Active eosinophils regulate host defence and immune responses in colitis.

In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.

The Short Chain Fatty Acid Butyrate Imprints an Antimicrobial Program in Macrophages.

Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis.

The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.

Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage.

Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-) mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1(-/-) and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. VIDEO ABSTRACT.

Helicobacter pylori Chronic-Stage Inflammation Undergoes Fluctuations That Are Altered in tlpA Mutants.

Helicobacter pylori colonizes half of the world's population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an 8-month mouse infection time course and comparison of the wild type (WT) and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic-stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from the wild type at some time points. tlpA mutants have equivalent total and gland colonization in late-stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to those by WT. Our results suggest the chronic inflammation setting is dynamic and may be influenced by colonization properties of early infection.

ATG5 promotes eosinopoiesis but inhibits eosinophil effector functions.

Eosinophils are white blood cells that contribute to the regulation of immunity and are involved in the pathogenesis of numerous inflammatory diseases. In contrast to other cells of the immune system, no information is available regarding the role of autophagy in eosinophil differentiation and functions. To study the autophagic pathway in eosinophils, we generated conditional knockout mice in which Atg5 is deleted within the eosinophil lineage only (designated Atg5eoΔ mice). Eosinophilia was provoked by crossbreeding Atg5eoΔ mice with Il5 (IL-5) overexpressing transgenic mice (designated Atg5eoΔIl5tg mice). Deletion of Atg5 in eosinophils resulted in a dramatic reduction in the number of mature eosinophils in blood and an increase of immature eosinophils in the bone marrow. Atg5-knockout eosinophil precursors exhibited reduced proliferation under both in vitro and in vivo conditions but no increased cell death. Moreover, reduced differentiation of eosinophils in the absence of Atg5 was also observed in mouse and human models of chronic eosinophilic leukemia. Atg5-knockout blood eosinophils exhibited augmented levels of degranulation and bacterial killing in vitro. Moreover, in an experimental in vivo model, we observed that Atg5eoΔ mice achieve better clearance of the local and systemic bacterial infection with Citrobacter rodentium. Evidence for increased degranulation of ATG5low-expressing human eosinophils was also obtained in both tissues and blood. Taken together, mouse and human eosinophil hematopoiesis and effector functions are regulated by ATG5, which controls the amplitude of overall antibacterial eosinophil immune responses.

Emergency Presentations for Dizziness-Radiological Findings, Final Diagnoses, and Mortality.

Background: Dizziness is a frequent presentation in patients presenting to emergency departments (EDs), often triggering extensive work-up, including neuroimaging. Therefore, gathering knowledge on final diagnoses and outcomes is important. We aimed to describe the incidence of dizziness as primary or secondary complaint, to list final diagnoses, and to determine the use and yield of neuroimaging and outcomes in these patients. Methods: Secondary analysis of two observational cohort studies, including all patients presenting to the ED of the University Hospital of Basel from 30th January 2017-19th February 2017 and from 18th March 2019-20th May 2019. Baseline demographics, Emergency Severity Index (ESI), hospitalization, admission to Intensive Care Units (ICUs), and mortality were extracted from the electronic health record database. At presentation, patients underwent a structured interview about their symptoms, defining their primary and secondary complaints. Neuroimaging results were obtained from the picture archiving and communication system (PACS). Patients were categorized into three non-overlapping groups: dizziness as primary complaint, dizziness as secondary complaint, and absence of dizziness. Results: Of 10076 presentations, 232 (2.3%) indicated dizziness as their primary and 984 (9.8%) as their secondary complaint. In dizziness as primary complaint, the three (out of 73 main conditions defined) main diagnoses were nonspecific dizziness (47, 20.3%), dysfunction of the peripheral vestibular system (37, 15.9%), as well as somatization, depression, and anxiety (20, 8.6%). 104 of 232 patients (44.8%) underwent neuroimaging, with relevant findings in 5 (4.8%). In dizziness as primary complaint 30-day mortality was 0%. Conclusion: Work-up for dizziness in emergency presentations has to consider a broad differential diagnosis, but due to the low yield, it should include neuroimaging only in few and selected cases, particularly with additional neurological abnormalities. Presentation with primary dizziness carries a generally favorable prognosis lacking short-term mortality. .

IRF4 Expression Is Required for the Immunoregulatory Activity of Conventional Type 2 Dendritic Cells in Settings of Chronic Bacterial Infection and Cancer.

