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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against complement factorH(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.

Original languageEnglish
Pages (from-to)9500-9510
Number of pages11
JournalJournal of Biological Chemistry
Volume290
Issue number15
DOIs
Publication statusPublished - Apr 10 2015

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Complement Factor H
Autoimmunity
Autoantibodies
Epitopes
Protein Deficiency
Proteins
Complement C1
Conformations
Hemolytic-Uremic Syndrome
N-Acetylneuraminic Acid
Polysaccharides
Complement System Proteins
Binding Sites
Atypical Hemolytic Uremic Syndrome
factor H-related protein 1
Mutation
Crystal structure
Association reactions

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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

In: Journal of Biological Chemistry, Vol. 290, No. 15, 10.04.2015, p. 9500-9510.

Research output: Contribution to journalArticle

Bhattacharjee, Arnab ; Reuter, Stefanie ; Trojnár, Eszter ; Kolodziejczyk, Robert ; Hyvärinen, Harald Seeberger Satu ; Uzonyi, Barbara ; Szilágyi, Ágnes ; Prohászka, Z. ; Goldman, Adrian ; Józsi, Mihály ; Jokiranta, T. Sakari. / 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. In: Journal of Biological Chemistry. 2015 ; Vol. 290, No. 15. pp. 9500-9510.
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AU - Trojnár, Eszter

AU - Kolodziejczyk, Robert

AU - Hyvärinen, Harald Seeberger Satu

AU - Uzonyi, Barbara

AU - Szilágyi, Ágnes

AU - Prohászka, Z.

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AU - Józsi, Mihály

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