4muc

Publication Abstract from PubMed

Atypical hemolytic uremic syndrome (aHUS) is characterized by complement attack against host cells due to mutations in complement proteins or autoantibodies against the complement regulator factor H (CFH). It is unknown why nearly all the patients with autoimmune aHUS lack CFH- related protein-1 (CFHR1). These patients have autoantibodies against CFH domains 19-20 (CFH19-20) which are nearly identical to CFHR1 domains 4-5 (CFHR14-5). Here, binding site mapping of autoantibodies from seventeen patients using mutant CFH19-20 constructs revealed an autoantibody epitope cluster within a loop on domain 20, next to the buried two residues different in CFH19-20 and CFHR14-5. Crystal structure of CFHR14-5 revealed difference in conformation of the autoantigenic loop on the carboxyl-terminal domains of CFH and CFHR1 explaining 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 a 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 owing to its structural difference to the autoantigenic CFH epitope suggesting a novel explanation for CFHR1 deficiency in pathogenesis of autoimmune aHUS.

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 A, Reuter S, Trojnar E, Kolodziejczyk R, Seeberger H, Hyvarinen S, Uzonyi B, Szilagyi A, Prohaszka Z, Goldman A, Jozsi M, Jokiranta TS J Biol Chem. 2015 Feb 6. pii: jbc.M114.630871. PMID:25659429^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.