The lamina propria of the gastrointestinal tract and other mucosal surfaces of humans and mice host a network of mononuclear phagocytes that differ in their ontogeny, surface marker and transcription factor expression, and functional specialization. Conventional dendritic cells (DCs) in particular exist as two major subpopulations in both lymphoid and nonlymphoid organs that can be distinguished based on their surface marker and transcription factor expression. In this study, we show in various Th1- and/or Th17-polarized settings of acute and chronic bacterial infection and of tumor growth that the conditional ablation of Irf4 in CD11c+ DCs results in more efficient immune control of Helicobacter pylori, Mycobacterium bovis bacillus Calmette-Guérin, and Citrobacter rodentium and of tumor growth in a syngeneic tumor model. We attribute the phenotype of IRF4ΔDC mice to unrestricted Th1 responses and in particular to IFN-γ- and TNF-α-expressing CD4+ T cells. This activity of IRF4-expressing DCs is linked to a DC-specific immunoregulatory transcriptional program. In contrast, in Th2-polarized settings such as house dust mite-induced allergic airway inflammation, the lack of IRF4 expression in the DC compartment alleviates inflammation and goblet cell metaplasia. The combined data provide evidence for immunoregulatory properties of this versatile DC population in Th1-polarized infection settings.

Validation of a Simple Score for Mortality Prediction in a Cohort of Unselected Emergency Patients.

Background: Prognostication is an important component of medical decision-making. A patients' general prognosis can be difficult to measure. The Simple Prognostic Score (SPS) was designed to include patients' age, mobility, aggregated vital signs, and the treating physician's decision to admit to aid prognostication. Study Aim. Our study aim is to validate the SPS, compare it with the Emergency Severity Index (ESI) regarding its prognostic performance, and test the interrater reliability of the subjective variable of the decision to admit. Methods: Over a period of 9 weeks all patients presenting to the ED were included, routinely interviewed, final disposition registered, and followed up for one year. The C-statistics of discrimination was used to compare SPS and ESI predictions of 7-day, 30-day, and 1-year mortality. Youden J Statistics and Odds ratio, using logistical regression, were calculated for the Simple Prognostic Score. In a subset, a chart review was performed by senior physicians for a secondary assessment of the decision to admit. Interrater reliability was calculated using percentages and Cohens Kappa. Results: Out of 5648 patients, 3272 (57.9%) had a low SPS (i.e., ≤ 1); none of these patients died within 7 days, 2 (0.1%) died within 30 days after presentation and 19 (0.6%) died within a year. The area under the curve for 1-year mortality of the Simple Prognostic Score was 0.848. Secondary analysis of the interrater agreement for the decision to admit was 92%. Conclusion: In a prospective study of unselected ED patients, the Simple Prognostic Score was validated as a reliable predictor of short- and long-term mortality.

BATF3-dependent dendritic cells drive both effector and regulatory T-cell responses in bacterially infected tissues.

The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion.

The Cellular Functions of Eosinophils: Collegium Internationale Allergologicum (CIA) Update 2020.

Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also reflect on patient data from clinical trials that feature anti-eosinophil therapeutics.

Stress-free single-cell transcriptomic profiling and functional genomics of murine eosinophils.

Eosinophils are a class of granulocytes with pleiotropic functions in homeostasis and various human diseases. Nevertheless, they are absent from conventional single-cell RNA sequencing atlases owing to technical difficulties preventing their transcriptomic interrogation. Consequently, eosinophil heterogeneity and the gene regulatory networks underpinning their diverse functions remain poorly understood. We have developed a stress-free protocol for single-cell RNA capture from murine tissue-resident eosinophils, which revealed distinct intestinal subsets and their roles in colitis. Here we describe in detail how to enrich eosinophils from multiple tissues of residence and how to capture high-quality single-cell transcriptomes by preventing transcript degradation. By combining magnetic eosinophil enrichment with microwell-based single-cell RNA capture (BD Rhapsody), our approach minimizes shear stress and processing time. Moreover, we report how to perform genome-wide CRISPR pooled genetic screening in ex vivo-conditioned bone marrow-derived eosinophils to functionally probe pathways required for their differentiation and intestinal maturation. These protocols can be performed by any researcher with basic skills in molecular biology and flow cytometry, and can be adapted to investigate other granulocytes, such as neutrophils and mast cells, thereby offering potential insights into their roles in both homeostasis and disease pathogenesis. Single-cell transcriptomics of eosinophils can be performed in 2-3 d, while functional genomics assays may require up to 1 month.

