Brouwer E, Huitema M G, Mulder A H, Heeringa P, van Goor H, Tervaert J W, Weening J J, Kallenberg C G
Department of Clinical Immunology, University of Groningen, The Netherlands.
Kidney Int. 1994 Apr;45(4):1120-31. doi: 10.1038/ki.1994.149.
The mechanisms underlying glomerular capillary wall injury in Wegener's granulomatosis (WG) are not well understood. Anti-neutrophil cytoplasmic antibodies (ANCA), present in sera from patients with WG, are known to stimulate respiratory burst and degranulation of primed polymorphonuclear neutrophils (PMN) in vitro. Experimental studies have shown that oxygen radical production and lysosomal enzymes are important mediators of glomerular capillary wall injury. In the present study we investigated the presence of activated PMN and the extracellular localization of lysosomal enzymes in 28 consecutive renal biopsies from patients with WG. The presence of activated PMN within the renal biopsies was compared with the capacity of ANCA, isolated from simultaneously drawn serum samples, to activate primed PMN obtained from a normal donor. Both parameters were also related to renal function. Renal biopsies were obtained from newly diagnosed WG patients before therapy had started. Activation of PMN in the biopsies was assessed by measuring hydrogen peroxide production in situ. The number of activated PMN in the biopsy correlated with the extent of impairment of renal function. Proteinase 3, myeloperoxidase, and elastase, all targets of ANCA, were localized extracellularly in renal tissue and were also found within tubular epithelial cells. All ANCA positive samples were capable of activating primed PMN. The amount of activation correlated with the ANCA titer in those samples. No correlation, however, was found between the in vitro capacity of ANCA-positive IgG fractions to activate primed PMN and the number of activated PMN present in the renal biopsy. We conclude that activated PMN producing toxic oxygen metabolites and releasing lysosomal enzymes, are present in renal biopsies from patients with WG. The amount of activated PMN present within the kidney, and not the capacity of the corresponding ANCA to activate PMN, correlates with renal tissue damage as assessed by serum creatinine levels.
韦格纳肉芽肿病（WG）中肾小球毛细血管壁损伤的潜在机制尚未完全明确。已知WG患者血清中存在的抗中性粒细胞胞浆抗体（ANCA）可在体外刺激致敏多形核中性粒细胞（PMN）的呼吸爆发和脱颗粒。实验研究表明，氧自由基生成和溶酶体酶是肾小球毛细血管壁损伤的重要介质。在本研究中，我们调查了28例连续的WG患者肾活检组织中活化PMN的存在情况以及溶酶体酶的细胞外定位。将肾活检组织中活化PMN的存在情况与从同时采集的血清样本中分离出的ANCA激活正常供体来源的致敏PMN的能力进行了比较。这两个参数也与肾功能相关。肾活检组织取自新诊断的WG患者，且在治疗开始前获取。通过原位测量过氧化氢生成来评估活检组织中PMN的活化情况。活检组织中活化PMN的数量与肾功能损害程度相关。蛋白酶3、髓过氧化物酶和弹性蛋白酶，均为ANCA的靶点，在肾组织细胞外定位，且在肾小管上皮细胞内也有发现。所有ANCA阳性样本均能够激活致敏PMN。活化程度与这些样本中的ANCA滴度相关。然而，在体外，ANCA阳性IgG组分激活致敏PMN的能力与肾活检组织中活化PMN的数量之间未发现相关性。我们得出结论，产生有毒氧代谢产物并释放溶酶体酶的活化PMN存在于WG患者的肾活检组织中。肾脏内活化PMN的数量而非相应ANCA激活PMN的能力，与通过血清肌酐水平评估的肾组织损伤相关。
