Roles of host defense lectin.s in innate immunity

宿主防御凝集素在先天免疫中的作用

基本信息

批准号：
13143204
负责人：
FUJITA Teizo
金额：
$ 67.39万
依托单位：
UNIVERCTTY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13143204/
关键词：
Complement Lectin Pathway MASP Ficolin Molecular Evolution 自然免疫レクチン MBL

项目摘要

Among pattern-recognition molecules, mannose-binding lectin (MBL) and ficolin have a unique ability to activate complement through their association with MBL-associated serine proteases (MASPs). Upon the binding of MBL and ficolin to PAMPs on pathogens, the proenzyme forms of MASPs are converted to the active forms and in turn MASPs activate the complement.In the present study, three lineages of MASP-deficient mice were established, including MASP・/3-deficient, MASP-2/sMAP-deficient and MASP-null mice. MASP-null mice were the most susceptible to bacterial infection, owing to the complete deficiency in the lectin pathway. As comparing with kinetics of the lectin pathway among the three lineages of MASP-deficient mice, MASP-1 was found to be involved in a unique route of the lectin pathway, termed `MASP-1 route', that was in a MASP-2-independent and C4-independent manner. By phenotype analysis of MASP-2/sMAP-deficient mice and its reconstitution with recombinant proteins, sMAP was demons … More trated to be a regulator of the lectin pathway, in which sMAP competitively inhibits the binding of MASP-2 to MBL.To define the role of ficolin in vivo, a lineage of ficolin A-deficient (FcnA^<-/->) mice was generated, which lacked ficolin A-based lectin complement pathway owing to the absence of ficolin A/MASPs complex in the serum. The defense activity of ficolin A-deficient mice against bacteria was significantly reduced, when it was assessed by bacterial growth inhibition in the blood. These results suggest that the lectin pathway is a highly sophisticated host defense system, consisting of two recognition molecules, three serine proteases and a regulator.In our phylogenetic approaches, the lectin pathway was identified in lamprey (a cyclostome belonging to the most primitive vertebrate) and ascidian (one of the most closest relatives to vertebrates), which lack the acquired immunity. This suggests that the lectin pathway has an ancient origin traced back to at least ascidians, and that it is crucial for innate immune defense in a wide animal world from the ascidians to mammals. Less

在模式识别分子中，甘露糖结合凝集素 (MBL) 和 ficolin 具有通过与 MBL 相关丝氨酸蛋白酶 (MASP) 结合而激活补体的独特能力。当 MBL 和 ficolin 与病原体上的 PAMP 结合时，会形成酶原。的 MASP 转化为活性形式，进而 MASP 激活补体。在本研究中，建立了三个 MASP 缺陷小鼠谱系，包括与凝集素途径的动力学相比，MASP·/3缺陷型、MASP-2/sMAP缺陷型和MASP缺失型小鼠最容易受到细菌感染。在 MASP 缺陷小鼠的三个谱系中，发现 MASP-1 参与凝集素途径的一种独特途径，称为“MASP-1 途径”，即通过对 MASP-2/sMAP 缺陷小鼠的表型分析及其用重组蛋白的重建，sMAP 被认为是凝集素途径的调节剂，其中 sMAP 竞争性抑制。 MASP-2 与 MBL 的结合。定义 ficolin 在体内的作用，ficolin A 缺陷谱系 (FcnA^</-/->)产生了由于血清中缺乏 ficolin A/MASP 复合物而缺乏基于 ficolin A 的凝集素补体途径的小鼠。通过细菌生长抑制来评估，ficolin A 缺陷小鼠对细菌的防御活性显着降低。这些结果表明，凝集素途径是一个高度复杂的宿主防御系统，由两个识别分子、三个丝氨酸蛋白酶和一个调节因子组成。在我们的系统发育方法中，在七鳃鳗中鉴定了凝集素途径。（属于最原始脊椎动物的环口动物）和海鞘（与脊椎动物最接近的亲戚之一）缺乏获得性免疫力，这表明凝集素途径的古老起源至少可以追溯到海鞘，并且它至关重要。用于从海鞘到哺乳动物的广泛动物世界的先天免疫防御。