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.

狼疮患者自身反应性gc的进化与表位扩散