Studies on the Influence of a Mutation of MASP‐2 on the Binding to MBL and Ficolins

Sørensen, R.; Gadjeva, M.; Thiel, S.; Jensenius, J. C.

The complement system is an important part of the innate immune system. The activation of complement proceeds through three different pathways that converge in the generation of C3‐activating enzyme complexes. Complement activation via the lectin pathway is initiated when recognition molecules, mannan‐binding lectin (MBL) or ficolin, bind to carbohydrate structures characteristic for microbial surfaces. In the circulation, MBL and ficolins are found in association with three structurally related MBL‐associated serine proteases (MASP)‐1, ‐2 and ‐3 and a small, nonenzymatic component, MAp19. MASP‐2 has been shown to elicit complement activation through the sequential proteolytic cleavage of C4 and C2 upon binding of MBL/MASP‐2 complexes to microbial surfaces. We have recently uncovered a polymorphism in the MASP‐2/MAp19 gene in a patient shown to be deficient in the lectin pathway of complement activation. The polymorphism results in a single amino acid substitution in the N‐terminal part of the MASP‐2 protein. Recombinant wildtype MASP‐2 and MASP‐2 containing the amino acid substitution in question was produced, and the ability to activate complement was studied. The mutation had a profound impact on MASP‐2 function, resulting in the lack of complement activation through the lectin pathway. ELISA‐based experiments showed that the mutation leads to the impairment of complement activation through influencing the binding of MASP‐2 to MBL or ficolins. Deficiencies in the lectin pathway of complement activation have so far been accounted for only by lack of functional MBL. The mutation described above is the first defect described affecting both activation through MBL and the ficolins.