L. de Ruiter

Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: A rationale for targeting TNF-α and IL-1β

Background  The pathogenesis of hidradenitis suppurativa (HS) is largely unknown and the disease is difficult to treat. Patients are in high need of an effective treatment. Although it is not known whether the levels of tumour necrosis factor (TNF)‐α are aberrant in HS skin, anti‐TNF‐α biologics are used, with variable clinical efficacy.

Alterations in leucocyte subsets and histomorphology in normal‐appearing perilesional skin and early and chronic hidradenitis suppurativa lesions

Summary Background  Current insight into the histopathological course of events during disease progression in hidradenitis suppurativa (HS) is fragmentary.

Adalimumab (antitumour necrosis factor‐α) treatment of hidradenitis suppurativa ameliorates skin inflammation: an in situ and ex vivo study

Background  Hidradenitis suppurativa (HS) is a difficult‐to‐manage disease. Randomized controlled trials with antitumour necrosis factor (TNF)‐α biologics have been conducted and in most studies disease activity was reduced. However, the mechanism of action in HS skin is so far unknown.

Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease.

Celiac disease (CD) is caused by inflammatory CD4+ T-cell responses to dietary gluten. It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores. High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1–2 lesions, whereas increased numbers of IL-17 secreting cells were not observed. Intraepithelial lymphocytes, CD4+ T cells and also neutrophils secreted IL-21. Flow cytometry of lamina propria cells revealed a large population of IL-21- and interferon-γ (IFN-γ)-secreting CD3+ T cells that did not secrete IL-17A. Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions. As duodenal tissue damage increases contact with microbe-associated molecular patterns, we hypothesized that microbial sensing by Toll-like receptors (TLRs) modulates T cell–derived cytokine secretion. Costimulation with TLR3 ligands during polyclonal T-cell activation significantly increased IL-21 secretion, whereas TLR2 ligands selectively enhanced IL-17A. These results demonstrate that an IL-17A-independent increase in IL-21 production by CD4+ T cells is characteristic of pediatric CD. We hypothesize that incidental IL-17 secretion is caused by tissue damage rather than gluten-specific responses.

Chemokine production by buccal epithelium as a distinctive feature of pediatric Crohn disease

Objectives: Inflammatory bowel diseases (IBD) represent an aberrant immune response by the mucosal immune system to luminal bacteria. Because the oral mucosa harbors the first epithelial cells that interact with microorganisms, we assessed the immunologic activity of buccal epithelium in children with IBD and adults with Crohn disease. Methods: Buccal epithelial cells were obtained from 17 children and 14 adults with Crohn disease, 18 children with ulcerative colitis, and 40 controls. Cells were cultured with and without microbial stimulation. Chemokine levels were determined in culture supernatants by cytometric bead array and enzyme-linked immunoabsorbent assay. CXCL-8 production was studied by immunohistochemical analysis of these cells. CXCL-8 production by lipopolysaccharide stimulated monocyte-derived dendritic cells from these patients was determined. Results: Compared with controls, pediatric ulcerative colitis patients, and adult Crohn disease patients, only in children with Crohn disease did buccal epithelial cells exhibit enhanced production of CXCL-8, CXCL-9, and CXCL-10. In vitro stimulation with lipopolysaccharide or zymosan resulted in a further increase of chemokine levels only in cells from pediatric Crohn disease patients. CXCL-8 production by stimulated monocyte-derived dendritic cells from children with Crohn disease was equal to that of children with ulcerative colitis. Conclusions: Buccal epithelium of children with Crohn disease is immunologically active, even in the absence of oral lesions. The enhanced chemokine production is associated with pediatric Crohn disease and appears restricted to cells derived from the epithelial barrier. Assessment of chemokine production by buccal epithelial cells may become a new, rapid, noninvasive test for screening and classification of IBD in children.

Production of IL12p70 and IL23 by monocyte-derived dendritic cells in children with inflammatory bowel disease

Inflammatory bowel disease (IBD) patients represent a heterogeneous group of patients that may need novel classification beyond just Crohns’ disease (CD) and ulcerative colitis (UC). Notably, based on patient specifics such as genetics, disease location, immune responses and drug responsiveness, it seems likely that early-onset IBDs represents a specific disease entity.1 Consequently, various disease-associated effector T cells have been identified, probably generated under the control of cytokines that are produced by antigen-presenting cells. In their recent publication, Kugathsan et al demonstrated that the level of IL12β2 (interleukin 12 receptor) expression by mucosal T cells may be a major determinant during the initial manifestations of CD for the development of the typically associated mucosal Th1 cytokine profile.2 In this case, the presence of a specific T cell receptor correlated …

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. SimonsOosterhuis1, 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

O-04: Secretory leukocyte protease inhibitor (SLPI) is a potent regulator of microbial induced monocyte activation and intestinal inflammation

O-01 IL-10 receptor dependent signals regulate the generation and function of anti-inflammatory macrophages in mice and humans S.B. Snapper1 *, D. Shouval1, A. Biswas1, J.A. Goettel1, K. McCann1, J.C. Escher2, J.N. Samsom2, R.S. Somech3, B. Weiss3, R. Beier4, L. Conklin5, C.L. Ebens6, F.G.M. Santos7, M. Sherlock8, C. Klein9, A.M. Muise10, B.H. Horwitz11. 1Boston Children’s Hospital, Boston, United States of America, 2Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands, 3Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel, 4Hannover Medical School, Hannover, Germany, 5Children’s National Medical Center, Washington DC, United States of America, 6University of Michigan, Ann Arbor, United States of America, 7Hospital das Clinicas, Federal University of Minas Gerais, Minas Gerais, Brazil, 8McMaster Children’s Hospital, West Hamilton, Canada, 9Dr von Hauner Children’s Hospital, Munich, Germany, 10Hospital for Sick Children, Toronto, Canada, 11Harvard Medical School, Boston, United States of America