title: Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.
abstract: OBJECTIVE
  Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder.
  
  
  METHODS
  We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT.
  
  
  RESULTS
  Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant.
  
  
  CONCLUSIONS
  We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kotlarz
authors.forename: Rita
authors.initials: R
authors.lastname: Beier
authors.forename: Dhaarini
authors.initials: D
authors.lastname: Murugan
authors.forename: Jana
authors.initials: J
authors.lastname: Diestelhorst
authors.forename: Ole
authors.initials: O
authors.lastname: Jensen
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.forename: Eva-Doreen
authors.initials: ED
authors.lastname: Pfister
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.forename: Jacek
authors.initials: J
authors.lastname: Puchalka
authors.forename: Jens
authors.initials: J
authors.lastname: Bohne
authors.forename: Odul
authors.initials: O
authors.lastname: Egritas
authors.forename: Buket
authors.initials: B
authors.lastname: Dalgic
authors.forename: Kaija-Leena
authors.initials: KL
authors.lastname: Kolho
authors.forename: Axel
authors.initials: A
authors.lastname: Sauerbrey
authors.forename: Stephan
authors.initials: S
authors.lastname: Buderus
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngör
authors.forename: Axel
authors.initials: A
authors.lastname: Enninger
authors.forename: Yu Kar Ling
authors.initials: YK
authors.lastname: Koda
authors.forename: Graziella
authors.initials: G
authors.lastname: Guariso
authors.forename: Batia
authors.initials: B
authors.lastname: Weiss
authors.forename: Selim
authors.initials: S
authors.lastname: Corbacioglu
authors.forename: Piotr
authors.initials: P
authors.lastname: Socha
authors.forename: Nuray
authors.initials: N
authors.lastname: Uslu
authors.forename: Ayse
authors.initials: A
authors.lastname: Metin
authors.forename: Ghassan T
authors.initials: GT
authors.lastname: Wahbeh
authors.forename: Khalid
authors.initials: K
authors.lastname: Husain
authors.forename: Dina
authors.initials: D
authors.lastname: Ramadan
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Martin
authors.initials: M
authors.lastname: Sauer
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D015153:Blotting, Western; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005819:Genetic Markers; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000235:genetics / Q000601:surgery; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics*; D053709:Interleukin-10 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics*; D053710:Interleukin-10 Receptor beta Subunit / Q000172:deficiency / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D016753:Interleukin-10