Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.
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.
Glocker
Erik-Oliver
EO
Department of Immunology, Royal Free Hospital and University College London, United Kingdom.
Kotlarz
Daniel
D
Boztug
Kaan
K
Gertz
E Michael
EM
Schäffer
Alejandro A
AA
Noyan
Fatih
F
Perro
Mario
M
Diestelhorst
Jana
J
Allroth
Anna
A
Murugan
Dhaarini
D
Hätscher
Nadine
N
Pfeifer
Dietmar
D
Sykora
Karl-Walter
KW
Sauer
Martin
M
Kreipe
Hans
H
Lacher
Martin
M
Nustede
Rainer
R
Woellner
Cristina
C
Baumann
Ulrich
U
Salzer
Ulrich
U
Koletzko
Sibylle
S
Shah
Neil
N
Segal
Anthony W
AW
Sauerbrey
Axel
A
Buderus
Stephan
S
Snapper
Scott B
SB
Grimbacher
Bodo
B
Klein
Christoph
C
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
D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10