The Role of Natural Human Anergic B cells in Systemic Lupus Erythematosus Patholo

天然人类无反应性 B 细胞在系统性红斑狼疮病理中的作用

• 批准号: 7684353
• 负责人: Patrick Christopher Wilson
• 金额: $ 18.8万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684353
• 关键词: Affect; Affinity; Age; Antibodies; Antibody Repertoire; Autoantibodies; Autoantigens; Autoimmune Responses; Autoimmunity; B-Cell Activation; B-Lymphocytes; Binding; Biological Markers; Cell physiology; Cells; Chicago; DNA; Data; Defect; Diagnosis; Disease; Flow Cytometry; Frequencies; Genes; Goals; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulin M; Immunoglobulins; Influenza vaccination; Lead; Light; Link; Lupus; Microarray Analysis; Molecular; Mus; Mutate; Pathology; Pathway interactions; Patients; Phenotype; Population; Receptors, Antigen, B-Cell; Recombinants; Recruitment Activity; Research; Role; Serum; Signal Transduction; Source; Specificity; Surface; Systemic Lupus Erythematosus; Testing; Thinking; Time; Tissues; Transcript; Translating; Tyrosine; Universities; Vaccination; anergy; antigen binding; autoreactive B cell; cohort; human monoclonal antibodies; improved; insight; novel; receptor; release of sequestered calcium ion into cytoplasm; research study; sex; treatment strategy

For the first time, we have characterized mature human B cells that have an anergic phenotype, providing a critical link to twenty years of research in mice. These IgM-Low naive B cells are predominantly autoreactive and they have a reduced capacity to flux calcium, phosphorylate tyrosines or survive after stimulation. Intense stimulation causes these cells to be activated, consistent with the long-standing view that anergic B cells may be a source of pathological autoantibodies in diseases such as systemic lupus erythematosus. The long term goal of the experiments proposed herein is to translate our new basic understanding of a central mechanism of immune tolerance in humans, anergy, into a new thinking that will lead to tangible treatments of lupus. We suspect there are defects in anergic B cells that may be typical in various lupus patients, each of which could substantially alter our understanding and treatment strategies of this disease. We hypothesize that anergy is not induced or maintained for autoreactive B cells in SLE patients, allowing these cells to become fully functional. Anergic B cells may be a pool of autoreactive B cells that produce pathological autoimmune responses. To test these hypotheses in Specific aim 1, we will use flow cytometry and molecular variable gene analysis to compare the frequency and phenotype of anergic B cells in a cohort of lupus patients with age and sex matched unaffected controls. In specific aim 2 we will determine if anergic B cells in lupus patients have altered function and the molecules involved, leading to full immune reactivity despite being autoreactive. In specific Aim 3 we will compare the specificities and affinities of a panel of recombinant human monoclonal antibodies from anergic B cells of lupus patients to antibodies from healthy controls. With this analysis we will identify natural autoantigens that may escape tolerance and cause pathology in SLE patients.

这是我们第一次鉴定了具有无反应性表型的成熟人B细胞，提供了 这是20年来小鼠研究的关键环节。这些IgM-低初始B细胞主要是自身反应性的 并且它们在刺激后流动钙、磷酸化酪氨酸或存活的能力降低。激烈 刺激导致这些细胞被激活，这与长期以来的观点一致，即无反应性B细胞可能 可能是系统性红斑狼疮等疾病中病理性自身抗体的来源。长期 本文提出的实验的目的是将我们对中枢机制的新的基本理解转化为 人类免疫耐受性，无反应性，转化为一种新的思维，这将导致狼疮的切实治疗。我们 我怀疑在各种狼疮患者中可能存在典型的无反应性B细胞缺陷，每种缺陷都可能 大大改变了我们对这种疾病的理解和治疗策略。我们假设无反应性是 SLE患者自身反应性B细胞未被诱导或维持，使这些细胞完全 不降低无反应性B细胞可能是自身反应性B细胞的集合，其产生病理性自身免疫 应答为了验证这些假设，我们将使用流式细胞术和分子可变基因， 分析比较了一组狼疮患者中无反应性B细胞的频率和表型， 性别匹配的未受影响的对照。在具体目标2中，我们将确定狼疮患者中的无反应性B细胞是否具有 改变的功能和相关分子，导致完全的免疫反应性，尽管是自身反应性的。在 特异性目的3我们将比较一组重组人单克隆抗体的特异性和亲和力， 来自狼疮患者的无反应性B细胞的抗体与来自健康对照的抗体。通过分析，我们将 鉴定可能逃避耐受并导致SLE患者病理学改变的天然自身抗原。