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IgM自身抗体的水平产生可以转化为 产生更多的疾病相关IgG自身抗体。 项目0001 将测试病毒感染多克隆B细胞激活的模型 随后通过病毒和自身抗原进行特异性免疫。 正常人产生抗CD 43（去唾液酸血型糖蛋白）的IgM自身抗体。 艾滋病毒 感染导致多克隆B细胞活化，在15-20%的受试者中， 形成针对CD 43的选择性IgG自身抗体。 这些现象 似乎与开发自身抗体的步骤平行 SLE的形成。 0002项目将测试独特型 涉及T细胞和B细胞的相互作用可以驱动 疾病相关的自身抗体 某些特殊类型的人，比如人类 独特型Id 16/6，在不同疾病相关免疫球蛋白上复发， 患者和沉积在组织病变中的免疫球蛋白。 有 实验证据表明，Id 16/6具有致病潜力，T 细胞在发病机制中起作用。 该项目将定义结构 通过抗体和T细胞识别Id 16/6的要求， 测试Id 16/6应答性T细胞克隆驱动IgG的能力 自身抗体形成。 项目0003将测试B细胞 的自身免疫小鼠本质上是异常的，因为它们沿着 一种CD 5阴性激活途径，对通常导致 通过CD 5阳性途径激活。 CD 5阳性通路是 与IgM天然自身抗体的产生相关，而CD 5- 负性途径导致疾病相关自身抗体的形成。 阐明自身抗体形成的机制可能提供基础 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.