Nonspecific stress biomarkers for mortality prediction in older emergency department patients presenting with falls: a prospective multicenter observational study.

BACKGROUND: Older patients presenting to the emergency department (ED) after falling are increasingly prevalent. Falls are associated with functional decline and death. Biomarkers predicting short-term mortality might facilitate decisions regarding resource allocation and disposition. D-dimer levels are used to rule out thromboembolic disease, while copeptin and adrenomedullin (MR-proADM) may be used as measures of the patient`s stress level. These nonspecific biomarkers were selected as potential predictors for mortality. METHODS: Prospective, international, multicenter, cross-sectional observation was performed in two tertiary and two regional hospitals in Germany and Switzerland. Patients aged 65 years or older presenting to the ED after a fall were enrolled. Demographic data, Activities of Daily Living (ADL), and D-dimers were collected upon presentation. Copeptin and MR-proADM levels were determined from frozen samples. Primary outcome was 30-day mortality; and secondary outcomes were mortality at 90, 180, and 365 days. RESULTS: Five hundred and seventy-two patients were included. Median age was 83 [IQR 78, 89] years, 236 (67.7%) were female. Mortality overall was 3.1% (30 d), 5.4% (90 d), 7.5% (180 d), and 13.8% (365 d), respectively. Non-survivors were older, had a lower ADL index and higher levels of all three biomarkers. Elevated levels of MR-proADM and D-dimer were associated with higher risk of mortality. MR-proADM and D-dimer showed high sensitivity and low negative likelihood ratio regarding short-term mortality, whereas copeptin did not. CONCLUSION: D-dimer and MR-proADM levels might be useful as prognostic markers in older patients presenting to the ED after a fall, by identifying patients at low risk of short-term mortality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02244983.

The C-terminally encoded, MHC class II-restricted T cell antigenicity of the Helicobacter pylori virulence factor CagA promotes gastric preneoplasia.

Chronic infection with the human bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to an increased gastric cancer risk. Consequently, H. pylori-specific vaccination is widely viewed as a promising strategy of gastric cancer prevention. H. pylori strains harboring the Cag pathogenicity island (PAI) are associated with particularly unfavorable disease outcomes in humans and experimental rodent models. We show in this study using a C57BL/6 mouse model of Cag-PAI(+) H. pylori infection that the only known protein substrate of the Cag-PAI-encoded type IV secretion system, the cytotoxin-associated gene A (CagA) protein, harbors MHC class II-restricted T cell epitopes. Several distinct nonoverlapping epitopes in CagA's central and C-terminal regions were predicted in silico and could be confirmed experimentally. CagA(+) infection elicits CD4(+) T cell responses in mice, which are strongly enhanced by prior mucosal or parenteral vaccination with recombinant CagA. The adoptive transfer of CagA-specific T cells to T cell-deficient, H. pylori-infected recipients is sufficient to induce the full range of preneoplastic immunopathology. Similarly, immunization with a cholera toxin-adjuvanted, CagA(+) whole-cell sonicate vaccine sensitizes mice to, rather than protects them from, H. pylori-associated gastric cancer precursor lesions. In contrast, H. pylori-specific tolerization by neonatal administration of H. pylori sonicate in conjunction with a CD40L-neutralizing Ab prevents H. pylori-specific, pathogenic T cell responses and gastric immunopathology. We conclude that active tolerization may be superior to vaccination strategies in gastric cancer prevention.

Emerging functions of tissue-resident eosinophils.

Eosinophils are typically considered tissue-damaging effector cells in type 2 immune-related diseases. However, they are also increasingly recognized as important modulators of various homeostatic processes, suggesting they retain the ability to adapt their function to different tissue contexts. In this review, we discuss recent progress in our understanding of eosinophil activities within tissues, with particular emphasis on the gastrointestinal tract, where a large population of these cells resides under non-inflammatory conditions. We further examine evidence of their transcriptional and functional heterogeneity and highlight environmental signals emerging as key regulators of their activities, beyond classical type 2 cytokines.

Throughput delays: causes, predictors, and outcomes - observational cohort in a Swiss emergency department.

