Dhaarini Murugan

Publications (2)64.97 Total impact

• Article: Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.

  Daniel Kotlarz, Rita Beier, Dhaarini Murugan, Jana Diestelhorst, Ole Jensen, Kaan Boztug, Dietmar Pfeifer, Hans Kreipe, Eva-Doreen Pfister, Ulrich Baumann, [......], Ayse Metin, Ghassan T Wahbeh, Khalid Husain, Dina Ramadan, Waleed Al-Herz, Bodo Grimbacher, Martin Sauer, Karl-Walter Sykora, Sibylle Koletzko, Christoph Klein
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  ABSTRACT: 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. 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. 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. 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.
  Gastroenterology 04/2012; 143(2):347-55. · 11.68 Impact Factor
• Article: Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.

  Erik-Oliver Glocker, Daniel Kotlarz, Kaan Boztug, E Michael Gertz, Alejandro A Schäffer, Fatih Noyan, Mario Perro, Jana Diestelhorst, Anna Allroth, Dhaarini Murugan, [......], Ulrich Baumann, Ulrich Salzer, Sibylle Koletzko, Neil Shah, Anthony W Segal, Axel Sauerbrey, Stephan Buderus, Scott B Snapper, Bodo Grimbacher, Christoph Klein
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  ABSTRACT: The molecular cause of inflammatory bowel disease is largely unknown. 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. 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. 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.
  New England Journal of Medicine 11/2009; 361(21):2033-45. · 53.30 Impact Factor