Molecular principles of enhanced complement activation by properdin

The complement system is an important part of our innate immunity. Complement is involved in the clearance of microorganisms, foreign particles and altered host cells. Initiation of complement activation can occur through three pathways. The classical pathway (CP) and lectin pathway (LP) require pattern recognition molecules for initiation, while the alternative pathway (AP) has a continuously low-level activity and does not depend specific pattern recognition for activation. Regulation of AP activation is vital to direct activation to appropriate surfaces and to protect healthy host cells. In this thesis we focused on properdin, which is the only known positive, activation stimulating, regulator of the complement system. Properdin positively stimulates activation by increasing the lifetime of the AP C3 convertase (C3bBb) that is pivotal to the AP. Furthermore, properdin reduces the proteolytic inactivation of C3b by factor I (FI). Positive regulation by properdin is crucial for complement-mediated host protection against infection by various microorganism, such as Chlamydia pneumoniae, Neisseria meningitides and gonorrhoeae. In addition, properdin plays an important role in multiple diseases that are caused by unwanted AP activation, including paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Using X-ray crystallography, we solved the 3D structure of properdin and of properdin in complex with a part of C3bBb. These structures, together with biochemical and biophysical data, provided novel insights into the molecular mechanism of positive regulation by properdin