BACKGROUND: Optimal throughput times in emergency departments can be adjudicated by emergency physicians. Emergency physicians can also define causes of delays during work-up, such as waiting for imaging, clinical chemistry, consultations, or exit blocks. For adequate streaming, the identification of predictors of delays is important, as the attribution of resources depends on acuity, resources, and expected throughput times. OBJECTIVE: This observational study aimed to identify the causes, predictors, and outcomes of emergency physician-adjudicated throughput delays. METHODS: Two prospective emergency department cohorts from January to February 2017 and from March to May 2019 around the clock in a tertiary care centre in Switzerland were investigated. All consenting patients were included. Delay was defined as the subjective adjudication of the responsible emergency physician regarding delay during emergency department work-up. Emergency physicians were interviewed for the occurrence and cause of delays. Baseline demographics, predictor values, and outcomes were recorded. The primary outcome - delay - was presented using descriptive statistics. Univariable and multivariable logistic regression analyses were performed to assess the associations between possible predictors and delays and hospitalization, intensive care, and death with delay. RESULTS: In 3656 (37.3%) of 9818 patients, delays were adjudicated. The patients with delays were older (59 years, interquartile range [IQR]: 39-76 years vs 49 years, IQR: 33-68 years) and more likely had impaired mobility, nonspecific complaints (weakness or fatigue), and frailty than the patients without delays. The main causes of delays were resident work-up (20.4%), consultations (20.2%), and imaging (19.4%). The predictors of delays were an Emergency Severity Index of 2 or 3 at triage (odds ratio [OR]: 3.00; confidence interval [CI]: 2.21-4.16; OR: 3.25; CI: 2.40-4.48), nonspecific complaints (OR: 1.70; CI: 1.41-2.04), and consultation and imaging (OR: 2.89; CI: 2.62-3.19). The patients with delays had an increased risk for admission (OR: 1.56; CI: 1.41-1.73) but not for mortality than those without delays. CONCLUSION: At triage, simple predictors such as age, immobility, nonspecific complaints, and frailty may help to identify patients at risk of delay, with the main reasons being resident work-up, imaging, and consultations. This hypothesis-generating observation will allow the design of studies aimed at the identification and elimination of possible throughput obstacles.

Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia.

BACKGROUND & AIMS: Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected persons will develop overt disease; most remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H pylori that is found both across and within populations. METHODS: We have established a C57BL/6 mouse model of H pylori infection with a strain that is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cells through the activity of a Cag-pathogenicity island-encoded type IV secretion system. RESULTS: Mice infected at 5-6 weeks of age with CagA(+)H pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia, and metaplasia in a type IV secretion system-dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H pylori-specific peripheral immunologic tolerance, which requires transforming growth factor-ß signaling and is mediated by long-lived, inducible regulatory T cells, and which controls the local CD4(+) T-cell responses that trigger premalignant transformation. Tolerance to H pylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and is favored by prolonged low-dose exposure to antigen. CONCLUSIONS: Using a novel CagA(+)H pylori infection model, we report here that the development of tolerance to H pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected persons to H pylori-associated disease manifestations.

Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins.

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathologic features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphoma-derived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self- and foreign antigens, including Helicobacter sonicate, immunoglobulin G (IgG), DNA, and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive enzyme-linked immunosorbent assays. A strong bias toward the use of V(H) gene segments previously linked to autoantibodies and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self- and foreign antigens, providing direct antigenic stimulation of the tumor cells via their B-cell receptor.

Adapting to their new home: Eosinophils remodel the gut architecture.

In this issue of JEM, Diny et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20210970) identify the aryl hydrocarbon receptor (AHR) as a key orchestrator of eosinophil tissue adaptation in the small intestine, controlling their lifespan, degranulation, and tissue-remodeling activities.

H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection.

Persistent infection with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to a high gastric cancer risk, but has also been linked to protection from allergic, chronic inflammatory and autoimmune diseases. In the course of tens of thousands of years of co-existence with its human host, H. pylori has evolved elaborate adaptations that allow it to persist in the hostile environment of the stomach in the face of a vigorous innate and adaptive immune response. For this review, we have identified several key immune cell types and signaling pathways that appear to be preferentially targeted by the bacteria to establish and maintain persistent infection. We explore the mechanisms that allow the bacteria to avoid detection by innate immune cells via their pattern recognition receptors, to escape T-cell mediated adaptive immunity, and to reprogram the immune system towards tolerance rather than immunity. The implications of the immunomodulatory properties of the bacteria for the prevention of allergic and auto-immune diseases in chronically infected individuals are also discussed.