Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome.
BACKGROUND
Atypical haemolytic uraemic syndrome (aHUS) is associated with defective complement regulation. Recently, an autoimmune aHUS form has been described that is associated with complement factor H (CFH) autoantibodies. The aim of this study was to address the pathologic relevance of CFH autoantibodies in aHUS.


METHODS
CFH autoantibodies were identified and antibody levels were analysed in three aHUS patients during the disease course by the ELISA method. Epitope mapping was performed using recombinant factor H fragments and domain-mapped monoclonal antibodies. The effect of the antibodies on cell-protective activity of CFH was measured by haemolytic assays. CFH:autoantibody complexes were analysed by ELISA.


RESULTS
All three autoantibodies bound to the C-terminal domain of CFH, which is essential for CFH binding to cell surfaces. In patient 1, plasma exchanges and immune adsorption temporarily reduced the autoantibody titre and led to temporary clinical improvement. In patient 2, plasma exchanges and long-term immunosuppression strongly reduced the CFH autoantibody level, and induced a stable remission of aHUS. Patient 3 had lower autoantibody levels that decreased during the follow-up and is in good clinical condition. The patients' plasma samples caused enhanced lysis of sheep erythrocytes, and the degree of lysis correlated with the CFH autoantibody titre and the amount of CFH:autoantibody complexes. An addition of purified CFH to aHUS plasma or removal of IgG inhibited the haemolytic activity.


CONCLUSIONS
These results support a direct role of the autoantibodies in aHUS pathology by inhibiting the regulatory function of CFH at cell surfaces and suggest that reduction of the autoantibody titre is beneficial for the patients.
Strobel
Stefanie
S
Junior Research Group Cellular Immunobiology, Leibniz Institute for Natural Product Research and Infection Biology-Hans KnöllInstitute, Jena, Germany.
Hoyer
Peter F
PF
Mache
Christoph J
CJ
Sulyok
Endre
E
Liu
Wei-Shih
WS
Richter
Heiko
H
Oppermann
Martin
M
Zipfel
Peter F
PF
Józsi
Mihály
M
D001323:Autoantibodies / Q000097:blood / Q000502:physiology*; D001327:Autoimmune Diseases / Q000097:blood / Q000276:immunology / Q000503:physiopathology; D002648:Child; D017242:Complement Factor H / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male
D001323:Autoantibodies; D007074:Immunoglobulin G; D017242:Complement Factor H