Activation and regulation of the lectin pathway

描述（由申请人提供）：先天免疫识别感染性生物体，迅速限制感染，并刺激适应性免疫系统。宿主的先天免疫反应在尚未形成成熟适应性免疫系统的幼儿中尤为重要。凝集素途径是补体系统中一个最近才被定义的分支，它是机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具有与C1q相似的结构，但它能激活不依赖抗体的补体。直到最近，人们还认为这种激活过程与经典途径相似。然而，我们自己对凝集素途径的研究表明，激活剂上C3/C5转化酶的形成、活性和调控与经典途径有很大不同。骨髓瘤胶原区的突变导致骨髓瘤的天然等位基因形式，这与儿童和成人的严重感染有关。等位基因形式的MBL在某些人群中经常发生，MBL替代疗法对MBL缺乏患者的感染治疗有效。这些发现强调了MBL对健康的重要性，并提示了MBL缺乏症的治疗潜力。我们提出的研究的总体目标是建立凝集素途径的激活和调控机制。针对目标1的研究将验证MBL胶原区突变改变与MASP1或MASP2结合相互作用的假设，并导致补体激活功能失调和/或MBL介导的吞噬作用中断。针对Aim 2的研究将验证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.