Thesis Richard Pouw

Summary

Complement is a crucial part of innate immunity and consists of proteins that circulate in blood and protect the body against pathogens that enter the bloodstream. In order to quickly detect and kill pathogens, complement is continuously active, causing it to ‘attack’ all cells it encounters. Under healthy conditions, human cells are protected against complement by regulators such as complement factor H (FH). If FH function is decreased, diseases like atypical hemolytic uremic syndrome (aHUS) can occur. Furthermore, to escape complement-mediated clearance, pathogens hijack FH. Humans also possess FH-related proteins (FHRs), which are thought to in turn regulate FH function. It is unknown how FHRs affect diseases like aHUS or the hijacking of FH by pathogens.
The research described in this thesis focused on FH and the FHRs during health, meningococcal disease (MD) and aHUS. The research led to the first determination of FHR levels in blood showing that FH is >60-fold abundant than FHR-3 and FHR-4A during health. FH and not FHR-3 was found to be a risk factor for MD, while increased FHR-3 levels were found in aHUS patients. The research has shown that FHR-3 plays a smaller role in MD than originally hypothesized. It also provides new tools and leads to investigate FHR proteins in various diseases. In addition, the research has led to the discovery of a new method to improve FH function, which has therapeutic potential in diseases in which FH function is decreased.