title: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
abstract: BACKGROUND
  The molecular cause of inflammatory bowel disease is largely unknown.
  
  
  METHODS
  We performed genetic-linkage analysis and candidate-gene sequencing on samples from two unrelated consanguineous families with children who were affected by early-onset inflammatory bowel disease. We screened six additional patients with early-onset colitis for mutations in two candidate genes and carried out functional assays in patients' peripheral-blood mononuclear cells. We performed an allogeneic hematopoietic stem-cell transplantation in one patient.
  
  
  RESULTS
  In four of nine patients with early-onset colitis, we identified three distinct homozygous mutations in genes IL10RA and IL10RB, encoding the IL10R1 and IL10R2 proteins, respectively, which form a heterotetramer to make up the interleukin-10 receptor. The mutations abrogate interleukin-10-induced signaling, as shown by deficient STAT3 (signal transducer and activator of transcription 3) phosphorylation on stimulation with interleukin-10. Consistent with this observation was the increased secretion of tumor necrosis factor alpha and other proinflammatory cytokines from peripheral-blood mononuclear cells from patients who were deficient in IL10R subunit proteins, suggesting that interleukin-10-dependent "negative feedback" regulation is disrupted in these cells. The allogeneic stem-cell transplantation performed in one patient was successful.
  
  
  CONCLUSIONS
  Mutations in genes encoding the IL10R subunit proteins were found in patients with early-onset enterocolitis, involving hyperinflammatory immune responses in the intestine. Allogeneic stem-cell transplantation resulted in disease remission in one patient.
authors.affiliation: Department of Immunology, Royal Free Hospital and University College London, United Kingdom.
authors.forename: Erik-Oliver
authors.initials: EO
authors.lastname: Glocker
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: E Michael
authors.initials: EM
authors.lastname: Gertz
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.forename: Mario
authors.initials: M
authors.lastname: Perro
authors.forename: Jana
authors.initials: J
authors.lastname: Diestelhorst
authors.forename: Anna
authors.initials: A
authors.lastname: Allroth
authors.forename: Dhaarini
authors.initials: D
authors.lastname: Murugan
authors.forename: Nadine
authors.initials: N
authors.lastname: Hätscher
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.forename: Martin
authors.initials: M
authors.lastname: Sauer
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.forename: Rainer
authors.initials: R
authors.lastname: Nustede
authors.forename: Cristina
authors.initials: C
authors.lastname: Woellner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.forename: Neil
authors.initials: N
authors.lastname: Shah
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Segal
authors.forename: Axel
authors.initials: A
authors.lastname: Sauerbrey
authors.forename: Stephan
authors.initials: S
authors.lastname: Buderus
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D017668:Age of Onset; D002880:Chromosomes, Human, Pair 11; D002891:Chromosomes, Human, Pair 21; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000628:therapy; D016753:Interleukin-10 / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics*; D053710:Interleukin-10 Receptor beta Subunit / Q000737:chemistry / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012074:Remission Induction; D017422:Sequence Analysis, DNA; D033581:Stem Cell Transplantation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10