RESUMEN
A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.
Asunto(s)
Enfermedades Autoinmunes , Bibliometría , Mucosa Gástrica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/epidemiología , Humanos , Gastritis/inmunología , Gastritis/microbiología , Gastritis/epidemiología , Gastritis/patología , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Lesiones Precancerosas/epidemiología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/epidemiología , Mucosa Gástrica/patología , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Metaplasia , Factores de Riesgo , Estómago/patología , Estómago/inmunología , Estómago/microbiología , Microbioma Gastrointestinal/inmunología , RatonesRESUMEN
Chemokine receptors are essential for the immune response in the oral and gut mucosa. The gastrointestinal mucosa is characterized by the presence of immune populations because it is susceptible to inflammatory and infectious diseases, necessitating immune surveillance. Chemokine receptors are expressed on immune cells and play a role in gastrointestinal tissue-homing, although other non-immune cells also express them for various biological functions. CCR9, CXCR3 and CXCR6 play an important role in the T cell response in inflammatory and neoplastic conditions of the gastrointestinal mucosa. However, CXCR6 could also be found in gastric cancer cells, highlighting the different roles of chemokine receptors in different pathologies. On the other hand, CCR4 and CCR8 are critical for Treg migration in gastrointestinal tissues, correlating with poor prognosis in mucosal cancers. Other chemokine receptors are also important in promoting myeloid infiltration with context-dependent roles. Further, CXCR4 and CXCR7 are also present in gastrointestinal tumor cells and are known to stimulate proliferation, migration, and invasion into other tissues, among other pro-tumorigenic functions. Determining the processes underlying mucosal immunity and creating tailored therapeutic approaches for gastrointestinal diseases requires an understanding of the complex interactions that occur between chemokine receptors and their ligands in these mucosal tissues.
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Receptores de Quimiocina , Humanos , Receptores de Quimiocina/metabolismo , Animales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunologíaRESUMEN
The mucus serves as a protective barrier in the gastrointestinal tract against microbial attacks. While its role extends beyond merely being a physical barrier, the extent of its active bactericidal properties remains unclear, and the mechanisms regulating these properties are not yet understood. We propose that inflammation induces epithelial cells to secrete antimicrobial peptides, transforming mucus into an active bactericidal agent. To investigate the properties of mucus, we previously developed mucosoid culture models that mimic the healthy human stomach epithelium. Similar to organoids, mucosoids are stem cell-driven cultures; however, the cells are cultivated on transwells at air-liquid interface. The epithelial cells of mucosoids form a polarized monolayer, allowing differentiation into all stomach lineages, including mucus-secreting cells. This setup facilitates the secretion and accumulation of mucus on the apical side of the mucosoids, enabling analysis of its bactericidal effects and protein composition, including antimicrobial peptides. Our findings show that TNFα, IL1ß, and IFNγ induce the secretion of antimicrobials such as lactotransferrin, lipocalin2, complement component 3, and CXCL9 into the mucus. This antimicrobial-enriched mucus can partially eliminate Helicobacter pylori, a key stomach pathogen. The bactericidal activity depends on the concentration of each antimicrobial and their gene expression is higher in patients with inflammation and H.pylori-associated chronic gastritis. However, we also find that H. pylori infection can reduce the expression of antimicrobial encoding genes promoted by inflammation. These findings suggest that controlling antimicrobial secretion in the mucus is a critical component of epithelial immunity. However, pathogens like H. pylori can overcome these defenses and survive in the mucosa.
Asunto(s)
Péptidos Antimicrobianos , Mucosa Gástrica , Helicobacter pylori , Inflamación , Moco , Humanos , Moco/metabolismo , Moco/microbiología , Péptidos Antimicrobianos/metabolismo , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Inflamación/metabolismo , Células Epiteliales/microbiología , Células Epiteliales/metabolismo , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/inmunología , Estómago/microbiología , Organoides/metabolismo , Organoides/microbiologíaRESUMEN
Gastrointestinal mucosal surface is frequently under challenge due to it's the large surface area and most common entry of microbes. IL-37, an anti-inflammatory cytokine, regulates local and systemic host immunity. H. pylori infection leads to the inhibition of IL-37 in the gastric mucosa, contributing to heightened mucosal inflammation and destruction, thereby facilitating increased proliferation of H. pylori. Food allergy, due to immune dysregulation, also contribute to GI injury. On the other hand, elevated levels of IL-37 observed in gastric cancer patients align with reduced host immunity at the cellular and humoral levels, indicating that IL-37 may contribute to the development of gastric cancer via suppressing pro-inflammatory responses. While IL-37 provides protection in an IBD animal model, the detection of highly produced IL-37 in IBD patients suggests a stage-dependent role, being protective in acute inflammation but potentially exacerbates the development of IBD in chronic conditions. Moreover, elevated colonic IL-37 in CRC correlates with overall survival time and disease time, indicating a protective role for IL-37 in CRC. The differential regulation and expression of IL-37 between upper- and lower-GI organs may be attributed to variations in the microbial flora. This information suggests that IL-37 could be a potential therapeutic agent, depending on the stage and location.
