Characterization of genetic predisposition and autoantibody profile in atypical haemolytic-uraemic syndrome

Abstract

We previously reported that Indian paediatric patients with atypical haemolytic–uraemic syndrome (aHUS) showed high frequencies of anti-complement factor H (FH) autoantibodies that are correlated with homozygous deletion of the genes for FH-related proteins 1 and 3 (FHR1 and FHR3) (FHR1/3–/–). We now report that Indian paediatric aHUS patients without anti-FH autoantibodies also showed modestly higher frequencies of the FHR1/3–/– genotype. Further, when we characterized epitope specificities and binding avidities of anti-FH autoantibodies in aHUS patients, most anti-FH autoantibodies were directed towards the FH cell-surface anchoring polyanionic binding site-containing C-terminal short conservative regions (SCRs) 17–20 with higher binding avidities than for native FH. FH SCR17–20-binding anti-FH autoantibodies also bound the other cell-surface anchoring polyanionic binding site-containing region FH SCR5–8, at lower binding avidities. Anti-FH autoantibody avidities correlated with antibody titres. These anti-FH autoantibody characteristics did not differ between aHUS patients with or without the FHR1/3–/– genotype. Our data suggest a complex matrix of interactions between FHR1-FHR3 deletion, immunomodulation and anti-FH autoantibodies in the aetiopathogenesis of aHUS.