Details

Autor(en) / Beteiligte

• Bhattacharjee, Arnab
• Reuter, Stefanie
• Trojnár, Eszter
• Kolodziejczyk, Robert
• Seeberger, Harald
• Hyvärinen, Satu
• Uzonyi, Barbara
• Szilágyi, Ágnes
• Prohászka, Zoltán
• Goldman, Adrian
• Józsi, Mihály
• Jokiranta, T. Sakari

Titel

The Major Autoantibody Epitope on Factor H in Atypical Hemolytic Uremic Syndrome Is Structurally Different from Its Homologous Site in Factor H-related Protein 1, Supporting a Novel Model for Induction of Autoimmunity in This Disease

Ist Teil von

• The Journal of biological chemistry, 2015-04, Vol.290 (15), p.9500-9510

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• Background: It is unknown why patients with autoantibodies against complement factor H (CFH) lack homologous CFHR1 protein. Results: The autoantibody epitope on CFH was identified, and the structure of the corresponding part of CFHR1 was solved. Conclusion: The autoantigenic epitope of CFH and its homologous site in CFHR1 are structurally different. Significance: A plausible explanation for formation of autoantibodies due to CFHR1 deficiency in autoimmune atypical hemolytic uremic syndrome was obtained. Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against complement factor H (CFH). It is unknown why nearly all patients with autoimmune aHUS lack CFHR1 (CFH-related protein-1). These patients have autoantibodies against CFH domains 19 and 20 (CFH19–20), which are nearly identical to CFHR1 domains 4 and 5 (CFHR14–5). Here, binding site mapping of autoantibodies from 17 patients using mutant CFH19–20 constructs revealed an autoantibody epitope cluster within a loop on domain 20, next to the two buried residues that are different in CFH19–20 and CFHR14–5. The crystal structure of CFHR14–5 revealed a difference in conformation of the autoantigenic loop in the C-terminal domains of CFH and CFHR1, explaining the variation in binding of autoantibodies from some aHUS patients to CFH19–20 and CFHR14–5. The autoantigenic loop on CFH seems to be generally flexible, as its conformation in previously published structures of CFH19–20 bound to the microbial protein OspE and a sialic acid glycan is somewhat altered. Cumulatively, our data suggest that association of CFHR1 deficiency with autoimmune aHUS could be due to the structural difference between CFHR1 and the autoantigenic CFH epitope, suggesting a novel explanation for CFHR1 deficiency in the pathogenesis of autoimmune aHUS.