Asunto(s)
Enfermedades Gastrointestinales , Interleucina-1 , Humanos , Interleucina-1/metabolismo , Animales , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/metabolismo , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Helicobacter pylori/inmunología , Microbioma Gastrointestinal/inmunologíaRESUMEN
Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity.NEW & NOTEWORTHY Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection.
Asunto(s)
Glucocorticoides , Infecciones por Helicobacter , Helicobacter pylori , Activación de Macrófagos , Macrófagos , Ratones Noqueados , Receptores de Glucocorticoides , Animales , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/microbiología , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Glucocorticoides/farmacología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Transducción de SeñalRESUMEN
The predominant characteristic of autoimmune gastritis (AIG) is corpus-dominant advanced atrophy, which is mostly observed in the middle to late stages. More reports are needed on the endoscopic features of the early stage. In this report, we present two cases of early-stage AIG in which endoscopic examinations showed no atrophy of the gastric mucosa but displayed a transition of collecting venules from a regular to an irregular arrangement. In addition, yellowish-white cobblestone-like elevations were observed in the fundic gland region. Histologically, the observed manifestations included pseudohypertrophy and protrusion of parietal cells into the lumen, possibly along with hyperplasia of G cells, lymphocytic infiltration and potentially pseudopyloric gland metaplasia. Serologically, the anti-parietal cell antibody returned positive results, whereas the anti-intrinsic factor antibody yielded negative results. In this study, we summarized some endoscopic features of two patients, aiming to provide clues for endoscopists to detect early-stage AIG.
Asunto(s)
Enfermedades Autoinmunes , Gastritis , Humanos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/patología , Masculino , Gastritis/inmunología , Gastritis/diagnóstico , Gastritis/patología , Femenino , Persona de Mediana Edad , Autoanticuerpos/inmunología , Mucosa Gástrica/patología , Mucosa Gástrica/inmunología , Células Parietales Gástricas/inmunología , Células Parietales Gástricas/patología , Gastroscopía , Biopsia , Anciano , AdultoRESUMEN
Immune-related adverse events (irAEs) are complications of the use of immune checkpoint inhibitors (ICIs). ICI-associated gastritis is one of the main irAEs. The gastric microbiota is often related to the occurrence and development of many gastric diseases. Gastric microbiota adjustment may be used to treat gastric disorders in the future. Faecal microbiota transplantation can alter the gut microbiota of patients and has been used for treating ICI-associated colitis. Therefore, we propose gastric microbiota transplantation as a supplementary treatment for patients with ICI-associated gastritis who do not respond well to conventional therapy.
