EFFECTS OF PR3-ANCA ON DISEASE PHENOTYPE

PR3-ANCA 对疾病表型的影响

• 批准号: 6171211
• 负责人: ULRICH SPECKS
• 金额: $ 10.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171211
• 关键词: Wegener's granulomatosis; antigen antibody reaction; autoantibody; cell transplantation; electroporation; enzyme linked immunosorbent assay; epitope mapping; gene expression; genetically modified animals; human tissue; hybrid antibody; immunofluorescence technique; immunoprecipitation; intermolecular interaction; laboratory mouse; model design /development; nucleic acid sequence; pathologic process; phenotype; polymerase chain reaction; protein structure function; serine proteinases

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are systemic autoimmune small vessel vasculitides. Their clinical manifestations are very heterogeneous. In the case of WG they may range from indolent cavitating pulmonary nodules to massive life threatening alveolar hemorrhage with or without associated glomerulonephritis. Essentially any organ may be affected, and it remains unclear what determines the predominant organ involvement observed in individual patients. These diseases are fatal if untreated. Immunosuppressive agents have significantly improved the prognosis, but are associated with substantial side effects. WG and MPA are associated with circulating autoantibodies, antineutrophil cytoplasmic antibodies (ANCA). The most prominent target antigen for ANCA in WG is the neutrophil azurophil granule serine protease, proteinase 3 (PR3). Clinical observations suggest that the type of ANCA may influence the prognosis and spectrum of clinical presentations. ANCA have been implicated in the pathogenesis of these diseases. Despite very compelling evidence derived from clinical observations, in vitro studies, and attempts to develop valid animal models, the exact mechanisms by which ANCA influence the heterogeneous disease manifestations remain elusive. A detailed understanding of the specific pathogenetic interactions of PR3-ANCA with its target antigen will provide the foundation for potential novel therapeutic approaches with less side effects. Therefore, we hypothesize that the interactions of PR3-ANCA with its target antigen are pathogenic. We further hypothesize that different subtypes of PR3-ANCA reacting with different epitopes on PR3 modulate specific PR3 functions and thereby affect clinical disease expression. To address this hypothesis, we will categorize PR3-ANCA subtypes, identify their target epitopes on the PR3 molecule, and determine their impact on PR3 function and specific organ manifestations of the disease (specific aim 1). To prove the pathogenicity of PR3-ANCA in vivo, we will develop mouse models based on the interactions of murine ANCA with their species-specific target antigen (specific aim 2). Our studies are fundamental to the understanding of the pathogenetic role of PR3-ANCA in pulmonary vasculitis, and for the development of novel mechanism-based therapeutic approaches for these devastating disease states.

韦格纳肉芽肿病（WG）和显微镜下多血管炎（MPA）是系统性自身免疫性小血管炎。 他们的临床表现是非常异质性。 在WG的情况下，它们的范围可以从惰性的空洞性肺结节到大量危及生命的肺泡出血，伴或不伴相关的肾小球肾炎。 基本上任何器官都可能受到影响，目前尚不清楚是什么决定了个体患者中观察到的主要器官受累。 这些疾病如果不治疗是致命的。 免疫抑制剂已显着改善预后，但与大量的副作用。 WG和MPA与循环自身抗体抗神经细胞胞浆抗体（ANCA）有关。 WG中ANCA最突出的靶抗原是嗜中性粒细胞嗜天青颗粒丝氨酸蛋白酶，蛋白酶3（PR 3）。临床观察表明，ANCA的类型可能会影响预后和临床表现的频谱。 ANCA参与了这些疾病的发病机制。 尽管来自临床观察、体外研究和开发有效动物模型的尝试提供了非常令人信服的证据，但ANCA影响异质性疾病表现的确切机制仍然难以捉摸。 详细了解PR 3-ANCA与其靶抗原的特异性致病相互作用将为潜在的副作用较小的新治疗方法提供基础。 因此，我们假设PR 3-ANCA与其靶抗原的相互作用是致病性的。 我们进一步假设，不同亚型的PR 3-ANCA与PR 3上的不同表位反应，调节特定的PR 3功能，从而影响临床疾病的表达。 为了解决这一假设，我们将对PR 3-ANCA亚型进行分类，鉴定其在PR 3分子上的靶表位，并确定其对PR 3功能和疾病的特定器官表现的影响（具体目标1）。为了证明PR 3-ANCA在体内的致病性，我们将基于鼠ANCA与其物种特异性靶抗原的相互作用开发小鼠模型（具体目的2）。 我们的研究对于了解PR 3-ANCA在肺血管炎中的发病作用以及开发针对这些破坏性疾病状态的基于机制的新治疗方法至关重要。