Always one step ahead: How pathogenic bacteria use the type III secretion system to manipulate the intestinal mucosal immune system

The intestinal immune system and the epithelium are the first line of defense in the gut. Constantly exposed to microorganisms from the environment, the gut has complex defense mechanisms to prevent infections, as well as regulatory pathways to tolerate commensal bacteria and food antigens. Intestinal pathogens have developed strategies to regulate intestinal immunity and inflammation in order to establish or prolong infection. The organisms that employ a type III secretion system use a molecular syringe to deliver effector proteins into the cytoplasm of host cells. These effectors target the host cell cytoskeleton, cell organelles and signaling pathways. This review addresses the multiple mechanisms by which the type III secretion system targets the intestinal immune response, with a special focus on pathogenic E. coli

The role of cytokines in the fibrotic responses in Crohn's disease

Crohn's disease is an idiopathic disorder of the gut thought to be caused by a combination of environmental and genetic factors in susceptible individuals. It is characterized by chronic transmural inflammation of the terminal ileum and colon, with typical transmural lesions. Complications, including fibrosis, mean that between 40 and 70% of patients require surgery in the first 10 years after diagnosis. Presently, there is no evidence that the current therapies which dampen inflammation modulate or reverse intestinal fibrosis. In this review, we focus on cytokines that may lead to fibrosis and stenosis and the contribution of experimental models for understanding and treatment of gut fibrosis.Instituto de Estudios Inmunológicos y Fisiopatológico

Interleukin-21 in cancer immunotherapy: Friend or foe?

Interleukin (IL)-21, a cytokine produced by activated conventional CD4+ T lymphocytes and Natural Killer T cells, drives anti-tumor immunity in the skin and kidney. However IL-21 is also pro-inflammatory in many tissues and promotes colitis-associated colon cancer. Understanding the biology of IL-21 in these different situations is needed to ensure maximal therapeutic benefit

Absence of skew scattering in two-dimensional systems: Testing the origins of the anomalous Hall effect

We study the anomalous Hall conductivity in spin-polarized, asymmetrically confined two-dimensional electron and hole systems, focusing on skew-scattering contributions to the transport. We find that the skew scattering, principally responsible for the extrinsic contribution to the anomalous Hall effect, vanishes for the two-dimensional electron system if both chiral Rashba subbands are partially occupied, and vanishes always for the two-dimensional hole gas studied here, regardless of the band filling. Our prediction can be tested with the proposed coplanar two-dimensional electron/hole gas device and can be used as a benchmark to understand the crossover from the intrisic to the extrinsic anomalous Hall effect.Comment: 4 pages, 2 figures include

Compartmentalised expression of meprin in small intestinal mucosa: enhanced expression in lamina propria in coeliac disease

Epithelial cells in the human small intestine express meprin, an astacin-like metalloprotease, which accumulates normally at the brush border membrane and in the gut lumen. Therefore, meprin is targeted towards luminal components. In coeliac disease patients, peptides from ingested cereals trigger mucosal inflammation in the small intestine, disrupting epithelial cell differentiation and function. Using in situ hybridisation on duodenal tissue sections, we observed a marked shift of meprin mRNA expression from epithelial cells, the predominant expression site in normal mucosa, to lamina propria leukocytes in coeliac disease. Meprin thereby gains access to the substrate repertoire present beneath the epitheliu

The role of cytokines in the fibrotic responses in Crohn's disease

Crohn's disease is an idiopathic disorder of the gut thought to be caused by a combination of environmental and genetic factors in susceptible individuals. It is characterized by chronic transmural inflammation of the terminal ileum and colon, with typical transmural lesions. Complications, including fibrosis, mean that between 40 and 70% of patients require surgery in the first 10 years after diagnosis. Presently, there is no evidence that the current therapies which dampen inflammation modulate or reverse intestinal fibrosis. In this review, we focus on cytokines that may lead to fibrosis and stenosis and the contribution of experimental models for understanding and treatment of gut fibrosis.Instituto de Estudios Inmunológicos y Fisiopatológico

