; Epitope spreading; Epitopes; Event; Evolution; Follicular Dendritic Cells; Generations; Growth; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Immunoglobulin G; Implant; Individual; Interferon-alpha; Interleukin-4; Ligands; Longitudinal Studies; Lupus; Marrow; Mediating; Memory; Memory B-Lymphocyte; Modeling; Mus; Nuclear; Parabiosis; Pathogenesis; Pathogenicity; Pathology; Patients; Peptides; Play; Population; Radiation Chimera; Reporter; Role; Signal Transduction; Structure; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Technology; Testing; Time; autoreactive B cell; autoreactivity; mouse model; novel; response

EVOLUTION OF AUTOREACTIVE GC AND EPITOPE SPREADING IN LUPUS Systemic lupus erythematosus (SLE) is an incurable autoimmune disease and represents a substantial health problem in the population. Longitudinal studies of patients and murine models of SLE identify development of autoantibodies against new epitopes over time that correlate with increased pathology. The phenomena is referred to as epitope spreading, i.e. development of autoantibodies against determinants other than the initiating self-antigen. While the mechanism underlying epitope spreading remains unclear, we propose that spontaneous autoreactive GC initiated by a single B cell clone along with T cell help can promote entry of multiple distinct clones of naïve self-reactive B cells where they can be positively selected and undergo affinity maturation, compete and differentiate into effector cells leading to epitope spreading. In order to characterize the dynamics of spontaneous autoreactive GC in more depth, we developed a novel mixed bone marrow chimeric model in which bone marrow from a lupus strain is mixed with marrow from WT mice and transferred into irradiated recipients. In characterization of the chimeras, we found, unexpectedly, that the self-reactive WT B cells underwent clonal selection and affinity maturation resulting in one or two clones dominating the GC response much like that observed for foreign antigen. Furthermore, we identified epitope spreading by the WT B cells (Degn 2017). Thus, in contrast to the predicted negative selection of self- reactive clones in GC, we found robust positive selection with the generation of pathogenic antibodies specific for self-antigens distinct from the original nucleolar antigen. In the current proposal, we will characterize further the events initiating spontaneous autoreactive GC using both radiation chimeras and a parabiosis approach. Further, we will determine the role of T follicular helper cells in promoting epitope spreading. Three aims are proposed: Aim 1. Characterize the dynamics of autoreactive germinal centers leading to epitope spreading. Aim 2. Characterize Tfh in epitope spreading of self-reactive GC B cells. Aim 3. Test hypothesis that self-reactive memory B cells cycle through GCs and diversify.

自身反应性GC的演变与狼疮表位扩展 系统性红斑狼疮（SLE）是一种无法治愈的自身免疫性疾病， 人口的健康问题。SLE患者和小鼠模型的纵向研究 随着时间的推移，针对新表位的自身抗体的发展与病理学的增加相关。的 这种现象被称为表位扩散，即针对决定簇的自身抗体的发展 除了初始自身抗原。虽然表位扩散的机制尚不清楚，但我们 提出由单个B细胞克隆沿着T细胞帮助启动的自发性自身反应性GC可以促进 多个不同的幼稚自身反应性B细胞克隆的进入，其中它们可以被阳性选择并经历 亲和力成熟、竞争并分化成效应细胞，导致表位扩散。 为了更深入地表征自发自反应GC的动力学，我们开发了一种 一种新的混合骨髓嵌合模型，其中来自狼疮株的骨髓与来自 WT小鼠，并转移到辐射受体。在嵌合体的特征分析中，我们意外地发现， 自身反应性WT B细胞经过克隆选择和亲和力成熟，导致一个或两个 控制GC反应的克隆非常类似于对外源抗原观察到的。此外，我们发现 WT B细胞的表位扩散（Degn 2017）。因此，与预测的自我否定选择相反， 在GC中的反应性克隆，我们发现了强大的阳性选择与致病性抗体的产生特异性 用于与原始核仁抗原不同的自身抗原。在目前的提案中，我们将进一步描述 使用放射嵌合体和联体方法引发自发性自身反应性GC的事件。 此外，我们将确定T滤泡辅助细胞在促进表位扩散中的作用。三个目标是 提议的： 目标1。表征导致表位扩散的自身反应性生发中心的动力学。 目标二。表征Tfh在自身反应性GC B细胞的表位扩展中的特性。 目标3.自我反应记忆B细胞通过GC循环并多样化。