Asunto(s)
Trasplante de Microbiota Fecal , Gastritis , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Humanos , Trasplante de Microbiota Fecal/métodos , Trasplante de Microbiota Fecal/efectos adversos , Mucosa Gástrica/microbiología , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Mucosa Gástrica/efectos de los fármacos , Gastritis/microbiología , Gastritis/inmunología , Gastritis/terapia , Gastritis/inducido químicamente , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estómago/microbiología , Estómago/inmunología , Estómago/cirugía , Resultado del TratamientoRESUMEN
Trained immunity is a concept in immunology in which innate immune cells, such as monocytes and macrophages, exhibit enhanced responsiveness and memory-like characteristics following initial contact with a pathogenic stimulus that may promote a more effective immune defense following subsequent contact with the same pathogen. Helicobacter pylori, a bacterium that colonizes the stomach lining, is etiologically associated with various gastrointestinal diseases, including gastritis, peptic ulcer, gastric adenocarcinoma, MALT lymphoma, and extra gastric disorders. It has been demonstrated that repeated exposure to H. pylori can induce trained immunity in the innate immune cells of the gastric mucosa, which become more responsive and better able to respond to subsequent H. pylori infections. However, interactions between H. pylori and trained immunity are intricate and produce both beneficial and detrimental effects. H. pylori infection is characterized histologically as the presence of both an acute and chronic inflammatory response called acute-on-chronic inflammation, or gastritis. The clinical outcomes of ongoing inflammation include intestinal metaplasia, gastric atrophy, and dysplasia. These same mechanisms may also reduce immunotolerance and trigger autoimmune pathologies in the host. This review focuses on the relationship between trained immunity and H. pylori and underscores the dynamic interplay between the immune system and the pathogen in the context of gastric colonization and inflammation.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Tolerancia Inmunológica , Inmunidad Innata , Humanos , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Animales , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/microbiología , Memoria Inmunológica , Inmunidad EntrenadaRESUMEN
BACKGROUND & AIMS: Type 2 innate lymphoid cells (ILC2s) and interleukin-13 (IL-13) promote the onset of spasmolytic polypeptide-expressing metaplasia (SPEM) cells. However, little is known about molecular effects of IL-13 in SPEM cells. We now sought to establish a reliable organoid model, Meta1 gastroids, to model SPEM cells in vitro. We evaluated cellular and molecular effects of ILC2s and IL-13 on maturation and proliferation of SPEM cells. METHODS: We performed single-cell RNA sequencing to characterize Meta1 gastroids, which were derived from stomachs of Mist1-Kras transgenic mice that displayed pyloric metaplasia. Cell sorting was used to isolate activated ILC2s from stomachs of IL-13-tdTomato reporter mice treated with L635. Three-dimensional co-culture was used to determine the effects of ILC2s on Meta1 gastroids. Mouse normal or metaplastic (Meta1) and human metaplastic gastroids were cultured with IL-13 to evaluate cell responses. Air-Liquid Interface culture was performed to test long-term culture effects of IL-13. In silico analysis determined possible STAT6-binding sites in gene promoter regions. STAT6 inhibition was performed to corroborate STAT6 role in SPEM cells maturation. RESULTS: Meta1 gastroids showed the characteristics of SPEM cell lineages in vitro even after several passages. We demonstrated that co-culture with ILC2s or IL-13 treatment can induce phosphorylation of STAT6 in Meta1 and normal gastroids and promote the maturation and proliferation of SPEM cell lineages. IL-13 up-regulated expression of mucin-related proteins in human metaplastic gastroids. Inhibition of STAT6 blocked SPEM-related gene expression in Meta1 gastroids and maturation of SPEM in both normal and Meta1 gastroids. CONCLUSIONS: IL-13 promotes the maturation and proliferation of SPEM cells consistent with gastric mucosal regeneration.
Asunto(s)
Proliferación Celular , Interleucina-13 , Metaplasia , Ratones Transgénicos , Factor de Transcripción STAT6 , Interleucina-13/metabolismo , Interleucina-13/farmacología , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Humanos , Factor de Transcripción STAT6/metabolismo , Mucosa Gástrica/inmunología , Mucosa Gástrica/citología , Mucosa Gástrica/patología , Mucosa Gástrica/metabolismo , Organoides/metabolismo , Linfocitos/metabolismo , Linfocitos/inmunología , Linfocitos/efectos de los fármacos , Inmunidad Innata , Estómago/patología , Estómago/citología , Análisis de la Célula Individual , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Bactrian camels inhabiting desert and semi-desert regions of China are valuable animal models for studying adaptation to desert environments and heat stress. In this study, 16S rRNA technology was employed to investigate the distribution characteristics and differences of mucosal microorganisms in the anterior gland area, posterior gland area, third gland area, cardia gland area, gastric fundic gland area and pyloric gland area of 5-peak adult healthy Bactrian camels. We aimed to explore the possible reasons for the observed microbial distribution from the aspects of histological structure and mucosal immunity. Bacteroides and Fibrobacteria accounted for 59.54% and 3.22% in the gland area, respectively, and 52.37% and 1.49% in the wrinkled stomach gland area, respectively. The gland area showed higher abundance of Bacteroides and Fibrobacteria than the wrinkled stomach gland area. Additionally, the anterior gland area, posterior gland area, third gland area, and cardia gland area of Bactrian camels mainly secreted acidic mucus, while the gastric fundic gland area mainly secreted neutral mucus and the pyloric region mainly secreted a mixture of acidic and neutral mucus. The results of immunohistochemistry techniques demonstrated that the number of IgA+ cells in the anterior glandular area, posterior glandular area, third glandular area, and cardia gland area was significantly higher than that in the fundic and pyloric gland area (p < 0.05), and the difference in IgA+ between the fundic and pyloric gland area was not significant (p > 0.05). The study revealed a large number of bacteria that can digest and degrade cellulose on the mucosa of the gastric gland area of Bactrian camels. The distribution of IgA+ cells, the structure of the mucosal tissue in the glandular region, and the composition of the mucus secreted on its surface may have a crucial influence on microbial fixation and differential distribution.
