INSITU PRODUCTION OF TNF-ALPHA, IL-1-BETA AND IL-2R IN ANCA-POSITIVE GLOMERULONEPHRITIS
INSITU PRODUCTION OF TNF-ALPHA, IL-1-BETA AND IL-2R IN ANCA-POSITIVE GLOMERULONEPHRITIS
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DOI：
10.1038/ki.1993.98
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发表时间：
1993-03-01
影响因子：
19.6
通讯作者：
WALDHERR, R
中科院分区：
文献类型：
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作者：
NORONHA, IL;KRUGER, C;WALDHERR, R
体液和细胞免疫机制被认为与各种形式的血管炎和肾小球肾炎有关。最近的临床和实验结果表明，细胞因子在ANCA阳性血管炎中起作用。本文分析了22例韦格纳肉芽肿和显微镜下多血管炎患者肾活检和血浆中肿瘤坏死因子-α(TNF-α)、白介素1β(IL-1β)和白介素2受体(IL-2R)的变化。肾活检组织用免疫细胞化学、聚合酶链式反应和原位杂交进行检测。22例活检组织中有21例可见肿瘤坏死因子-α、IL-1β和/或IL-2R阳性的浸润性细胞。肿瘤坏死因子-α、白介素1-β和白介素2受体在肾间质、肾小球周围和血管周围有明显的表达。在活动性病变的活检组织中，阳性细胞明显增多。阳性细胞还见于细胞和纤维细胞新月体、周围的簇状坏死以及急性血管病变的动脉和小动脉的壁上。部分肾小管上皮细胞表达肿瘤坏死因子-α和白介素1β。肿瘤坏死因子-α、白介素1-β和白介素2受体阳性的浸润性细胞与肾脏组织学活动性病变的存在相关。通过聚合酶链式反应在mRNA水平评估肿瘤坏死因子-α和白介素1-β的表达，发现所有分析的6个病例中均有肿瘤坏死因子-α和白介素1-β的特异转录本。原位杂交显示肿瘤坏死因子-α和白介素1-β在浸润性单个核细胞、鲍曼囊上皮细胞和部分肾小管中表达增加，主要见于活动性肾损害患者。在mRNA水平上的结果与免疫细胞化学结果相关。与健康人相比，脉管炎患者血浆中肿瘤坏死因子-α水平升高(34.4+/-16.6pg/ml(扫描电子显微镜)vs。对照组为1.9+/-0.7pg/ml；P<；0.01)。所有患者的sIL-2R水平均显著升高(35.12+/-485U/ml比397+/-21U/ml；P<；0.001)。大多数血浆标本中未检测到IL-1β。血浆中TNF-α和sIL-2R水平升高与肾脏活动性损害有关。我们的研究清楚地表明，在ANCA阳性的血管炎中，肿瘤坏死因子-α和白介素1-β是由活化的浸润性单个核细胞和常驻肾细胞原位产生的。细胞因子产生细胞在肾内的定位以及细胞因子产生与组织学活动标志之间的相关性表明，肿瘤坏死因子-α和IL-1β在血管炎/肾小球肾炎过程中是重要的局部作用介质。
Humoral and cellular immune mechanisms are thought to be involved in various forms of vasculitis and glomerulonephritis. Recent clinical and experimental results point to a role of cytokines in ANCA-positive vasculitides. We analyzed tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-2 receptors (IL-2R) in renal biopsies and in plasma from 22 patients with Wegener's granulomatosis and microscopic polyangiitis. Kidney biopsies were examined by immunocytochemistry, polymerase chain reaction and in situ hybridization. Immunoreactive TNF-alpha, IL-1beta and/or IL-2R positive infiltrating cells were observed in 21 of 22 biopsies. TNF-alpha, IL-1beta and IL-2R staining was evident in the interstitium and at periglomerular and perivascular sites. The number of positive cells was markedly increased in biopsies with active lesions. Positive cells were also present in cellular and fibrocellular crescents, surrounding tuft necrosis and in the walls of arteries and arterioles with acute vasculitic lesion. Some tubular epithelial cells stained for TNF-alpha and IL-1beta. TNF-alpha, IL-1beta and IL-2R positive infiltrating cells correlated with the presence of histologically active renal lesions. The evaluation of TNF-alpha and IL-1beta expression at the mRNA level assessed by the polymerase chain reaction demonstrated specific transcripts for TNF-alpha and IL-1beta in all six cases analyzed. In situ hybridization studies showed an increased expression of mRNA for TNF-alpha and IL-1beta in infiltrating mononuclear cells, in epithelial cells of Bowman's capsule and in some tubules, predominantly of patients with active renal lesions. The results at the mRNA level correlated with the immunocytochemical findings. Compared to healthy individuals higher TNF-alpha plasma levels were observed in patients with vasculitis (34.4 +/- 16.6 pg/ml (SEM) VS. 1.9 +/- 0.7 pg/ml in controls; P < 0.01). All patients presented a marked increase in sIL-2R plasma levels (3512 +/- 485 U/ml vs. 397 +/- 21 U/ml in healthy controls; P < 0.001). IL-1beta was not detected in most plasma samples. Elevated TNF-alpha and sIL-2R plasma levels were related to active renal lesions. Our study clearly demonstrates that in ANCA-positive vasculitis TNF-alpha and IL-1beta are produced in situ by activated infiltrating mononuclear cells and resident renal cells. Intrarenal localization of cytokine producing cells and the correlation between cytokine production and histological signs of activity suggest that TNF-alpha and IL-1beta are important locally acting mediators in the vasculitic/glomerulonephritic process.