EFFECTS OF PR3-ANCA ON DISEASE PHENOTYPE

韦格纳肉芽肿病（WG）和显微多血管炎（MPA）是系统性自身免疫性小血管病变。它们的临床表现很不相同。在急性肾小球肾炎的情况下，它们的范围从惰性空化肺结节到大量危及生命的肺泡出血，伴有或不伴有肾小球肾炎。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在个别患者中观察到的主要器官受累。如果不治疗，这些疾病是致命的。免疫抑制剂可以显著改善预后，但也有明显的副作用。WG和MPA与循环自身抗体，抗中性粒细胞胞浆抗体（ANCA）有关。在WG中，ANCA最重要的靶抗原是中性粒细胞azurophil颗粒丝氨酸蛋白酶PR3。临床观察表明，ANCA的类型可能影响预后和临床表现谱。ANCA与这些疾病的发病机制有关。尽管从临床观察、体外研究和建立有效动物模型中获得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PR3-ANCA与其靶抗原的具体致病相互作用将为潜在的副作用更小的新治疗方法提供基础。因此，我们假设PR3-ANCA与其靶抗原的相互作用具有致病性。我们进一步假设PR3- anca的不同亚型与PR3的不同表位反应，从而调节PR3的特异性功能，从而影响临床疾病的表达。为了解决这一假设，我们将对PR3- anca亚型进行分类，确定它们在PR3分子上的靶表位，并确定它们对PR3功能和疾病的特定器官表现的影响（specific aim 1）。为了证明PR3-ANCA在体内的致病性，我们将基于小鼠ANCA与其物种特异性靶抗原（specific aim 2）的相互作用建立小鼠模型。我们的研究是理解PR3-ANCA在肺血管炎中的发病作用的基础，也是开发针对这些破坏性疾病状态的基于机制的新治疗方法的基础。

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.