Crohn's Patients and Healthy Infants Share Immunodominant B Cell Response to Commensal Flagellin Peptide Epitopes.

Background & Aims: Inflammatory bowel disease (IBD) is a chronic manifestation of dysregulated immune response to the gut microbiota in genetically predisposed hosts. Nearly half of patients with Crohn's disease (CD) develop selective serum immunoglobulin (Ig)G response to flagellin proteins expressed by bacteria in the Lachnospiraceae family. This study aimed to identify the binding epitopes of these IgG antibodies and assess their relevance in CD and in homeostasis.

Crohn's patients and healthy infants share immunodominant B cell response to commensal flagellin peptide epitopes.

About half of patients with Crohn's disease (CD) develop selective serum IgG response to flagellin proteins of the family. Here, we identified a dominant B cell peptide epitope in CD, locating in the highly conserved "hinge region" between the D0 and D1 domains at the amino-terminus of flagellins. Serum IgG reactive to this epitope is present at an elevated level in adult CD patients and in pediatric CD patients at diagnosis.

Crohn's Disease Patients Uniquely Contain Inflammatory Responses to Flagellin in a CD4 Effector Memory Subset.

Background: Specific microbial antigens stimulate production of antibodies indicative of the aberrant immune response in Crohn's disease (CD). We tested for T cell reactivity linkage to B cell responses and now report on the prevalence, functionality, and phenotypic differences of flagellin-specific T cells among CD patients, ulcerative colitis (UC) patients, and control subjects and association with clinical features and flagellin seropositivity within CD patients.

Methods: Sera from non-inflammatory bowel disease control subjects, CD patients, and UC patients were probed for antibody reactivity to gut bacterial recombinant flagellin antigens.

Human Microbiota Flagellins Drive Adaptive Immune Responses in Crohn's Disease.

Background And Aims: Crohn's disease and ulcerative colitis are characterized by dysregulated adaptive immune responses to the microbiota in genetically susceptible individuals, but the specificity of these responses remains largely undefined. Therefore, we developed a microbiota antigen microarray to characterize microbial antibody reactivity, particularly to human-derived microbiota flagellins, in inflammatory bowel disease.

Methods: Sera from healthy volunteers (n = 87) at the University of Alabama at Birmingham and from patients recruited from the Kirklin Clinic of University of Alabama at Birmingham Hospital, including patients with Crohn's disease (n = 152) and ulcerative colitis (n = 170), were individually probed against microbiota bacterial flagellins of both mouse and human origin and analyzed for IgG and IgA antibody responses.

CD4 T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis.

Microbiota-reactive CD4 T memory (T) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4 T effector (T) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike T cells, T cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset.

Flagellin-Specific CD4 Cytokine Production in Crohn Disease and Controls Is Limited to a Small Subset of Antigen-Induced CD40L T Cells.

Flagellin is an immunodominant Ag in Crohn disease, with many patients showing anti-flagellin Abs. To study the clonality of flagellin-reactive CD4 cells in Crohn patients, we used a common CD154-based enrichment method following short-term Ag exposure to identify Ag-reactive CD4 cells. CD154 expression and cytokine production following Ag exposure compared with negative control responses (no Ag exposure) revealed that only a small fraction of CD154-enriched cells could be defined by Ag-reactive cytokine responses.

Mucosa-Associated Microbiota in Barrett's Esophagus, Dysplasia, and Esophageal Adenocarcinoma Differ Similarly Compared With Healthy Controls.

Introduction: Alterations in the composition of the human gut microbiome and its metabolites have been linked to gut epithelial neoplasia. We hypothesized that differences in mucosa-adherent Barrett's microbiota could link to risk factors, providing risk of progression to neoplasia.

Methods: Paired biopsies from both diseased and nonaffected esophagus (as well as gastric cardia and gastric juice for comparison) from patients with intestinal metaplasia (n = 10), low grade dysplasia (n = 10), high grade dysplasia (n = 10), esophageal adenocarcinoma (n = 12), and controls (n = 10) were processed for mucosa-associated bacteria and analyzed by 16S ribosomal ribonucleic acid V4 gene DNA sequencing.

Human seroreactivity to gut microbiota antigens.

Background: Although immune responses directed against antigens from the intestinal microbiota are observed in certain diseases, the normal human adaptive immune response to intestinal microbiota is poorly defined.

Objective: Our goal was to assess the adaptive immune response to the intestinal microbiota present in 143 healthy adults and compare this response with the response observed in 52 children and their mothers at risk of having allergic disease.

Methods: Human serum was collected from adults and children followed from birth to 7 years of age, and the serum IgG response to a panel of intestinal microbiota antigens was assessed by using a novel protein microarray.

