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: 10736511
• 负责人: Michael Craig Carroll
• 金额: $ 48.29万
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736511
• 关键词: Adoptive Transfer; Affinity; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; B-Lymphocytes; CD11 Antigens; CXCR3 gene; Cell surface; Cells; Chimera organism; Clone Cells; Complement 3d Receptors; Complement Receptor; Development; Disease; Effector Cell; Environment; Epitope spreading; Epitopes; Event; Evolution; Genetic; Health; ITGAX gene; Immunoglobulin-Secreting Cells; Kinetics; Longitudinal Studies; Lupus; Lymphoid; Malpighian corpuscles; Mediating; Modeling; Mus; Nuclear Antigens; Pathogenesis; Pathology; Patients; Peptides; Phenotype; Population; Regulation; Reporting; Role; Site; Specificity; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Time; autoreactive B cell; autoreactivity; humoral immunity deficiency; migration; mouse model; mutant; novel; pathogenic autoantibodies; response; transcriptomics

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 activation of a single B cell clone along with T cell help can promote activation and expansion of multiple distinct clones of nai"ve self-reactive B cells in both GC-dependent and -independent sites 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 self-reactive B cells arising in GC-dependent and -independent sites in more depth, we developed a novel adoptive transfer model. In this mouse model, donor B cells from WT or genetic mutants are transferred into lupus mice bearing a single BCR specific for nuclear antigen. We found that the self-reactive WT B cells underwent clonal selection and affinity maturation resulting in single WT clones dominating the GC response much like that observed in our previously reported mixed BM chimeras using the same lupus strain. Remarkably, the donor B cells rapidly expanded over 7 divisions in a GC-independent response that was Tlr 7 and MHC II dependent resulting in selection of a novel subset of effector B cells with a DN2-like phenotype observed in lupus patients (CD11c+CD21 lo). Unexpectedly, donor B cells deficient in CD11c failed to compete with WT donor cells and develop into effector B cells. In the current proposal, we will characterize further the events initiating spontaneous escape of B and T cell tolerance in GC-dependent and -independent responses resulting in epitope spreading. Moreover, we will characterize single TCR that provide functional help in co-stimulation of self-reactive B cells and their antigen specificity. Finally, we will track migration of activated donor cells in the splenic white pulp that give rise to self-reactive effector B cells using a novel spacial transcriptomics approach referred to as MERFISH. Two broad aims are proposed: Aim 1. Characterize the developmental kinetics and functional dynamics of self-reactive extra follicular ASCs. Aim 2. Characterize the role of Tfh cells in epitope spreading of GC-dependent and -independent self-reactive B cells.

系统性红斑狼疮（SLE）是一种无法治愈的自身免疫性疾病，在人群中代表了一个实质性的健康问题。对SLE患者和小鼠模型的纵向研究发现，随着时间的推移，针对新表位的自身抗体的发展与病理增加有关。这种现象被称为表位扩散，即针对除初始自身抗原以外的决定因子的自身抗体的发展。虽然表位扩散的机制尚不清楚，但我们提出，单个B细胞克隆在T细胞的帮助下自发激活可以促进gc依赖和非依赖位点的多个不同的nai“ve自反应性B细胞克隆的激活和扩增，在这些克隆中，它们可以被积极选择并经历亲和成熟、竞争和分化为效应细胞，从而导致表位扩散。