Activation and regulation of the lectin pathway

描述(申请人提供)：先天免疫识别感染性生物，快速限制感染，并刺激适应性免疫系统。对于尚未形成成熟适应性免疫系统的幼儿来说，宿主的先天免疫反应尤为重要。凝集素途径是补体系统的一个较新的分支，构成了人体对感染的先天免疫反应之一。通过这一途径激活补体依赖于甘露聚糖结合凝集素(MBL)与微生物细胞表面甘露糖残基的结合。虽然MBL的结构类似于C1q，但它不依赖抗体就能激活补体。直到最近，人们还认为激活过程类似于经典途径。然而，我们自己对凝集素途径的研究表明，C3/C5转换酶在激活剂上的形成、活性和调节与经典途径显著不同。MBL胶原区的突变导致MBL的天然等位基因形式，这与儿童和成人的严重感染有关。MBL的等位基因形式在某些人群中频繁发生，MBL替代疗法已经有效地治疗了MBL缺陷患者的感染。这些发现强调了MBL对健康的重要性，并暗示了MBL缺乏症的治疗潜力。我们建议的研究的总体目标是建立凝集素途径的激活和调节机制。针对目标1的研究将检验这一假设，即MBL胶原区的突变改变了与MASP1或MASP2的结合作用，并导致补体激活功能障碍和/或MBL介导的吞噬功能中断。针对目标2的研究将检验凝集素途径的激活和调节过程不同于经典途径的假设，经典途径一直是凝集素诱导补体激活的公认模型。

DESCRIPTION (provided by applicant): Innate immunity recognizes infectious organisms, quickly restricts the infection, and stimulates the adaptive immune system. The host's innate immune response is particularly important in young children who have not yet developed a mature adaptive immune system. The lectin pathway, a more recently defined branch of the complement system, constitutes one of the body's innate immune responses to infection. Activation of complement via this pathway depends on the binding of mannan binding lectin (MBL) to mannose residues on the cell surface of microorganisms. Although, MBL has a structure similar to C1q, it activates complement independent of antibodies. Until recently, it was assumed that the activation process was similar to that of the classical pathway. However, our own studies of the lectin pathway suggest that the formation, activity, and regulation of C3/C5 convertases on an activator differ significantly from those of the classical pathway. Mutations in the collagen region of MBL result in natural allelic forms of MBL that are associated with serious infections in children and adults. The allelic forms of MBL occur frequently in certain populations, and MBL replacement therapy has been effective for treatment of infections in MBL deficient patients. These findings underscore the importance of MBL for health and suggest a potential for therapy of MBL deficiency. Our overall goal in the proposed studies is to establish the mechanisms of activation and regulation of the lectin pathway. Studies that address Aim 1 will test the hypothesis that mutations in the collagen region of MBL alter binding interactions with MASP1 or MASP2 and result in dysfunctional complement activation and/or disruption of MBL-mediated phagocytosis. Studies that address Aim 2 will test the hypothesis that the processes of activation and regulation of the lectin pathway differ from those of the classical pathway, which has been the accepted model for lectin-induced complement activation.