Journal of the American Society of Nephrology
2007 JASN IMPACT FACTOR 7.111 HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP 
    advanced
CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION


Published ahead of print on January 17, 2007
J Am Soc Nephrol 18: 506-514, 2007
© 2007 American Society of Nephrology
doi: 10.1681/ASN.2006091069
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ASN.2006091069v1
18/2/506    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Heinen, S.
Right arrow Articles by Zipfel, P. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Heinen, S.
Right arrow Articles by Zipfel, P. F.

Basic Immunology and Pathology

Hemolytic Uremic Syndrome: A Factor H Mutation (E1172Stop) Causes Defective Complement Control at the Surface of Endothelial Cells

Stefan Heinen*, Mihály Józsi*, Andrea Hartmann*, Marina Noris{dagger}, Giuseppe Remuzzi{dagger}, Christine Skerka* and Peter F. Zipfel*,{ddagger}

* Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, and {ddagger} Faculty of Biology, Friedrich Schiller University, Jena, Germany; and {dagger} Mario Negri Institute for Pharmacological Research Villa Camozzi, Ranica, Bergamo, Italy

Address correspondence to: Prof. Dr. Peter F. Zipfel, Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Hans Knoell Institute, Beutenbergstrasse 11a, D-07745 Jena, Germany. Phone: +49-3641-656-900; Fax: +49-3641-656-902; E-mail: peter.zipfel{at}hki-jena.de

Received for publication September 30, 2006. Accepted for publication November 24, 2006.

Defective complement regulation results in hemolytic uremic syndrome (HUS), a disease that is characterized by microangiopathy, thrombocytopenia, and acute renal failure and that causes endothelial cell damage. For characterization of how defective complement regulation relates to the pathophysiology, the role of the complement regulator factor H and also of a mutant factor H protein was studied on the surface of human umbilical vein endothelial cells. The mutant 145-kD factor H protein was purified to homogeneity, from plasma of a patient with HUS, who is heterozygous for a factor H gene mutation G3587T, which introduces a stop codon at position 1172. Functional analyses show that the lack of the most C-terminal domain short consensus repeats 20 severely affected recognition functions (i.e., binding to heparin, C3b, C3d, and the surface of endothelial cells). Wild-type factor H as well as the mutant protein formed dimers in solution as shown by cross-linking studies and mass spectroscopy. When assayed in fluid phase, the complement regulatory activity of the mutant protein was normal and comparable to wild-type factor H. However, on the surface of endothelial cells, the mutant factor H protein showed severely reduced regulatory activities and lacked protective functions. Similarly, with the use of sheep erythrocytes, the mutant protein lacked the protective activity and caused increased hemolysis when it was added to factor H–depleted plasma. This study shows how a mutation that affects the C-terminal region of the factor H protein leads to defective complement control on cell surfaces and damage to endothelial cells in patients with HUS. These effects explain how mutant factor H causes defective complement control and in HUS—particularly under condition of inflammation and complement activation—causes endothelial cell damage.




This article has been cited by other articles:


Home page
 BloodHome page
A.-l. Stahl, F. Vaziri-Sani, S. Heinen, A.-C. Kristoffersson, K.-H. Gydell, R. Raafat, A. Gutierrez, O. Beringer, P. F. Zipfel, and D. Karpman
Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation
Blood, June 1, 2008; 111(11): 5307 - 5315.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Jozsi, C. Licht, S. Strobel, S. L. H. Zipfel, H. Richter, S. Heinen, P. F. Zipfel, and C. Skerka
Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency
Blood, February 1, 2008; 111(3): 1512 - 1514.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Kunert, J. Losse, C. Gruszin, M. Huhn, K. Kaendler, S. Mikkat, D. Volke, R. Hoffmann, T. S. Jokiranta, H. Seeberger, et al.
Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein
J. Immunol., September 1, 2007; 179(5): 2979 - 2988.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Jozsi, S. Strobel, H.-M. Dahse, W.-s. Liu, P. F. Hoyer, M. Oppermann, C. Skerka, and P. F. Zipfel
Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome
Blood, September 1, 2007; 110(5): 1516 - 1518.
[Abstract] [Full Text] [PDF]


HOME CURRENT ISSUE ARCHIVES JASN Express ONLINE SUBMISSION AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673