Factor H autoantibodies and deletion of Complement Factor H-Related protein-1 in rheumatic diseases in comparison to atypical hemolytic uremic syndrome

Anna Foltyn Zadura,Sara C Nilsson,Peter F Zipfel,Leendert A Trouw,Andreas Hillarp,Maria I Bokarewa,Anna M Blom,Gunnar Sturfelt,Andreas Jönsen,Tore Saxne

doi:10.1186/ar4016

Abstract

IntroductionComplement 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.MethodsAutoantibodies 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.ResultsFH 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.ConclusionsAutoantibodies 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.

Highlights

Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome
It is well established that the presence of autoantibodies against complement factor H (FH) is associated with atypical hemolytic uremic syndrome (aHUS) [16,17,18,19,20] and it was reported that the deletion of complement FH-related proteins 1 and 3 (CFHR1/ CFHR3) in aHUS patients are associated with the disease [21,22]
FH autoantibodies are present in sera of patients with rheumatic diseases Autoantibodies against FH (Figure 1A-D), Factor I (FI) (Figure 1E) and C4b-binding protein (C4BP) (Figure 1F) were analyzed in samples of lupus anticoagulants (LA)+, SLE, RA and aHUS patients as well as in healthy controls using ELISA

Summary

Introduction

Complement activation is involved in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and atypical hemolytic uremic syndrome (aHUS). Defective activation of complement as well as insufficient inhibition are associated with pathological processes in a number of autoimmune and inflammatory diseases [8] including rheumatoid arthritis (RA) [9], systemic lupus erythematosus (SLE) [10,11,12], anti-phospholipid syndrome (APS) [13] and atypical hemolytic uremic syndrome (aHUS) [14]. It is well established that the presence of autoantibodies against complement FH is associated with aHUS [16,17,18,19,20] and it was reported that the deletion of complement FH-related proteins 1 and 3 (CFHR1/ CFHR3) in aHUS patients are associated with the disease [21,22]. Most of the FH- autoantibodies in aHUS are directed against the Cterminal recognition region of FH [17]

Methods

Results

Discussion

Conclusion