Inciting immunogens in ANCA glomerulonephritis: A role for complementary proteins

这个项目的基础是现在发表在《自然医学》上的一系列工作。我们为自身免疫的发展开发了一个完善的理论，即自身抗原互补性理论。其成分表明，自身免疫不是由自身抗原引起的，而是由与自身抗原互补的蛋白质表面结构引起的，即，与来自自身抗原基因的翻译反义RNA的氨基酸序列同源或相同的蛋白质。互补蛋白刺激产生抗体（Ab 1），引发抗抗体或抗独特型反应（Ab 2）。抗独特型抗体（Ab 2或自身抗体）现在识别并与自身抗原反应。我们有强有力的证据表明一种蛋白质 与PR 3互补的自身抗体引起PR 3-ANCA肾小球肾炎，并且自身抗体（ANCA）作为独特型网络的结果产生。我们在第二个资助期的总体目标是继续研究工作，为这一新开发的理论提供支持和扩展。在具体目标1中，我们提出确定是否存在可以激发导致致病性ANCA产生的级联反应的互补蛋白的限制性区域。当我们鉴定与不同表位反应的抗体时，我们将确定与互补蛋白反应的抗体之间的独特型关系 和ANCA。在这种情况下，我们计划随着时间的推移跟踪患者，以确定抗补体抗体库是否随疾病活动而变化，并评估这如何影响ANCA特异性。最后，我们将确定来自ANCA患者的T细胞是否对互补蛋白产生反应。在具体目标2中，我们提出分离和鉴定互补蛋白质的来源，其作为激发免疫原起作用。一个潜在的来源是入侵的微生物，第二个是个体通过翻译反义RNA自己产生它。在具体目标3中，我们提出通过探索自身抗原互补性在抗GBM疾病中的组成部分来确定自身抗原互补性理论的一般性质。

The foundation for this Project is a body of work now published in Nature Medicine. We developed a refined theory for the development of autoimmunity, the theory of autoantigen complementarity. Its components indicate that autoimmunity is not incited by the autoantigen but by a protein complementary surface structure to the autoantigen, i.e., a protein homologous to or identical to the amino acid sequence of the translated antisense RNA from the autoantigen gene. The complementary protein incites the production of antibodies (Ab1), which elicit an anti-antibody or anti-idiotypic response (Ab2). The anti-idiotypic antibody (Ab2 or autoantibody) now recognizes and reacts with the autoantigen. We have strong evidence that a protein complementary to PR3 incites PR3-ANCA glomerulonephritis and that the autoantibodies (ANCA) are produced as a consequence of the idiotypic network. Our overall objective through this second funding period is to continue research efforts to provide support for and extend this newly developed theory. In specific aim 1, we propose to determine if there are restricted regions of the complementary-proteins that can incite the cascade leading to the production of pathogenic ANCA. As we identify antibodies reactive with varying epitopes, we will determine idiotypic relationships between antibodies reactive with compementary-proteins and ANCA. In this context, we plan to follow patients over time to ascertain whether the anticomplementary-antibody repertoire varies with disease activity and assess how this affects ANCA specificity. Lastly, we will determine if T-cells from ANCA patients respond to the complementary proteins. In specific aim 2, we propose to isolate and identify the source of the complementary proteins, which function as inciting immunogens. One potential source is an invading microbe, and a second is that the individuals are producing it themselves by translating antisense RNA. In specific aim 3 we propose to determine the general nature of the theory of autoantigen complementarity by exploring its components in anti-GBM disease.