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.

狼疮中自动反应性GC和表位扩散的演变 全身性红斑狼疮（SLE）是一种无法治愈的自身免疫性疾病，代表了一个实质性的 人口中的健康问题。对SLE识别的患者和鼠模型的纵向研究 随着时间的推移，针对新表位的自身抗体发展与病理增加相关。这 现象被称为表位传播，即针对确定剂的自身抗体开发 除了开始自我抗原。虽然发作的基础机制尚不清楚，但我们 提议由单个B细胞克隆引发的赞助自动反应性GC以及T细胞帮助可以促进 幼稚的自我反应B细胞的多个不同的克隆进入可以正面选择并经历它们 亲和力成熟，竞争并分化为效应细胞，导致表位扩散。 为了更深入地表征赞助自动反应性GC的动态，我们开发了一个 新型混合骨髓嵌合模型，其中狼疮菌株的骨髓与骨髓混合 WT小鼠并转移到辐照受体中。在嵌合体的特征中，我们出乎意料地发现 自反应的WT B细胞接受克隆选择和亲和力成熟，导致一两个 克隆占主导地位的GC反应，就像外国抗原观察到的克隆一样。此外，我们确定了 表位由WT B细胞扩散（Degn 2017）。与预测的自我选择相反 在GC中的反应性克隆，我们发现了特异性抗体的产生强大的阳性选择 与原始核抗原不同的自我抗原。在当前的建议中，我们将进一步表征 这些事件使用辐射嵌合体和抛物线方法进行了赞助自动反应性GC。 此外，我们将确定T卵泡辅助细胞在促进发作扩散中的作用。三个目标是 建议的： 目标1。表征自动反应性生发中心的动力学，导致表位扩散。 AIM 2。在自反应性GC B细胞的表位扩散中表征TFH。 目标3。检验假设，即自反应性记忆B细胞通过GC循环并多样化。