Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.
Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa.
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DOI：
10.4049/jimmunol.153.3.1271
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发表时间：
1994-08
影响因子：
4.4
通讯作者：
A. Porges;P. Redecha;W. Kimberly;Elena Csernok;W. Gross;R. Kimberly
中科院分区：
文献类型：
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作者：
A. Porges;P. Redecha;W. Kimberly;Elena Csernok;W. Gross;R. Kimberly
抗中性粒细胞胞浆抗体（ANCA）的存在，在许多系统性血管炎患者表明，ANCA可能在疾病的发病机制中发挥作用。来自韦格纳肉芽肿病患者的中性粒细胞通常在其表面上表达ANCA靶标Ag（髓过氧化物酶（MPO）和蛋白酶3（PR 3）），使得这些细胞内初级颗粒酶可接近这些自身抗体。类似地，正常中性粒细胞可以在体外被诱导将MPO和PR 3易位到细胞表面，并且我们证明了鼠mAb ANCA IgG而不是IgM结合ANCA靶标并接合人中性粒细胞表面上的Fc γ RIIa配体结合位点。与ANCA IgM相反，ANCA IgG还诱导中性粒细胞中的氧化爆发（抗PR 3 IgG的二氢罗丹明氧化= 91 +/-15荧光单位，抗PR 3 IgM的二氢罗丹明氧化= 17 +/-2，p < 0.001）。用抗结合位点mAb Fab阻断Fc γ RIIa的配体结合位点显著降低了这种ANCA IgG触发的活性氧物质的产生（p < 0.01）。类似地，人ANCA结合ANCA靶标，接合Fc γ RIIa，并诱导中性粒细胞中的氧化爆发。Fc γ RIIa的等位基因表型强烈影响Fc γ受体与配体的结合，Fc γ RIIa纯合供体在活性氧中间体（ROI）的定量产生方面差异超过3倍（p < 0.01）。因此，ANCA的Fc区与Fc γ RIIa的结合是这些自身抗体激活人嗜中性粒细胞中受体介导的信号转导系统以启动炎症和组织损伤程序的一种机制。Fc γ受体等位基因可能代表影响这种过程的程度的遗传性疾病风险因素。
The presence of anti-neutrophil cytoplasmic Abs (ANCA) in many patients with systemic vasculitis suggests that ANCA may play a role in disease pathogenesis. Neutrophils from patients with Wegener's granulomatosis often express ANCA target Ags (myeloperoxidase (MPO) and proteinase 3 (PR3)) on their surface, making these intracellular primary granule enzymes accessible to these autoantibodies. Similarly, normal neutrophils can be induced to translocate MPO and PR3 to the cell surface in vitro, and we demonstrate that murine mAb ANCA IgG, but not IgM, binds to the ANCA target and engages the Fc gamma RIIa ligand-binding site on the surface of human neutrophils. In contrast to ANCA IgM, ANCA IgG also induces an oxidative burst in neutrophils (oxidation of dihydrorhodamine = 91 +/- 15 fluorescence units with anti-PR3 IgG vs 17 +/- 2 with anti-PR3 IgM, p < 0.001). Blockade of the ligand-binding site of Fc gamma RIIa with an antibinding site mAb Fab significantly reduces this ANCA IgG-triggered production of reactive oxygen species (p < 0.01). Similarly, human ANCA bind the ANCA target, engage Fc gamma RIIa, and induce an oxidative burst in neutrophils. The allelic phenotype of Fc gamma RIIa strongly influences the Fc gamma receptor engagement by ligand, and Fc gamma RIIa homozygous donors differ by more than threefold in the quantitative production of reactive oxygen intermediates (ROI) (p < 0.01). Thus, engagement of Fc gamma RIIa by the Fc region of ANCA is one mechanism by which these autoantibodies activate receptor-mediated signal transduction systems in human neutrophils to initiate programs of inflammation and tissue injury. Fc gamma receptor alleles may represent heritable disease risk factors influencing the magnitude of such a process.