| Co-Investigator(Kenkyū-buntansha) |
ENDO Yuidii Fukushima Medical University School of Medidne, Associate Professor, 医学部, 助教授 (20117427)
IWAKI Daisuke Fukushima Medical University School of Medickte, Researth Associate, 医学部, 助手 (10315492)
NAKATA Munehiro Ibalaki University, Department of Applied Biochemistry and Institute of Glycotechnology, Associate Proessor, 工学部, 助教授 (00266371)
NAAKMURA Takanori Kagawa University, Faculty of Medicine, Professor, 医学部, 教授 (70183887)
AZUMI Kaoru Hokkaido University, Graduate School of Pharmaceutical Scienoa, Research Associate, 大学院・薬学研究科, 助手 (90221720)
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| Research Abstract |
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
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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
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