Matsushita Misao, Matsushita Akiko, Endo Yuichi, Nakata Munehiro, Kojima Naoya, Mizuochi Tsuguo, Fujita Teizo
Department of Biochemistry, Fukushima Medical University School of Medicine, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Fukushima 960-1295, Japan.
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10127-31. doi: 10.1073/pnas.0402180101. Epub 2004 Jun 24.
The lectin complement pathway in innate immunity is closely related to the classical complement pathway in adaptive immunity, with respect to the structures and functions of their components. Both pathways are initiated by complexes consisting of collagenous proteins and serine proteases of the mannose-binding lectin (MBL)-associated serine protease (MASP)/C1r/C1s family. It has been speculated that the classical pathway emerged after the lectin pathway, and that the activation mechanism of the latter was partially conserved. The classical and lectin pathways can be traced back to at least cartilaginous fish and ascidian (urochordata), respectively. To elucidate the evolution of the complement system, we isolated and characterized a GlcNAc-binding lectin from sera of lamprey (agnathans), the most primitive vertebrate that lacks the classical pathway. Lamprey GlcNAc-binding lectin was an oligomer consisting of 24-kDa subunits. cDNA and phylogenetic analyses revealed that the lamprey GlcNAc-binding lectin is an orthologue of mammalian C1q, a collagenous subcomponent of the first component involved in binding to immunoglobulins in the classical pathway. Lamprey C1q copurified with MASP-A, a serine protease of the MASP/C1r/C1s family, which exhibited proteolytic activity against lamprey C3. Surface plasmon resonance analysis showed that lamprey C1q specifically bound to GlcNAc, but not various other carbohydrates tested. These results suggest that C1q may have emerged as a lectin and may have functioned as an initial recognition molecule of the complement system in innate immunity before the establishment of adaptive immunity such as immunoglobulins in the cartilaginous fish.
就其组成成分的结构和功能而言，先天免疫中的凝集素补体途径与适应性免疫中的经典补体途径密切相关。这两条途径均由包含胶原蛋白和甘露糖结合凝集素（MBL）相关丝氨酸蛋白酶（MASP）/C1r/C1s家族丝氨酸蛋白酶的复合物启动。据推测，经典途径在凝集素途径之后出现，且后者的激活机制部分得以保留。经典途径和凝集素途径分别至少可追溯到软骨鱼和海鞘（尾索动物）。为阐明补体系统的进化，我们从七鳃鳗（无颌类）血清中分离并鉴定了一种结合N-乙酰葡糖胺的凝集素，七鳃鳗是最原始的脊椎动物，缺乏经典途径。七鳃鳗结合N-乙酰葡糖胺的凝集素是一种由24 kDa亚基组成的寡聚体。cDNA和系统发育分析表明，七鳃鳗结合N-乙酰葡糖胺的凝集素是哺乳动物C1q的直系同源物，C1q是经典途径中参与结合免疫球蛋白的第一成分的胶原亚成分。七鳃鳗C1q与MASP-A（MASP/C1r/C1s家族的丝氨酸蛋白酶）共纯化，MASP-A对七鳃鳗C3具有蛋白水解活性。表面等离子体共振分析表明，七鳃鳗C1q特异性结合N-乙酰葡糖胺，而不结合所测试的其他各种碳水化合物。这些结果表明，C1q可能最初是以凝集素形式出现的，并且在软骨鱼等适应性免疫（如免疫球蛋白）建立之前，可能在先天免疫中作为补体系统的初始识别分子发挥作用。
