Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors.
Modulation of immune complex-induced inflammation in vivo by the coordinate expression of activation and inhibitory Fc receptors.
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DOI：
10.1084/jem.189.1.179
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发表时间：
1999-01-04
期刊：
影响因子：
--
通讯作者：
Ravetch JV
中科院分区：
文献类型：
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作者：
Clynes R;Maizes JS;Guinamard R;Ono M;Takai T;Ravetch JV
自身抗体和免疫复合物是自身免疫损伤的主要致病因素，负责引发炎症级联及其导致的组织损伤。这种激活是由含有激活基序（ITAM）的免疫球蛋白（Ig）G Fc受体与免疫复合物（ic）和细胞毒性自身抗体相互作用引起的，免疫复合物和细胞毒性自身抗体启动并传播炎症反应。在体外，这一途径可以通过与含有抑制基序（ITIM）的IgG Fc受体Fcγ riib结合而中断。在这篇报道中，我们用IC肺泡炎小鼠模型描述了FcγRII缺乏在炎症反应中的体内后果。在低于阈值浓度的ic不能引起野生型小鼠的炎症反应时，fc γ rii缺陷小鼠出现了强烈的炎症反应，其特征是出血、水肿和中性粒细胞浸润增加。来自FcγRII - / -刺激小鼠的支气管肺泡液含有更高水平的肿瘤坏死因子和趋化活性，表明FcγRII缺乏降低了肺泡巨噬细胞等常驻细胞的IC刺激阈值。相比之下，补体和补体受体缺陷小鼠对ic超过阈值水平会产生正常的炎症反应，而FcRγ−/−小鼠则完全免受炎症损伤。通过对FcγRII−/−巨噬细胞的分析，证实了FcγRII对巨噬细胞的抑制作用，在FcγRIII的作用下，巨噬细胞表现出更大的吞噬和钙通量反应。这些数据揭示了IgG细胞受体在炎症细胞上的不同作用，为基于ITIM和ITAM FcγR表达比例设定IC敏感性阈值提供了一种调节机制。因此，利用FcγRII抑制途径可以为调节抗体引发的炎症提供新的治疗方法。
Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.