Blocking Fcα Receptor I on Granulocytes Prevents Tissue Damage Induced by IgA Autoantibodies
Blocking Fcα Receptor I on Granulocytes Prevents Tissue Damage Induced by IgA Autoantibodies
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DOI：
10.4049/jimmunol.1101763
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发表时间：
2012-08-15
影响因子：
4.4
通讯作者：
van Egmond, Marjolein
中科院分区：
文献类型：
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作者：
van der Steen, Lydia P.;Bakema, Jantine E.;van Egmond, Marjolein
伊加代表粘膜表面上最突出的Ab类别，并且是人血液中仅次于IgG的第二最普遍的Ab。我们最近证明，通过伊加交联粒细胞伊加FcR（Fc α RI）可诱导趋化驱动的正反馈迁移环，从而扩大粒细胞向伊加沉积物的募集。因此，我们推测，异常的IgA-Ag复合物，这可以发现在IgA介导的疾病的组织，是负责组织损伤诱导连续粒细胞迁移和激活。使用IgA依赖性皮肤起泡疾病作为模型系统，我们证明了患有这种疾病的患者的病变皮肤的冷冻切片中FcaRI阳性粒细胞浸润与伊加的共定位。此外，我们在体内显示了粒细胞迁移到人皮肤外植体和Fc α RI转基因小鼠的小鼠皮肤中注射的伊加沉积物。重要的是，通过阻断FcaRI来抑制离体迁移和组织损伤，表明这些事件依赖于伊加自身抗体与FcaRI的相互作用。因此，通过阻断FcaRI来中断粒细胞迁移环减少了具有异常IgA-免疫复合物的疾病中的组织损伤。因此，我们的研究结果可能会导致IgA介导的慢性炎症性疾病的新疗法的发展，从而降低严重的发病率和改善这些患者的生活质量。免疫学杂志，2012，189：1594-1601。
IgA represents the most prominent Ab class at mucosal surfaces and the second most prevalent Ab in human blood after IgG. We recently demonstrated that cross-linking of the granulocyte IgA FcR (Fc alpha RI) by IgA induces a chemotactic-driven positive-feedback migration loop, hereby amplifying recruitment of granulocytes to IgA deposits. Therefore, we postulated that aberrant IgA-Ag complexes, which can be found in tissues in IgA-mediated diseases, are responsible for tissue damage by inducing continuous granulocyte migration and activation. Using an IgA-dependent skin-blistering disease as a model system, we demonstrated colocalization of FcaRI-positive granulocyte infiltrates with IgA in cryosections of lesional skin of patients suffering from this disease. Furthermore, we showed granulocyte migration to IgA deposits injected in human skin explants and in murine skin of Fc alpha RI transgenic mice in vivo. Importantly, ex vivo migration and tissue damage were inhibited by blocking FcaRI, indicating that these events are dependent on the interaction of IgA autoantibodies with Fc alpha RI. Thus, interrupting the granulocyte migration loop by blocking FcaRI reduces tissue damage in diseases with aberrant IgA-immune complexes. As such, our results may lead to development of new therapies for IgA-mediated chronic inflammatory diseases, hereby decreasing severe morbidity and improving quality of life for these patients. The Journal of Immunology, 2012, 189: 1594-1601.