PDF(Pubmed)
Abstract：
Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.
摘要：
缓激肽生成级联的启动是某些类型的血管性水肿发作的原因。由于C1抑制剂缺乏(HAE-C1-INH)引起的遗传性血管性水肿是这样的临床实体之一。在本文中,我们探索了现有的证据，即肥大细胞（MC）脱颗粒可能有助于激肽释放酶-激肽系统级联的激活，其次是缓激肽形成和血管性水肿。我们介绍了MC衍生的肝素和其他聚阴离子对激肽-激肽释放酶系统主要成分的多向作用，特别是对因子XII的激活。虽然,缓激肽和组胺介导的症状是不同的临床现象，它们有一些共同的特点，例如一些类似的触发因素和在肥大细胞驻留的部位发生的倾向，即皮肤和粘膜。此外,最近的观察表明,在HAE-C1-INH患者人群中,与MC脱颗粒相关的超敏反应发生率较高.然而,并非所有这些都可以通过IgE依赖性机制来解释。肥大细胞相关G蛋白偶联受体X2(MRGPRX2),最近引起了科学兴趣，可能通过不同的途径参与MC的激活。因此,我们回顾了MRGPRX2配体,HAE-C1-INH患者在日常生活中可能接触到这些配体,这些配体可能会影响MC的脱颗粒.我们还讨论了HAE-C1-INH过程中已知的个体间和个体内变异性与引起对MRGPRX2受体刺激的反应强度可能变异性的因素有关。以上问题为今后的研究提出了几个问题。目前尚不清楚针对一种机制（肥大细胞脱粒）途径的预防性或治疗性干预可能在多大程度上影响另一种机制（缓激肽产生）。或者特定身体部位的肥大细胞数量及其对压力等触发器的反应性，过敏原或MRGPRX2激动剂可影响HAE-C1-INH在该位点的发作。