Body Mass Index Is Associated With Mucosal Disease in Crohn's: Results of a Case-Control Study.

Background: Recent studies have suggested that increased body mass index (BMI) may have an adverse effect on treatment outcomes and natural history in Crohn's disease (CD). We aimed to test the hypothesis that CD patients with higher BMI would be more likely than those with lower BMI to have persistent active mucosal disease.

Methods: We designed a case-control study.

Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells.

Increased apoptotic death of gastric epithelial cells is a hallmark of Helicobacter pylori infection, and altered epithelial cell turnover is an important contributor to gastric carcinogenesis. To address the fate of apoptotic gastric epithelial cells and their role in H. pylori mucosal disease, we investigated phagocyte clearance of apoptotic gastric epithelial cells in H.

Extracorporeal photopheresis (ECP) in patients with steroid-dependent Crohn's disease: an open-label, multicenter, prospective trial.

Background: Extracorporeal photopheresis (ECP) involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permits corticosteroid withdrawal in steroid-dependent Crohn's disease (CD) patients who were in clinical remission. We studied the effect of ECP on steroid withdrawal in steroid-dependent CD.

Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn's disease.

Introduction: Human mesenchymal stem cells (Prochymal brand of remestemcel-L) have been developed for experimental use in Crohn's disease and other conditions. Mesenchymal stems cells (MSCs) have been shown to inhibit inflammatory responses of innate and adaptive immune cells as well as have reparative effects on inflamed tissues. Promising preliminary therapeutic results of MSCs on gastrointestinal graft-versus-host disease have lead to Phase III trials for active Crohn's disease.

The effect of intermittent IL-2 therapy on CD4 T cells in the gut in HIV-1-infected patients.

We sought to determine the effects of interleukin-2 administered in combination with antiretroviral therapy (ART) on CD4+ T cells in the gut. Lymphocytes from whole blood, colon, and terminal ileum of HIV-infected adults treated with interleukin-2 and ART or ART alone were examined. There were no differences between groups in the proportion of CD4+ T cells or in expression of CD25 or Ki67 by CD4+ T cells in the gut.

Suppression of inflammation in ulcerative colitis by interferon-β-1a is accompanied by inhibition of IL-13 production.

Objective: Ulcerative colitis is associated with increased interleukin 13 (IL-13) production by natural killer T cells. Taking advantage of the inhibitory actions of interferon β on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of ulcerative colitis symptoms.

Design: Open-label interventional drug trial.

Multiple endoscopic biopsies in research subjects: safety results from a National Institutes of Health series.

Background: Routine endoscopic mucosal biopsies are generally considered safe. However, the outcomes of performing large numbers of biopsies in subjects enrolled in research protocols have not been reported.

Objective: Our purpose was to assess the safety of taking numerous mucosal biopsy specimens during endoscopic procedures (eg, >20/endoscopic procedure) in research subjects.

Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy.

Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time.

Anti-IgE treatment of eosinophil-associated gastrointestinal disorders.

Background: Eosinophil-associated gastrointestinal disorders (EGIDs) are commonly associated with atopy and are being recognized with increasing frequency. Current therapy for EGIDs is inadequate.

Objective: We sought to determine the efficacy of anti-IgE therapy in EGIDs and investigate the role of IgE in disease pathogenesis.

Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency.

Background & Aims: Common variable immunodeficiency (CVID) patients can develop an idiopathic inflammatory bowel disease resulting in chronic diarrhea and life-threatening malabsorption. This study was designed to assess the status of the gastrointestinal tract and to define the mucosal immune abnormalities in patients with and without symptomatic gut inflammatory disease.

Methods: CVID patients underwent tests of gut absorption, peripheral blood mononuclear cell phenotyping, and upper and lower endoscopy for histology and lamina propria mononuclear cell (LPMC) cytokine production.

Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.

Background: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb).

Methods: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported.

Anti-interleukin-12 antibody for active Crohn's disease.

Background: Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses.

Methods: This double-blind trial evaluated the safety and efficacy of a human monoclonal antibody against interleukin-12 (anti-interleukin-12) in 79 patients with active Crohn's disease.

Peptide YY as a growth factor for intestinal epithelium.

Peptide YY is an abundant distal gut hormone that may play a significant role in intestinal epithelial proliferation. Gut epithelial cells express specific receptors for PYY, PYY induces proliferation in intestinal cells in vivo and in vitro, and the Y1 receptor subtype couples to mitogenic signaling pathways. In addition to proposed physiologic effects on gut mucosal maintenance, PYY proliferative effects may be hypothesized to contribute to pathophysiologic consequences of stimulated growth.