Gencik M, Meller S, Borgmann S, Fricke H
Molecular Human Genetics, Ruhr-University Bochum, and Medizinische Klinik, Klinikum Innenstadt, Universität München, München, Germany.
Kidney Int. 2000 Dec;58(6):2473-7. doi: 10.1046/j.1523-1755.2000.00430.x.
Wegener's granulomatosis (WG) is a rare systemic autoimmune disease characterized by small-vessel vasculitis leading to organ damage and the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs were shown to be involved in the pathogenesis of the disease by increasing adhesion of polymorphonuclear cells (PMNs) to endothelial cells and through activation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil- and monocyte-derived neutral serine protease. The association of WG with individuals continuously expressing a high level of PR3 on the surface of PMNs suggests that PR3 variants or altered regulation of PR3 expression might be directly involved in the pathogenesis of the disease.
We screened the entire coding and promoter sequences of the PR3 gene for polymorphisms by means of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequencies were compared between 79 WG patients and a cohort of 129 healthy controls.
Seven single-nucleotide polymorphisms (SNPs), one amino acid change (Val119Ile), one 84 bp insertion/deletion, and a microsatellite were identified. An association with WG could be demonstrated for the A-564G polymorphism in the PR3 promoter affecting a putative transcription factor-binding site.
This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls. Overexpression of PR3, however, might predispose the patient to the development of autoimmune ANCA-associated vasculitis.
韦格纳肉芽肿（WG）是一种罕见的系统性自身免疫性疾病，其特征为导致器官损伤的小血管炎以及抗中性粒细胞胞浆自身抗体（ANCA）的存在。已表明ANCA通过增加多形核细胞（PMN）与内皮细胞的黏附以及通过激活致敏的PMN参与该疾病的发病机制。WG中ANCA的主要自身抗原是蛋白酶3（PR3），一种源自中性粒细胞和单核细胞的中性丝氨酸蛋白酶。WG与在PMN表面持续高水平表达PR3的个体之间的关联表明，PR3变体或PR3表达的调节改变可能直接参与该疾病的发病机制。
我们通过聚合酶链反应单链构象多态性（PCR-SSCP）筛查PR3基因的整个编码和启动子序列中的多态性。比较了79例WG患者和129名健康对照者的等位基因、基因型和单倍型频率。
鉴定出7个单核苷酸多态性（SNP）、1个氨基酸变化（Val119Ile）、1个84 bp的插入/缺失以及1个微卫星。影响假定转录因子结合位点的PR3启动子中的A-564G多态性与WG存在关联。
本研究排除了某些PR3表位变体作为WG中的自身抗原刺激，因为Val119Ile多态性在患者和对照之间未显示出差异。然而，PR3的过度表达可能使患者易患自身免疫性ANCA相关血管炎。
