Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy


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Kotlarz D., Beier R., Murugan D., Diestelhorst J., Jensen O., Boztug K., ...More

GASTROENTEROLOGY, vol.143, no.2, pp.347-355, 2012 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 143 Issue: 2
  • Publication Date: 2012
  • Doi Number: 10.1053/j.gastro.2012.04.045
  • Journal Name: GASTROENTEROLOGY
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.347-355
  • Keywords: Children, Genetic Defect, Immunodeficiency, Intestinal Inflammation, STEM-CELL TRANSPLANTATION, BONE-MARROW-TRANSPLANTATION, GENOME-WIDE ASSOCIATION, REFRACTORY CROHNS-DISEASE, NON-HODGKINS-LYMPHOMA, COMPLETE REMISSION, RECEPTOR, PATHOGENESIS, LEUKEMIA, COLITIS
  • Gazi University Affiliated: Yes

Abstract

BACKGROUND & AIMS: 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.