Characterization of anergic human B cells

无反应性人类 B 细胞的表征

• 批准号: 7282734
• 负责人: John C Cambier
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282734
• 关键词: Address; Adult; Affinity; Age; Antibodies; Antibody Specificity; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biology; Bone Marrow; Calcium; Cells; Characteristics; Childhood; Classification; Clonal Deletion; Condition; Frequencies; Human; Hybridomas; Immature Bone; Immune Tolerance; Immune response; Immunoglobulin Genes; Immunoglobulins; Individual; Lead; Measurement; Measures; Monitor; Mus; Mutate; Numbers; Peripheral; Physiological; Play; Population; Process; Production; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Sequence Analysis; Somatic Mutation; Sorting - Cell Movement; Specificity; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; Transgenic Mice; Work; anergy; autoreactive B cell; disease characteristic; driving force; prevent; receptor; research study; success; tool

DESCRIPTION (provided by applicant): It has been estimated that as many as 75% of newly produced B cells are autoreactive. Three complementary mechanisms prevent these autoreactive cells from causing autoimmunity; clonal deletion, receptor editing, and anergy. We have recently shown that up to 50% of immature B cells are destined to become anergic. Thus anergy may silence the majority of autoreactive B cells. Unlike clonal deletion and editing, which occur primarily in immature bone marrow B cells, anergy can occur in peripheral B cells and is reversible. Therefore, anergy may be particularly important physiologically for silencing autoreactive B cells generated in germinal centers by somatic mutation. Reversal or escape from anergy would allow such B cells to participate in autoimmunity. Until recently it has not been possible to study the frequency and/or biology of anergic cells in a physiologic (nontransgenic) setting. This has led to skepticism regarding the physiologic significance of anergy. We have recently defined a marker set that allows identification, isolation, and study of anergic B cells from a normal repertoire, and extension of our studies to humans. Using these tools we propose to address the hypothesis that anergic B cells arise by somatic mutation in germinal centers as well as from autoreactive germline specificities. We hypothesize that the high frequency production of autoreactive cells in humans dictates that a significant population of anergic B cells must exist in this species. We will address two specific questions. AIM 1: What are the origins of anergic B cells in wildtype mice? Proposed experiments will determine if there is a bias in the autoantibody specificities or affinities that are silenced by anergy in mice and quantitiate the frequency of cells bearing somatically mutated receptors in this population. AIM2: What markers define anergic B cells in humans? We will also determine the frequency of somatically mutated receptor in this population and the specificities and affinities of autoantibodies that lead to anergy in humans. Relevance: Autoantibodies are characteristic of many autoimmune diseases. Anergy is one mechanism by which B cells are prevented frombecoming effective antigen presenting cells and producing autoantibodies. This work will allow us to identify anergic cells in humans and further our understanding of the conditions which lead to B cell anergy.

描述（由申请人提供）：据估计，新产生的 B 细胞中有多达 75% 具有自身反应性。三种互补机制可防止这些自身反应细胞引起自身免疫；克隆删除、受体编辑和无反应性。我们最近发现，高达 50% 的未成熟 B 细胞注定会变得无活性。因此，无反应可能会使大多数自身反应性 B 细胞沉默。与主要发生在未成熟骨髓 B 细胞中的克隆删除和编辑不同，无反应性可能发生在外周 B 细胞中，并且是可逆的。因此，无反应性对于沉默生发中心通过体细胞突变产生的自身反应性 B 细胞在生理上可能特别重要。逆转或摆脱无反应状态将使此类 B 细胞参与自身免疫。直到最近，还不可能在生理（非转基因）环境中研究无能细胞的频率和/或生物学。这导致了对无反应性生理意义的怀疑。我们最近定义了一个标记集，可以从正常细胞库中识别、分离和研究无反应性 B 细胞，并将我们的研究扩展到人类。使用这些工具，我们建议解决以下假设：无反应性 B 细胞是由生发中心的体细胞突变以及自身反应性种系特异性产生的。我们假设人类自身反应细胞的高频率产生决定了该物种中必须存在大量无反应性 B 细胞。我们将解决两个具体问题。目标 1：野生型小鼠中无能 B 细胞的起源是什么？拟议的实验将确定小鼠中无反应性沉默的自身抗体特异性或亲和力是否存在偏差，并量化该群体中携带体细胞突变受体的细胞的频率。 AIM2：哪些标记物定义了人类无反应性 B 细胞？我们还将确定该人群中体细胞突变受体的频率以及导致人类无反应的自身抗体的特异性和亲和力。相关性：自身抗体是许多自身免疫性疾病的特征。无反应性是阻止 B 细胞成为有效抗原呈递细胞并产生自身抗体的一种机制。这项工作将使我们能够识别人体中的无反应细胞，并进一步了解导致 B 细胞无反应的条件。