Studies of the role of complement factor H in hemolytic uremic syndrome

Abstract

Factor H is the main fluid phase regulator of the alternative pathway of complement. Factor H acts as a co-factor for factor I-mediated C3b degradation, inhibits the formation of the C3bBb convertase and accelerates its decay. By discriminating between host and foreign cells, factor H inhibits complement-mediated injury to host cells. Factor H mutations have been associated with atypical hemolytic uremic syndrome (aHUS) a condition characterized by non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The mechanism by which factor H mutations lead to aHUS is unclear. The purpose of these studies was therefore to examine the interaction of normal and mutated factor H with platelets and endothelial cells as well as the phenotypic expression of factor H in aHUS patients.



Factor H bound to washed human platelets in a dose-dependent manner mainly via the C terminal of the protein and the heparin-binding sites. On platelets, factor H bound via the GPIIb/IIIa receptor as well as thrombospondin. Mutated factor H exhibited less binding, a finding that was verified using mutated factor H purified from the serum of a patient with aHUS. The same patient was found to have activation of the alternative complement pathway on platelets demonstrated by the presence of C3 and C5b-9 on the cell surface. Using the patient's serum we showed that the mutated factor H had reduced ability to protect normal platelets from complement activation. The phenotypic expression of factor H mutations was studied in two other patients in whom we demonstrated that the protein either accumulated in cells or exhibited reduced binding to host cells. Both these mechanisms could result in complement activation on host cells (endothelium and platelets), which would in turn promote endothelial cell injury as well as platelet activation and consumption in thrombi.

Abstract (Swedish)

Popular Abstract in Swedish

Faktor H är den viktigaste cirkulerande hämmare av den alternativa komplementvägen. Den fungerar som co-faktor för faktor-I medierad C3b nedbrytning, hindrar bildning av C3bBb konvertas och främjar dess nedbrytning. Genom att skilja mellan kroppens egna och främmande celler kan faktor H inhibera komplementmedierad värdcellsskada. Mutationer i faktor H har hittats hos patienter med atypiskt hemolytiskt uremiskt syndrom (aHUS), ett tillstånd som kännetecknas av icke immun hemolytiskt anemi, trombocytopeni och akut njursvikt. Det är dock oklart hur faktor H mutationer leder till aHUS. Syftet med dessa studier var därför att undersöka interaktion mellan normal och muterad faktor H och trombocyter eller endotelceller och att studera det fenotypiska uttrycket av faktor H hos patienter med aHUS. Vi fann att faktor H kunde binda till tvättade humana trombocyter, att bindning var dosrelaterad och ägde rum huvudsakligen genom proteinets C terminal och heparinbindande ställen. På trombocytnivå var receptorn GPIIb/IIIa samt trombospondin inblandade. Rekombinant muterad faktor H uppvisade sämre bindningsförmåga vilket bekräftades också genom rening av faktor H från serum tagen från en patient med aHUS. Samma patient uppvisade aktivering av den alternativa vägen av komplement på trombocyter genom förekomst av C3 och C5b-9 på cellytan. Försök med patientens serum visade att muterad faktor H hade sämre förmåga att skydda normala trombocyter från komplementaktivering. Det fenotypiska uttrycket av faktor H mutationer studerades hos två andra patienter med aHUS där vi kunde visa att proteinet antigen ackumulerades i celler eller hade sänkt bindningsförmåga till celler. Båda mekanismerna kunde resultera i komplementaktivering på värdsceller (endotel och trombocyter) som i sin tur skulle leda till endotelcellsskada och trombocytaktivering med trombbildning.

• author: Vaziri Sani, Fariba
• supervisor: Diana Karpman
• opponent: Professor Nilsson-Ekdahl, Kristina, Kalmar/Uppsala Universitet
• organization: Paediatrics (Lund)
• publishing date: 2006
• type: Thesis
• publication status: published
• subject: Pediatrics
• keywords: Pediatri, Pediatrics, Hemolytic uremic syndrome, complement system, factor H
• in: Journal of thrombosis and haemostasis, and Kidney International
• pages: 90 pages
• defense location: Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17, Lund
• defense date: 2006-03-16 09:00:00
• ISSN: 1652-8220
• ISBN: 91-85481-62-9
• language: English
• LU publication?: yes
• additional info: F Vaziri-Sani, J Hellwage, P.F Zipfel, A.G Sjöholm and D Karpman. 2005. Factor H binds to washed human platelets. J Thromb Haemost., vol 3 pp 154-162.; F Vaziri-Sani, A-C Kristoffersson, A.G Sjöholm, K-H Gydell and D Karpman. 2006. Defective complement regulation on platelets from a patient with hemolytic uremic syndrome and a factor H mutation. (submitted); F Vaziri-Sani, L Holmberg, A.G Sjöholm, A-C Kristoffersson, M Manea, V Frémeauz-Bacchi, I Fehrman-Ekholm, R Raafat and D Karpman. 2006. Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome. Kidney International,, vol doi:10.1038/sj.ki.5000155
• id: d7a0abb8-50e4-4a88-a487-5431d787783d (old id 546349)
• date added to LUP: 2016-04-01 16:04:50
• date last changed: 2022-03-22 13:04:30