Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release - Role of surface proteinase-3, alpha 1-antitrypsin, and Fc gamma receptors
Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release - Role of surface proteinase-3, alpha 1-antitrypsin, and Fc gamma receptors
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DOI：
10.1172/jci119662
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
Wewers, MD
中科院分区：
文献类型：
--
作者：
Ralston, DR;Warsh, CB;Wewers, MD
伴随Wegener肉芽肿（WG）中所见的嗜酸性血管炎的细胞质抗神经细胞胞质抗体（cANCA）针对蛋白酶-3（PR-3），这是一种位于嗜中性粒细胞和单核细胞的嗜天青颗粒中的丝氨酸蛋白酶。当在TNF α致敏的嗜中性粒细胞的表面上表达时，PR-3可以通过复合cANCA并促进伴随的Fc γ受体（Fc γ R）交联来直接激活嗜中性粒细胞。尽管已经研究了嗜中性粒细胞在WG中的致病作用，但尚未探索单核细胞的作用。具有释放细胞因子和调节嗜中性粒细胞流入的能力的单核细胞也表达PR-3。因此，单核细胞可能通过表面PR-3与cANCA的相互作用在WG中起重要作用，诱导单核细胞释放细胞因子。为了检验这一假设，研究了单核细胞响应于cANCA IgG的PR-3表达和IL-8释放，从健康供体获得的PBMC显示出显著的表面PR-3表达，如通过免疫组织化学和流式细胞术检测到的，其响应于0.5- 100 μ g/ml的TNF-α。在TNF α（2 ng/ml）脉冲处理1h后，加入TNF α致敏的PBMC中的纯化的单克隆抗PR-3 IgG诱导的IL-8释放是同种型对照抗体的45倍。（α 1-AT）是主要的PR-3抗蛋白酶，可抑制抗PR-3诱导的IL-8释放80%，重要的是，不导致Fc γ受体交联的抗PR-3 IgG的Fab和F（ab '）（2）片段不诱导IL-8释放。作为相关物，与从正常健康志愿者分离的IgG相比，从具有WG的cANCA阳性患者分离的IgG诱导6倍多的PBMC IL-8释放。与PR-3相关的IL-8诱导一致，α 1-AT显著抑制了这种作用。这些观察结果表明，cANCA可以通过促进单核细胞IL-8释放来募集和靶向中性粒细胞。这种诱导通过Fc γ受体交联介导，并部分受α 1-AT调节。
Cytoplasmic antineutrophil cytoplasmic antibodies (cANCA) that accompany the neutrophilic vasculitis seen in Wegener's granulomatosis (WG), are directed against proteinase-3 (PR-3), a serine proteinase which is located in azurophilic granules of neutrophils and monocytes. PR-3, when expressed on the surface of TNF alpha-primed neutrophils, can directly activate neutrophils by complexing cANCA and promoting concomitant Fc gamma receptor (Fc gamma R) cross-linking, Although the neutrophil's pathogenic role in WG has been studied, the role of the monocyte has not been explored, The monocyte, with its ability to release cytokines and regulate neutrophil influx, also expresses PR-3. Therefore, the monocyte may play a significant role in WG via the interaction of surface PR-3 with cANCA, inducing cytokine release by the monocyte, To test this hypothesis, monocytes were studied for PR-3 expression and for IL-8 release in response to cANCA IgG, PBMC obtained from healthy donors displayed dramatic surface PR-3 expression as detected by immunohistochemistry and flow cytometry in response to 0.5-h pulse with TNF alpha (2 ng/ml), Purified monoclonal anti-PR-3 IgG added to TNF alpha-primed PBMC induced 45-fold more IL-8 release than an isotype control antibody, Furthermore, alpha l-antitrypsin (alpha 1-AT), the primary PR-3 antiprotease, inhibited the anti-PR-3 induced IL-8 release by 80%, Importantly, Fab and F(ab')(2) fragments of anti-PR-3 IgG, which do not result in Fc gamma receptor cross-linking, do not induce IL-8 release, As a correlate, IgG isolated from cANCA positive patients with WG induced six times as much PBMC IL-8 release as compared to IgG isolated from normal healthy volunteers. Consistent with PR-3 associated IL-8 induction, alpha 1-AT significantly inhibited this effect, These observations suggest that cANCA may recruit and target neutrophils through promoting monocyte IL-8 release, This induction is mediated via Fc gamma receptor cross-linking and is regulated in part by alpha 1-AT.