Regulation and control of the complement system in immunity

The complement system is vital in preventing disease caused by infections. The system is also implicated in many diseases associated with excess inflammation.

For example, after a heart attack a condition called reperfusion injury occurs when blood supply returns to the tissue after a period of lack of oxygen. Reperfusion injury results from excessive inflammation caused by overactivity of the complement system. This results in reocclusion of the circulation and another heart attack. This strongly implies that control of the complement pathway in this context would prevent heart disease.

We are studying the classical and mannose-binding lectin (MBL) pathways of complement activation, both of which are associated with inflammatory diseases. These pathways involve the sequential activation of proteins by a cascade of proteases. Our lab focuses on the initiating proteases of the two pathways: C1r, C1s and the MBL-associated serine proteases (MASPs).

There are three of the latter enzymes, with MASP-1 and MASP-2 playing important roles in complement activation. It is not clear what role MASP-3 plays in activating complement, but mutants of the enzyme are associated with a developmental disorder called the 3MC syndrome. We have recently determined the structure of a 3MC syndrome-related mutant of MASP-3 and showed definitively that it is inactive. However, the substrates for the enzyme and how it is activated within the context of the neural crest stem cells is not clear.

Our lab examines how these proteases interact with their target substrates: the complement C2 and C4 proteins, and their regulatory inhibitor, C1-inhibitor. We have shown that C1s have a previously unrecognised "exosite" (site of interaction with a substrate on an enzyme other than an active site) on its serine protease domain and characterised this site extensively.

Based on these results, we plan to develop specific protein and peptide inhibitors of the different proteases to determine their roles in diseases. We are also interested in determining the roles of MASP-3, in particular, we want to determine what are the biologically relevant substrates of the enzyme.