PATHWAY TO PRODUCTION OF DISEASE-RELATED AUTOANTIBODY

该计划项目将测试三种拟议的机制，通过这些机制 天然免疫球蛋白M自身抗体的产生水平可转化为 产生更多与疾病相关的免疫球蛋白自身抗体。项目0001 将测试一种通过病毒感染激活多克隆B细胞的模型 之后是病毒和自身抗原的特异性免疫。 正常人产生CD43(去唾液酸糖蛋白)的IgM自身抗体。艾滋病病毒 感染导致多克隆B细胞激活，在15%-20%的受试者中， 形成CD43的选择性免疫球蛋白抗体。这些现象 似乎与发展自身抗体的步骤平行 系统性红斑狼疮形成。项目0002将测试独特型的提议 T细胞和B细胞的相互作用可以推动这种形成 与疾病相关的自身抗体。某些类型的人，比如人类 独特型ID16/6，复发于不同疾病相关的免疫球蛋白 患者，以及沉积在组织病变中的免疫球蛋白。的确有 实验证据表明，ID16/6具有致病潜力，T细胞 细胞在发病机制中起着重要作用。该项目将定义结构 抗体和T细胞识别ID16/6的要求和 检测ID16/6反应性T细胞克隆驱动免疫球蛋白的能力 自身抗体的形成。项目0003将测试B细胞 的自体免疫小鼠是天生不正常的，因为它们是沿着 CD5负性激活通路对刺激的反应 通过CD5阳性途径激活。CD5阳性途径是 与产生IgM天然自身抗体有关，而CD5- 负通路导致疾病相关自身抗体的形成。 阐明自身抗体的形成机制可为临床治疗提供依据 用于制定治疗措施。

This Program Project will test three proposed mechanisms by which the low level production of natural IgM autoantibodies may be converted into a larger production of disease associated IgG autoantibodies. Project 0001 will test a model in which polyclonal B cell activation by viral infection is followed by specific immunization by both viral and self antigens. Normal humans produce IgM autoantibodies to CD43 (asialoglycophorin). HIV infection leads to polyclonal B cell activation and, in 15-20% of subjects, to formation of selective IgG autoantibodies to CD43. These phenomena appear parallel to the steps proposed for development of autoantibody formation in SLE. Project 0002 will test the proposal that idiotype interactions involving T cells as well as B cells can drive the formation of disease-associated autoantibodies. Certain idiotypes, such as the human idiotype Id 16/6, recur on disease associated immunoglobulins in different patients, and on immunoglobulins deposited in tissue lesions. There is experimental evidence that Id 16/6 has pathogenic potential and that T cells play a role in pathogenesis. This project will define the structural requirements for recognition of Id 16/6 by both antibodies and T cells and test the ability of Id 16/6-responsive T cell clones to drive IgG autoantibody formation. Project 0003 will test the proposal that B cells of autoimmune mice are intrinsically abnormal, in that they develop along a CD5-negative activation pathway in response to stimuli that normally lead to activation through a CD5-positive pathway. The CD5-positive pathway is associated with production of IgM natural autoantibodies, whereas the CD5- negative pathway leads to formation of disease-associated autoantibodies. Elucidation of the mechanisms of autoantibody formation may provide a basis for development of therapeutic measures.