Lamprecht P, Gross W L
Department of Rheumatology, University Hospital of Schleswig-Holstein, Campus Lübeck, and Rheumaklinik Bad Bramstedt, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Clin Exp Rheumatol. 2007 Jan-Feb;25(1 Suppl 44):S49-51.
Wegener's granulomatosis (WG) usually starts as granulomatous disease of the respiratory tract (so-called localized WG) before it converts to systemic disease (generalized WG) with the emergence of proteinase 3-specific antineutrophil cytoplasmic autoantibodies (PR3-ANCA) and PR3-ANCA associated autoimmune vasculitis. So far, it remains unresolved how tolerance to "Wegener's autoantigen" PR3 is broken and the immune response to PR3 sustained. Further, the relationship between granulomatous lesions and systemic vasculitis is poorly understood. None of the ANCA-animal-models has reproduced granulomata typical of WG so far. A number of endogenous and exogenous factors (HLA-DPB10401/PTPN22620W, respiratory epithelial barrier dysfunction? S. aureus, cPR3?) could favour initial formation of granulomata in the respiratory tract and break of tolerance. PR3 induces dendritic cell maturation via the protease activated receptor (PAR)-2 and evokes a strong Th1-type T-cell res-ponse in WG. Clusters of PR3+ cells (neutrophils/monocytes) surrounded by antigen-presenting cells, Th1-type CD4+CD28- effector memory T-cells, maturing B- and plasmacells are found in WG-granulomata of the upper respiratory tract. Thus, WG-granulomata might provide the necessary "proinflammatory environment" for the break of tolerance and display features of lymphoid-like tissue neoformation, in which autoimmunity to PR3 could be sustained. Subsequent PR3-ANCA associated systemic vasculitis gives rise to new inflammatory lesions in many other organs, thereby promoting a self-perpetuating pathology characterized by inflammation and autoimmunity to PR3.
韦格纳肉芽肿（WG）通常始于呼吸道的肉芽肿性疾病（所谓局限性WG），之后随着蛋白酶3特异性抗中性粒细胞胞浆自身抗体（PR3-ANCA）及PR3-ANCA相关自身免疫性血管炎的出现转变为系统性疾病（全身性WG）。到目前为止，对“韦格纳自身抗原”PR3的耐受性是如何被打破以及对PR3的免疫反应是如何持续的，仍未得到解决。此外，肉芽肿性病变与系统性血管炎之间的关系也知之甚少。目前尚无一种ANCA动物模型能够复制出典型的WG肉芽肿。许多内源性和外源性因素（HLA-DPB10401/PTPN22620W、呼吸道上皮屏障功能障碍？金黄色葡萄球菌、cPR3？）可能有利于呼吸道肉芽肿的初始形成及耐受性的打破。PR3通过蛋白酶激活受体（PAR）-2诱导树突状细胞成熟，并在WG中引发强烈的Th1型T细胞反应。在上呼吸道的WG肉芽肿中可发现被抗原呈递细胞、Th1型CD4+CD28-效应记忆T细胞、成熟的B细胞和浆细胞包围的PR3+细胞（中性粒细胞/单核细胞）簇。因此，WG肉芽肿可能为耐受性的打破提供必要的“促炎环境”，并表现出类淋巴组织新形成的特征，其中对PR3的自身免疫可能得以持续。随后，PR3-ANCA相关的系统性血管炎在许多其他器官中引发新的炎症病变，从而促进以炎症和对PR3的自身免疫为特征的自我持续病理过程。
