Modulation of B-cell tolerance by coreceptor molecules

共受体分子调节 B 细胞耐受性

• 批准号: 6879051
• 负责人: ROBERT C RICKERT
• 金额: $ 23.88万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879051
• 关键词: B cell receptor; B lymphocyte; CD antigens; CD19 molecule; arthritis; autoantigens; autoimmune disorder; biological signal transduction; complement; complement receptor; disease /disorder etiology; enzyme linked immunosorbent assay; genetically modified animals; immune complex; immune tolerance /unresponsiveness; immunocytochemistry; immunoregulation; laboratory mouse; leukocyte activation /transformation; protein protein interaction; receptor binding; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (provided by applicant): Induction of autoimmunity by infection and inflammation has been suggested in connection with a number of diseases and has been supported by demonstrations of cross-reactivity of certain self- and microbial antigens. It is noteworthy that B-lymphocytes are critical antigen presenting cells in the development of diabetes, arthritis and lupus in model systems. In this application, we seek to establish complement C3d generation as a predisposing factor for B cell-dependent autoimmune disease. Notably, C3d is deposited in the kidney and excreted in the urine during the advanced symptoms of renal disease. In this application, we will test the hypothesis that C3d is not only correlative, but can be causative of arthritis or a lupus-like disease when bound to the inducing self-antigen. This hypothesis will be examined in the type II collagen (CII)- and the glucose-6-phosphate isomerase (GPI)-induced models of arthritis by coupling C3d to CII or GPI and determining the potential of these C3d-bound self-antigens to induce disease. A similar approach will be used to form immunoconjugates of the Sm ribonucleoprotein and C3d to create a model of systemic lupus erythematosus (SLE). C3d-bound antigens promote B cell activation by binding the B cell receptor and CD21, which signals via CD19. CD19 has also been implicated as a target for negative regulation by Fc-gammaRIIB when co-engaged by immune complexes. To understand how CD21 binding may lead to a breach in B cell tolerance, experiments are proposed to address the role of CD21 in central tolerance of newly formed B cells. Moreover, we will investigate the issue of signal integration by the co-receptors as applied to the physiologic context of immune complexes and C3d-bound antigen co-engaging CD19/CD21/CD32 and the BCR. Completion of this R21 will lay the foundation for future studies defining the molecular basis of C3d/CD21 adjuvant potential in autoimmune disease, with the prospect of designing reagents to block CD21 function in some contexts to ameliorate disease.

描述（由申请人提供）：已经提出了与多种疾病有关的感染和炎症诱导自身免疫性，并得到了某些自我和微生物抗原的交叉反应性的支持。值得注意的是，B淋巴细胞是模型系统中糖尿病，关节炎和狼疮的发育中的关键抗原细胞。在此应用中，我们试图建立补体C3D生成作为B细胞依赖性自身免疫性疾病的诱发因素。值得注意的是，在肾脏疾病的晚期症状期间，C3D沉积在肾脏中，并排泄在尿液中。在此应用中，我们将检验以下假设：C3D不仅相关，而且在与诱导的自我抗原结合时可能是关节炎或类似狼疮的疾病。该假设将在II型胶原蛋白（CII）和葡萄糖-6-磷酸异构酶（GPI）引起的关节炎模型中通过将C3D耦合到CII或GPI，并确定这些C3D结合的自我抗原的潜力，并确定这些假设。诱导疾病。类似的方法将用于形成SM核糖核蛋白和C3D的免疫缀合物，以创建一个系统性红斑狼疮模型（SLE）。 C3D结合的抗原通过结合B细胞受体和CD21促进B细胞的活化，该抗原通过CD19发出信号。当通过免疫复合物共同参与时，CD19也被认为是FC-GammariiB负调控的靶标。为了了解CD21结合如何导致B细胞耐受性违反，提出了实验来解决CD21在新形成的B细胞中心耐受性中的作用。此外，我们将研究由共受体的信号积分问题，这些问题应用于免疫复合物的生理环境，以及C3D结合的抗原共同参与CD19/CD21/CD32和BCR。该R21的完成将为未来的研究奠定基础，该研究定义了自身免疫性疾病中C3D/CD21辅助潜力的分子基础，并具有设计试剂以阻止CD21在某些情况下起作用以改善疾病的前景。