Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome.
BACKGROUND
Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Autoantibodies to complement inhibitor factor H (FH), particularly in association with deletions of the gene coding for FH-related protein 1 (CFHR1), are associated with aHUS.


METHODS
Autoantibodies against FH, factor I (FI) and C4b-binding protein (C4BP) were measured by ELISA, while CFHR1 homozygous deletion was determined with Western blotting of sera. Epitopes for FH autoantibodies were mapped using recombinant fragments of FH.


RESULTS
FH autoantibodies were detected in SLE (6.7%, n = 60, RA patients (16.5%, n = 97 in the Swedish cohort and 9.2%, n = 217 in the Dutch cohort) and thrombosis patients positive for the lupus anticoagulants (LA+) test (9.4%, n = 64) compared with aHUS patients (11.7%, n = 103). In the control groups (n = 354), an average of 4% of individuals were positive for FH autoantibodies. The frequencies observed in both RA cohorts and LA+ patients were statistically significantly higher than in controls. We also found that an average of 15.2% of the FH-autoantibody positive individuals in all studied disease groups had homozygous deficiency of CFHR1 compared with 3.8% of the FH autoantibody negative patients. The levels of FH autoantibodies varied in individual patients over time. FH autoantibodies found in LA+, SLE and RA were directed against several epitopes across FH in contrast to those found in aHUS, which bound mainly to the C-terminus. Autoantibodies against FI and C4BP were detected in some patients and controls but they were not associated with any of the diseases analyzed in this study.


CONCLUSIONS
Autoantibodies against FH are not specific for aHUS but are present at a significant frequency in rheumatic diseases where they could be involved in pathophysiological mechanisms.
Anna
A
Foltyn Zadura
Peter F
PF
Zipfel
Maria I
MI
Bokarewa
Gunnar
G
Sturfelt
Andreas
A
Jönsen
Sara C
SC
Nilsson
Andreas
A
Hillarp
Tore
T
Saxne
Leendert A
LA
Trouw
Anna M
AM
Blom
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065766:Atypical Hemolytic Uremic Syndrome / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D001323:Autoantibodies / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003180:Complement C3b Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D012216:Rheumatic Diseases / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
D001323:Autoantibodies; D015415:Biomarkers; C493495:CFH protein, human; C517621:CFHR1 protein, human; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H