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1.
Mucosal Immunol ; 14(5): 1172-1182, 2021 09.
Article in English | MEDLINE | ID: mdl-34226674

ABSTRACT

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.


Subject(s)
Colitis/etiology , Colitis/metabolism , Gene Duplication , Genetic Predisposition to Disease , Interleukin-2 Receptor alpha Subunit/genetics , Interleukin-2/metabolism , Signal Transduction , Age of Onset , Alleles , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Case-Control Studies , Chromosomes, Human, Pair 10 , Colitis/diagnosis , Cytokines/metabolism , Drug Resistance , Gene Expression , Genetic Association Studies , Genetic Loci , Humans , Immunohistochemistry , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Interleukin-2 Receptor alpha Subunit/metabolism , Lymphocyte Activation , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism
2.
J Pediatr Gastroenterol Nutr ; 65(1): e5-e15, 2017 07.
Article in English | MEDLINE | ID: mdl-28644354

ABSTRACT

OBJECTIVE: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS: Biomaterial was collected from the IL10RA-deficient patient, pediatric patients with IBD, and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co-stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte-derived dendritic cells from the IL10RA-deficient patient released increased amounts of tumor necrosis factor α compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T-cell cytokines interferon γ and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient's decreased peripheral blood mononuclear cell-derived tumor necrosis factor production. CONCLUSIONS: With time and during immunosuppressive treatment the IL10RA-deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing interferon γ and IL-17-mediated T-cell responses.


Subject(s)
Adaptive Immunity/physiology , Dendritic Cells/metabolism , Immunity, Innate/physiology , Inflammatory Bowel Diseases/immunology , Interleukin-10 Receptor alpha Subunit/deficiency , T-Lymphocyte Subsets/metabolism , Adolescent , Adult , Biomarkers/metabolism , Case-Control Studies , Child , Child, Preschool , Codon, Nonsense , Female , Frameshift Mutation , Genetic Markers , Humans , Infant , Inflammatory Bowel Diseases/genetics , Interleukin-10 Receptor alpha Subunit/genetics , Male , Middle Aged
3.
Virol J ; 4: 55, 2007 Jun 07.
Article in English | MEDLINE | ID: mdl-17555580

ABSTRACT

Cyclooxygenases (COXs) play a significant role in many different viral infections with respect to replication and pathogenesis. Here we investigated the role of COXs in the mouse hepatitis coronavirus (MHV) infection cycle. Blocking COX activity by different inhibitors or by RNA interference affected MHV infection in different cells. The COX inhibitors reduced MHV infection at a post-binding step, but early in the replication cycle. Both viral RNA and viral protein synthesis were affected with subsequent loss of progeny virus production. Thus, COX activity appears to be required for efficient MHV replication, providing a potential target for anti-coronaviral therapy.


Subject(s)
Murine hepatitis virus/growth & development , Prostaglandin-Endoperoxide Synthases/physiology , Virus Replication/physiology , Caco-2 Cells , Cyclooxygenase Inhibitors/pharmacology , Humans , Isoenzymes/biosynthesis , Isoenzymes/genetics , Isoenzymes/physiology , Prostaglandin-Endoperoxide Synthases/biosynthesis , Prostaglandin-Endoperoxide Synthases/genetics , RNA Interference , RNA, Viral/biosynthesis , Viral Proteins/biosynthesis
4.
J Pediatr Gastroenterol Nutr ; 43(5): 576-83, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17130731

ABSTRACT

OBJECTIVES: Bowel segments distal to a congenital intestinal obstruction have been suggested to be immature. In other words, luminal components such as amniotic fluid (before birth) and/or enteral nutrition (after birth) may be required to activate intestinal epithelial protein expression, thereby influencing epithelial differentiation. We investigated cell-type-specific protein expression proximal and distal to jejunal and ileal atresias in human newborns. PATIENTS AND METHODS: We immunohistochemically studied intestinal tissue specimens of 16 newborns who had undergone surgery for jejunal or ileal atresia. Sections were taken from both the proximal and distal sides of the atresias. RESULTS: For all patients, the enterocyte-specific markers lactase, sucrase-isomaltase, sodium glucose cotransporter 1, glucose transporters 2 and 5, intestinal fatty acid-binding protein and alkaline phosphatase were expressed at a mean 3 +/- 1 days after birth, both proximal and distal to jejunal and ileal atresias. Expression of goblet cell-specific markers mucin 2 and trefoil factor 3 and that of the Paneth cell marker lysozyme was maintained at either side of the atretic segment. CONCLUSIONS: With respect to the markers used, the human small intestinal epithelium is already differentiated shortly after birth. The absence of intestinal continuity in case of a jejunal or ileal atresia does not affect epithelial protein expression. This would seem to indicate that the developing small intestinal epithelium matures independently of luminal components.


Subject(s)
Intestinal Atresia/metabolism , Intestinal Atresia/pathology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestine, Small/abnormalities , Intestine, Small/metabolism , Biomarkers/metabolism , Female , Humans , Immunohistochemistry , Infant, Newborn , Male , Peptides/metabolism , Trefoil Factor-3
5.
J Virol ; 78(18): 9721-30, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15331705

ABSTRACT

Elevated levels of prostaglandins (PGs), products of cyclooxygenases (COXs), are found in the plasma and stool of rotavirus-infected children. We sought to determine the role of COXs, PGs, and the signal transduction pathways involved in rotavirus infection to elucidate possible new targets for antiviral therapy. Human intestinal Caco-2 cells were infected with human rotavirus Wa or simian rotavirus SA-11. COX-2 mRNA expression and secreted PGE2 levels were determined at different time points postinfection, and the effect of COX inhibitors on rotavirus infection was studied by an immunofluorescence assay (IFA). To reveal the signal transduction pathways involved, the effect of MEK, protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), and NF-kappaB inhibitors on rotavirus infection was analyzed. In infected Caco-2 cells, increased COX-2 mRNA expression and secreted PGE2 levels were detected. Indomethacin (inhibiting both COX-1 and COX-2) and specific COX-1 and COX-2 inhibitors reduced rotavirus infection by 85 and 50%, respectively, as measured by an IFA. Indomethacin reduced virus infection at a postbinding step early in the infection cycle, inhibiting virus protein synthesis. Indomethacin did not seem to affect viral RNA synthesis. Inhibitors of MEK, PKA, p38 MAPK, and NF-kappaB decreased rotavirus infection by at least 40%. PGE2 counteracted the effect of the COX and PKA inhibitors but not of the MEK, p38 MAPK, and NF-kappaB inhibitors. Conclusively, COXs and PGE2 are important mediators of rotavirus infection at a postbinding step. The ERK1/2 pathway mediated by PKA is involved in COX induction by rotavirus infection. MAPK and NF-kappaB pathways are involved in rotavirus infection but in a PGE2-independent manner. This report offers new perspectives in the search for therapeutic agents in treatment of severe rotavirus-mediated diarrhea in children.


Subject(s)
Cyclooxygenase Inhibitors/pharmacology , Rotavirus Infections/drug therapy , Rotavirus Infections/enzymology , Rotavirus/drug effects , Antiviral Agents/pharmacology , Caco-2 Cells , Child , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Dinoprostone/metabolism , Humans , Indomethacin/pharmacology , Isoenzymes/genetics , MAP Kinase Signaling System , Membrane Proteins , NF-kappa B/metabolism , Prostaglandin-Endoperoxide Synthases/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Viral/biosynthesis , Rotavirus/pathogenicity , Rotavirus/physiology , Rotavirus Infections/etiology , Viral Proteins/biosynthesis
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