A CD3-Specific Antibody Reduces Cytokine Production and Alters Phosphoprotein Profiles in Intestinal Tissues From Patients With Inflammatory Bowel Disease

NOTICE: this is the author’s version of a work that was accepted for publication in Gastroenterology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in GASTROENTEROLOGY, 10.1053/j.gastro.2014.03.04

Aryl Hydrocarbon Receptor-Induced Signals Up-regulate IL-22 Production and Inhibit Inflammation in the Gastrointestinal Tract

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Autocrine Regulation of IL-21 Production in Human T Lymphocytes

Abstract IL-21 has pathologic function in immune-inflammatory diseases. IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21R, and the common γ-chain. IL-21 is mostly produced by CD4+ T cells, but molecular mechanisms that regulate IL-21 synthesis are not fully understood. The fact that CD4+ T cells express high levels of IL-21R and are capable of functionally responding to IL-21 raises the possibility that IL-21 may regulate its own production. We here show that IL-21 enhances IL-21 RNA and protein expression in human peripheral blood CD3+ T cells in a dose- and time-dependent fashion. Additionally, both IL-7 and IL-15, but not IL-4, induce IL-21, thus suggesting that common γ-chain signals are not sufficient to promote IL-21 synthesis. Analysis of molecular mechanisms underlying IL-21 induction reveals that IL-21 activates Stat3 and enhances its recruitment to IL-21 gene promoter. Pharmacologic inhibition and knockdown of Stat3 by small interference RNA largely prevent IL-21 induction in IL-21-treated cells. Consistently, IL-21 is inducible in T cells by IL-6, another cytokine that activates Stat3. Finally, we show that IL-21 positively regulates its own expression in human intestinal CD3+ lamina propria lymphocytes, and blockade of endogenous IL-21 in cultures of CD3+ lamina propria lymphocytes isolated from patients with Crohn's disease, a chronic inflammatory bowel disease characterized by high IL-21, down-regulates Stat3 activation and IL-21 expression. These data suggest the existence of a positive autocrine loop that could help to amplify and stabilize IL-21-driven, T cell-mediated responses

The PRE-Derived NMR Model of the 38.8-kDa Tri-Domain IsdH Protein from Staphylococcus aureus Suggests That It Adaptively Recognizes Human Hemoglobin

Staphylococcus aureus is a medically important bacterial pathogen that, during infections, acquires iron from human hemoglobin (Hb). It uses two closely related iron-regulated surface determinant (Isd) proteins to capture and extract the oxidized form of heme (hemin) from Hb, IsdH and IsdB. Both receptors rapidly extract hemin using a conserved tri-domain unit consisting of two NEAT (near iron transporter) domains connected by a helical linker domain. To gain insight into the mechanism of extraction, we used NMR to investigate the structure and dynamics of the 38.8-kDa tri-domain IsdH protein (IsdHN2N3, A326–D660 with a Y642A mutation that prevents hemin binding). The structure was modeled using long-range paramagnetic relaxation enhancement (PRE) distance restraints, dihedral angle, small-angle X-ray scattering, residual dipolar coupling and inter-domain NOE nuclear Overhauser effect data. The receptor adopts an extended conformation wherein the linker and N3 domains pack against each other via a hydrophobic interface. In contrast, the N2 domain contacts the linker domain via a hydrophilic interface and, based on NMR relaxation data, undergoes inter-domain motions enabling it to reorient with respect to the body of the protein. Ensemble calculations were used to estimate the range of N2 domain positions compatible with the PRE data. A comparison of the Hb-free and Hb-bound forms reveals that Hb binding alters the positioning of the N2 domain. We propose that binding occurs through a combination of conformational selection and induced-fit mechanisms that may promote hemin release from Hb by altering the position of its F helix