Humbles A A, Lu B, Nilsson C A, Lilly C, Israel E, Fujiwara Y, Gerard N P, Gerard C
Ina Sue Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2000 Aug 31;406(6799):998-1001. doi: 10.1038/35023175.
Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a. Complement activation forms a central core of innate immune defence against mucosal bacteria, viruses, fungi, helminths and other pathogens. As a system of 'pattern-recognition molecules', foreign surface antigens and immune complexes lead to a proteolytic cascade culminating in a lytic membrane attack. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability. Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of ligand C3a following intra-pulmonary deposition of allergen, but not saline. We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.
哮喘是一种气道和肺黏膜的慢性炎症性疾病，与特应性和获得性（IgE）免疫密切相关。然而，支气管哮喘的许多特征，如平滑肌收缩、黏液分泌和炎症细胞募集，都与补体过敏毒素，特别是C3a和C5a的作用一致。补体激活形成了针对黏膜细菌、病毒、真菌、蠕虫和其他病原体的固有免疫防御的核心。作为一个“模式识别分子”系统，外来表面抗原和免疫复合物会引发蛋白水解级联反应，最终导致溶解性膜攻击。过敏毒素C3a和C5a作为激活副产物被释放出来，是强效的促炎介质，它们与特定的细胞表面受体结合，导致白细胞激活、平滑肌收缩和血管通透性增加。在此，我们表明，在过敏性气道疾病的小鼠模型中，C3a受体的基因缺失可防止过敏原激发后出现的肺生理变化。此外，人类哮喘患者在肺内注入过敏原而非生理盐水后，会产生显著水平的配体C3a。我们提出，除了获得性免疫反应外，固有免疫系统和补体（特别是C3a）也参与了哮喘的发病机制。
