Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2
Antiendothelial cell antibodies mediate enhanced leukocyte adhesion to cytokine-activated endothelial cells through a novel mechanism requiring cooperation between FcγRIIa and CXCR1/2
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DOI：
10.1182/blood-2006-08-044669
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Haskard, Dorian O.
中科院分区：
文献类型：
--
作者：
Florey, Oliver J.;Johns, Michael;Haskard, Dorian O.
抗内皮细胞抗体（aeca）通常在与血管损伤相关的疾病中检测到，包括系统性红斑狼疮（SLE）、系统性硬化症、高松动脉炎、韦格纳肉芽肿病、Behcet综合征和移植动脉硬化。在这里，我们探讨了这些抗体可能在炎症中增加多形核白细胞（PMN）对内皮细胞的粘附的假设。最初，我们建立了与内皮细胞（ECs）结合的小鼠IgG单抗，以Fc γ riia依赖的方式显著增加PMN对细胞因子刺激的内皮的粘附。中和抗体和静息ec的腺病毒转导表明，e -选择素、CXCR1/2和132个整合素的结合对于这一过程是必要和充分的。我们使用直接从SLE患者分离的AECA IgG观察到相同的机制。组装的免疫复合物也增强了PMN对内皮细胞的粘附，但与aeca引起的粘附相反，这一过程不需要CXCR1/2，也不受百日咳毒素的抑制，并且依赖于Fc γ RIIIb而不是Fc γ FRIIa。这些数据首次证明了单独的非冗余Fc γ RIIa和Fc γ riiib介导的机制，通过ec结合的单体IgG和组装的免疫复合物在动态条件下增强白细胞粘附。此外，观察到Fc γ RIIa和CXCR1/2在AECAs存在下协同增强PMN募集，这表明AECAs可能在炎症反应中增加组织损伤的机制。
Antiendothelial cell antibodies (AECAs) are commonly detectable in diseases associated with vascular injury, including systemic lupus erythematosus (SLE), systemic sclerosis, Takayasu arteritis, Wegener granulomatosis, Behcet syndrome and transplant arteriosclerosis. Here, we explore the hypothesis that these antibodies might augment polymorphonuclear leukocyte (PMN) adhesion to endothelium in inflammation. Initially, we established that a mouse IgG mAb bound to endothelial cells (ECs) significantly increased PMN adhesion to cytokine-stimulated endothelium in an Fc gamma RIIa-dependent manner. Neutralizing antibodies, and adenoviral transduction of resting ECs, demonstrated that the combination of E-selectin, CXCR1/2, and 132 integrins is both necessary and sufficient for this process. We observed an identical mechanism using AECA IgG isolated directly from patients with SLE. Assembled immune complexes also enhanced PMN adhesion to endothelium, but, in contrast to adhesion because of AECAs, this process did not require CXCR1/2, was not inhibited by pertussis toxin, and was Fc gamma RIIIb rather than Fc gamma FRIIa dependent. These data are the first to demonstrate separate nonredundant Fc gamma RIIa and Fc gamma RIIIb-mediated mechanisms by which EC-bound monomeric IgG and assembled immune complexes amplify leukocyte adhesion under dynamic conditions. Furthermore, the observation that Fc gamma RIIa and CXCR1/2 cooperate to enhance PMN recruitment in the presence of AECAs suggests a mechanism whereby AECAs may augment tissue injury during inflammatory responses.