title: The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome.
abstract: BACKGROUND
  Atypical forms of haemolytic uraemic syndrome (aHUS) include HUS caused by defects in the regulation of alternative complement pathway and HUS linked to neuraminidase-producing pathogens, such as Streptococcus pneumoniae. Increasing data support a pathogenic role of neuraminidase in the development of S. pneumoniae-associated haemolytic uraemic syndrome (SP-HUS), but the role of complement has never been clarified in detail. Therefore, we aimed to investigate whether the pathologic complement profile and genetic risk factors of aHUS are present in patients with SP-HUS.
  
  
  METHODS
  Enrolling five patients with SP-HUS classical and alternative pathway activity, besides C3, C4, factors H, B, I and anti-factor H autoantibody levels were determined. The coding regions of CFH, CFI, CD46 (MCP), THBD, C3 and CFB genes were sequenced and the copy number of CFI, CD46, CFH and related genes were also analyzed.
  
  
  RESULTS
  We found that in the acute phase samples of SP-HUS patients, complement components C4, C3 and activity of the classical and alternative pathways were decreased, indicating severe activation and complement consumption, but most of these alterations normalized later in remission. Three of the patients carried mutations and risk haplotypes in complement-mediated aHUS associated genes. The identified mutations include a previously published CFI variant (P50A) and two novel ones in CFH (R1149X) and THBD (T44I) genes.
  
  
  CONCLUSIONS
  Our results suggest that severe complement dysregulation and consumption accompany the progress of invasive pneumococcal disease (IPD)-associated SP-HUS and genetic variations of complement genes may contribute to the development of this complication in a proportion of the affected patients.
authors.affiliation: 3rd Department of Medicine, Research Laboratory, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Szilágyi
authors.forename: Nóra
authors.initials: N
authors.lastname: Kiss
authors.forename: Csaba
authors.initials: C
authors.lastname: Bereczki
authors.forename: Gyula
authors.initials: G
authors.lastname: Tálosi
authors.forename: Katalin
authors.initials: K
authors.lastname: Rácz
authors.forename: Sándor
authors.initials: S
authors.lastname: Túri
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Györke
authors.forename: Edina
authors.initials: E
authors.lastname: Simon
authors.forename: Eszter
authors.initials: E
authors.lastname: Horváth
authors.forename: Kata
authors.initials: K
authors.lastname: Kelen
authors.forename: György S
authors.initials: GS
authors.lastname: Reusz
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Szabó
authors.forename: Tivadar
authors.initials: T
authors.lastname: Tulassay
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D002675:Child, Preschool; D003165:Complement System Proteins / Q000235:genetics* / Q000276:immunology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D007223:Infant; D009154:Mutation / Q000235:genetics; D009439:Neuraminidase / Q000378:metabolism; D011008:Pneumococcal Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*
chemical_list: D003165:Complement System Proteins; D009439:Neuraminidase; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: Streptococcus pneumoniae; alternative pathway; classical pathway; complement, mutation; haemolytic uraemic syndrome