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1. Functional consequences of a novel IL-10 receptor alpha mutation on innate and adaptive immunity in early-onset inflammatory bowel disease

M.A. van Leeuwen1, S. Veenbergen1, R. Kersseboom2, L.F. de Ruiter1, H. Raatgeep1, D.J. Lindenbergh-Kortleve1, Y. Simons-Oosterhuis1, L. de Ridder1, G.J.A. Driessen3, J.C. Escher1, J.N. Samsom1, 1Erasmus Medical Centre – Sophia Children's Hospital, Dept. of Paediatric Gastroenterology, Rotterdam, 2Erasmus Medical Centre, Dept. of Clinical Genetics, Rotterdam, 3Erasmus Medical Centre, Dept. of Paediatric Infectious Disease and Immunology, Rotterdam, Netherlands


Inflammatory bowel disease (IBD) is driven by aberrant T-cell responses to intestinal microbiota. Although interleukin-10 (IL-10) is known to be crucial for maintaining intestinal immune homeostasis, its mechanisms of action in the human intestine are not well studied. In this study we aimed to identify the effect of IL-10 receptor alpha deficiency on intestinal inflammation and antigen presenting cell- and T cell-function in human.


Antigen presenting cell- and T cell-function were assessed by in vitro culture of peripheral blood leukocytes with various stimuli and subsequent flow-cytometric analysis. Cytokine secretion was determined using cytometric bead array and enzyme linked immuno sorbent assay. Immunohistochemistry was used to characterize cytokine producing cells in the intestinal lesions.


Here, we describe a now 10-year old IBD patient with a novel homozygous frameshift mutation in the IL-10 receptor alpha chain, who developed severe early-onset colitis and fistulising perianal disease in the first weeks of life. In vitro studies showed that IL-10 suppression of lipopolysaccharide (LPS)-mediated TNFalpha production was defective in PBMCs. Additionally; deficient STAT3 phosphorylation after IL-10 stimulation confirmed the impaired IL-10-mediated signalling in patient PBMCs. In contrast to a healthy control, patient monocyte-derived dendritic cells did not down-regulate co-stimulatory molecule expression or TNFalpha and IL-6 secretion after stimulation with LPS-and IL-10. During treatment, normal frequencies of Foxp3+ regulatory T cells, T helper 1 (Th1) and Th17 cells were found in patient peripheral blood. However, IL-10 failed to control IFNgamma and IL-17 production by activated patient CD4+ T cells in vitro. In agreement, lesional intestinal tissue taken at onset of disease contained high numbers of IL-17+ and Tbet+ (Th1) cells. Disease remission is currently achieved with thalidomide, intravenous immunoglobulin (IVIG) and colchicine. Interestingly, in vitro studies showed that IVIG efficiently suppressed anti-CD3-driven IL-17 and IFNgamma release while thalidomide inhibited LPS-mediated TNF production by PBMCs.


Taken together, our study describes the functional consequences of a novel IL-10 receptor mutation and reveals that IL-10 controls both antigen presenting cells and effector T cells in human intestinal immune responses.