To determine genetic susceptibility factors for Helicobacter pylori infection, polymorphic T-cell receptor gene elements were investigated in 203 H. pylori-infected individuals and 180 uninfected individuals (controls).H. pylori infection is highly associated with individuals homozygous for the nonfunctional TCRBV6S1B element (odds ratio ؍ 5.9; 2 ؍ 13; P ؍ 0.00032; P value corrected for multiple comparisons [Bonferroni correction] ؍ 0.00063).Presentation of bacterial antigens and recognition via T lymphocytes play a central role in the immune response to most bacterial antigens, including Helicobacter pylori (1, 6). We investigated three highly polymorphic microsatellites, TCRBV6S7, TCRBV6S1, and TCRBV6S3 (3, 7), and correlated them with exonic polymorphisms of the T-cell receptor (4) for associated susceptibility to H. pylori infection.A total of 383 unrelated, German individuals (ranging in age from 16 to 94 years; mean age, 59 years) undergoing gastroesophageal duodenoscopy for various clinical indications such as upper abdominal pain or noncardiac chest pain were included in this study after giving informed consent. Persons with a history of eradication therapy, acid-suppressive therapy within the last 4 weeks, evidence of malignancy, immunosuppression, or history of gastric surgery were excluded. H. pylori status was determined by rapid urease test, culture, and histology. At least two procedures had to yield positive results before subjects were considered infected. Individuals were considered H. pylori negative if all tests gave negative results. If one test result differed from the other two, serology was performed (Helicobacter pylori IgG ELISA kit; Medac, Hamburg, Germany). A total of 203 individuals were determined to be H. pylori positive and 180 individuals were determined to be H. pylori negative. In the H. pylori-positive group, 40 individuals suffered from gastric ulcer or had a history of gastric ulcer and 40 individuals had developed duodenal ulcer. There was no evidence for acute ulceration or history of ulcer disease in 123 individuals.DNA preparation and microsatellite analysis were performed as described previously (8,11). Haplotype frequencies were estimated by using ARLEQUIN software (standard deviation computed by 50 bootstraps) (14). Allele frequencies and estimated haplotype frequencies were compared by using a 2 ϫ 2 contingency table and 2 statistics and were considered significantly different if the P values were Ͻ0.05. Differences in allele or genotype distribution between the infected cohort and control cohort were quantitated using odds ratios (OR). Only
The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis. MIF-deficient mice failed to develop disease, but reconstitution of MIF-deficient mice with wild-type innate immune cells restored colitis. In addition, established colitis could be treated with anti-MIF immunoglobulins. Thus, murine colitis is dependent on continuous MIF production by the innate immune system. Because we found increased plasma MIF concentrations in patients with Crohn's disease, these data suggested that MIF is a new target for intervention in Crohn's disease.
Inflammatory bowel diseases (IBD) can be broadly divided into Crohn's disease (CD) and ulcerative colitis (UC) from their clinical phenotypes. Over 150 host susceptibility genes have been described, although most overlap between CD, UC and their subtypes, and they do not adequately account for the overall incidence or the highly variable severity of disease. Replicating key findings between two long-term IBD cohorts we have defined distinct networks of taxa associations within intestinal biopsies of CD and UC patients. Disturbances in an association network containing taxa of the Lachnospiraceae and Ruminococcaceae families, typically producing short chain fatty acids, characterize frequently relapsing disease and poor responses to treatment with anti-TNF-α therapeutic antibodies. Alterations of taxa within this network also characterize risk of later disease recurrence of patients in remission after the active inflamed segment of CD has been surgically removed.
Whereas the median delay for diagnosing CD, UC, and IC seems to be acceptable, there exists a long delay in a considerable proportion of CD patients. More public awareness work needs to be done in order to reduce patient and doctor delays in this target population.
In an analysis of a large cohort of subjects with IBD, we found a significant association between symptoms of depression or anxiety and clinical recurrence. Patients with IBD should therefore be screened for clinically relevant levels of depression and anxiety and referred to psychologists or psychiatrists for further evaluation and treatment.
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