Role of different pathways of the complement cascade in experimental bullous pemphigoid
Role of different pathways of the complement cascade in experimental bullous pemphigoid
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DOI：
10.1172/jci17891
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发表时间：
2006-11-01
影响因子：
15.9
通讯作者：
Liu, Zhi
中科院分区：
文献类型：
--
作者：
Nelson, Kelly C.;Zhao, Minglang;Liu, Zhi
大疱性类天疱疮（BP）是一种自身免疫性表皮下起疱性疾病，与针对半粒酶体蛋白BP180和BP230的自身抗体和炎症相关。小鼠BP180 （mBP180）抗体的被动转移诱导了一种与人类BP非常相似的皮肤病。在本研究中，我们定义了不同的补体激活途径在该模型系统中的作用。缺乏替代途径成分因子B （Fb）并注射致病性抗mbp180 IgG的小鼠出现延迟且强度较低的表皮下水泡。缺乏经典途径补体组分4 （C4）的小鼠和用针对经典途径第一组分C1q的中和抗体预处理的WT小鼠对实验性BP具有抗性。这些小鼠的皮肤肥大细胞脱颗粒和多形核中性粒细胞（PMN）浸润水平显著降低。皮内给药48/80，一种肥大细胞脱颗粒剂，恢复C4（-/-）小鼠的BP疾病。此外，C4（-/-）小鼠在局部注射PMN趋化剂IL-8或局部重建PMN后，对实验性BP易感。这些发现为我们的知识提供了第一个直接证据，即补体激活通过经典途径和替代途径在实验性BP的皮下水疱形成中至关重要。
Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4(-/-) mice. Furthermore, C4(-/-) mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP.