B Cell Tolerance in Lupus

狼疮中的 B 细胞耐受性

• 批准号: 8822634
• 负责人: DWIGHT H KONO
• 金额: $ 23.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822634
• 关键词: Address; Affect; Affinity; Amplifiers; Animal Model; Antibodies; Antigen Receptors; Antigen-Antibody Complex; Antigens; Antinuclear Antibodies; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmune Responses; Autoimmunity; B cell repertoire; B-Cell Development; B-Lymphocytes; Binding; Cells; Characteristics; Collaborations; DNA; DNA Binding; Data; Development; Disease; Event; Generations; Genes; Health; Immune; Immunoglobulin Class Switching; Immunoglobulin Somatic Hypermutation; Injury; Laboratories; Lupus; Mature B-Lymphocyte; Mediating; Modeling; Mus; Nuclear Antigens; Nucleic Acids; Participant; Pathogenesis; Play; Process; Production; Reaction; Receptors, Antigen, B-Cell; Regulation; Research Personnel; Role; SLEB1 gene; Specificity; Staging; Structure of germinal center of lymph node; Surface; System; Systemic Lupus Erythematosus; Testing; Tissues; Toll-like receptors; Transgenic Model; Transgenic Organisms; antigen binding; autoreactivity; central tolerance; chronic graft versus host disease; disorder control; insight; novel; novel strategies; receptor

DESCRIPTION (provided by applicant): There is abundant evidence that autoantibodies (autoAbs) are generated through somatic hypermutation (SHM) and that tolerance of B cells that acquire self-reactivity through this process is impaired in systemic lupus erythematosus (SLE). Although recent studies have provided considerable insights into the participants and cellular dynamics in germinal center (GC) reactions where SHM takes place, there has been little progress in understanding the mechanisms for maintaining tolerance of newly generated self-reactive B cells, largely because of the absence of an appropriate model. We, in collaboration with other investigators, have recently used a novel ¿2a-macroself antigen (Ag) transgenic (Tg) system to show that Fas-deficient mice are defective in censoring B cells that have acquired autoreactivity to a surface-bound Ag. This model, however, utilizes an artificial Ag with characteristics that differ substantially from the purported autoAgs in SLE. To address these limitations, we have developed a new B cell receptor Tg model, called FLEx-autoAb, that will allow conditional replacement of an innocuous antigen-receptor with a DNA-binding receptor in B cells and seek to use this model to investigate post-SHM tolerance mechanisms in normal and autoimmune mice. To accomplish this, two aims are proposed. Specific aim 1 will use the FLEx-autoAb system to study tolerance of B cells that become autoreactive in the periphery in autoimmune B6-Faslpr mice specifically focusing on tolerance of germinal center B cells. Specific aim 2 will use this new system to study tolerance of B cells in the periphery in four models of systemic autoimmunity. This project has the potential for discovering new regulatory mechanisms, relevant to SLE and likely other autoAb-mediated-diseases, that control B cells that acquire autoreactivity in the periphery.

描述（由申请方提供）：有大量证据表明，自身抗体（autoAb）是通过体细胞超突变（SHM）产生的，并且系统性红斑狼疮（SLE）中通过该过程获得自身反应性的B细胞的耐受性受损。虽然最近的研究已经提供了相当多的见解，参与者和细胞动力学的生发中心（GC）的反应，SHM发生，有很少的进展，在了解机制，维持新产生的自我反应性B细胞的耐受性，主要是因为缺乏一个适当的模型。我们与其他研究人员合作，最近使用了一种新的<$2a-巨自身抗原（Ag）转基因（Tg）系统，以表明Fas缺陷小鼠在审查已获得对表面结合Ag的自身反应性的B细胞方面存在缺陷。然而，该模型利用了具有与SLE中声称的autoAg显著不同的特征的人工Ag。为了解决这些局限性，我们开发了一种新的B细胞受体Tg模型，称为FLEx-autoAb，它允许在B细胞中用DNA结合受体有条件地替换无害的抗原受体，并试图使用该模型来研究正常和自身免疫小鼠中的SHM后耐受机制。为实现这一目标，提出了两个目标。具体目标1将使用FLEx-autoAb系统来研究自身免疫B6-Faslpr小鼠中在外周中变成自身反应性的B细胞的耐受性，特别关注生发中心B细胞的耐受性。具体目标2将使用该新系统研究四种系统性自身免疫模型中外周B细胞的耐受性。该项目有可能发现新的调控机制，与SLE和可能的其他autoAb介导的疾病，控制B细胞获得自身反应性的外周。