A second serine protease associated with mannan-binding lectin that activates complement

The complement system comprises a complex array of enzymes and non-enzymatic proteins that is essential for the operation of the innate as well as the adaptive immune defence1. The complement system can be activated in three ways: by the classical pathway which is initiated by antibody–antigen complexes, by the alternative pathway initiated by certain structures on microbial surfaces, and by an antibody-independent pathway2 that is initiated by the binding of mannan-binding lectin (MBL; first described as mannan-binding protein3) to carbohydrates. MBL is structurally related to the complement Cl subcomponent, Clq, and seems to activate the complement system through an associated serine protease known as MASP (ref. 4) or p100 (ref. 5), which is similar to Clr and Cls of the classical pathway. MBL binds to specific carbohydrate structures found on the surface of a range of microorganisms, including bacteria, yeasts, parasitic protozoa and viruses6, and exhibits antibacterial activity through killing mediated by the terminal, lytic complement components7 or by promoting phagocytosis8. The level of MBL in plasma is genetically determined9–11, and deficiency is associated with frequent infections in childhood12,13, and possibly also in adults14,15 (for review, see ref. 6). We have now identified a new MBL-associated serine protease (MASP-2) which shows a striking homology with the previously reported MASP (MASP-1) and the two Clq-associated serine proteases Clr and Cls. Thus complement activation through MBL, like the classical pathway, involves two serine proteases and may antedate the development of the specific immune system of vertebrates.