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Camelus , Mucosa Gástrica , Inmunidad Mucosa , ARN Ribosómico 16S , Animales , Camelus/microbiología , Camelus/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , ARN Ribosómico 16S/genética , Bacterias/clasificación , Inmunoglobulina A/metabolismo , MasculinoRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) can evade the host's immune response and persist for a long time on the gastric mucosa. T helper (Th) cells appear to be involved in the control of H. pylori bacteria but promote mucosal inflammation. In contrast, regulatory T cells (Tregs) may reduce inflammation but promote H. pylori persistence. CC motif chemokine receptor 6 (CCR6) is involved in the migration of various cells into inflamed gastric mucosa. In this study, we examined CCR6+ Th cells and CCR6+ Tregs during H. pylori infection in humans. MATERIALS AND METHODS: Isolation of cells from blood and mucosal biopsies, magnetic separation of Рcells, CD4+ and CD4+CCR6+CD45RO+ T cells, antigen-specific activation, B cell response in vitro, flow cytometry, determination of CD4+CD25hiFoxP3+ Tregs and various groups of Th cells. RESULTS: CD4+CCR6+ blood lymphocytes from healthy donors included Th cells and Tregs. These CCR6+ Th cells produced proinflammatory cytokines and also stimulated plasma cell maturation and antibody production in vitro. H. pylori gastritis and peptic ulcer disease were associated with an increase in the number of circulate CD4+CCR6+CD45RO+ cells and the percentage of Th1, Th17 and Th1/17 cells in this lymphocyte subgroup. In H. pylori-positive patients, circulating CD4+CCR6+ cells contained a higher proportion of H. pylori-specific cells compared with their CD4+CCR6- counterparts. H. pylori infection strongly increased the content of CD4+ lymphocytes in the inflamed gastric mucosa, with the majority of these CD4+ lymphocytes expressing CCR6. CD4+CCR6+ lymphocytes from H. pylori-infected stomach included Tregs and in vivo activated T cells, some of which produced interferon-γ without ex vivo stimulation. CONCLUSION: H. pylori infection causes an increase in the number of mature CD4+CCR6+ lymphocytes in the blood, with a pro-inflammatory shift in their composition and enrichment of the gastric mucosa with CD4+CCR6+ lymphocytes, including CCR6+ Th1 cells and Tregs.
Asunto(s)
Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter pylori , Receptores CCR6 , Linfocitos T Reguladores , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Citometría de Flujo , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Receptores CCR6/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. . IMPORTANCE: Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.
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Mucosa Gástrica , Infecciones por Helicobacter , Helicobacter felis , Helicobacter pylori , Metaplasia , Ratones Endogámicos C57BL , Animales , Helicobacter pylori/inmunología , Helicobacter pylori/patogenicidad , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/inmunología , Ratones , Helicobacter felis/patogenicidad , Metaplasia/microbiología , Metaplasia/patología , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Mucosa Gástrica/inmunología , Gastritis/microbiología , Gastritis/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Inflamación/microbiología , Inflamación/patología , Femenino , Citocinas/metabolismo , Modelos Animales de Enfermedad , Estómago/patología , Estómago/microbiologíaRESUMEN
BACKGROUND: Due to increased anthelmintic resistance, alternative methods to drugs are necessary to control gastrointestinal nematodes (GINs). Some of the most promising alternatives are based on the immune response of the host, such as the selection of genetically resistant breeds or the use of vaccines against these parasites. Given the limited information available on the immune response against GINs in goats, this study investigated the local immune response of goat kids of an indigenous Canary Islands breed (Majorera breed) experimentally infected with Teladorsagia circumcincta, one of the most pathogenic and prevalent GIN species. METHODS: For this purpose, the relationship between different parasitological (number of mature and immature worms, worm length, and number of intrauterine eggs) and immunological parameters at the local level (related to both the humoral and cellular immune response) was analyzed at early (1 week post-infection [wpi]) and late (8 wpi) stages of infection. RESULTS: Primary infection of goat kids with T. circumcincta infective larvae (L3) generated a complex immune response that could be defined as Th2 type, characterized by increased infiltration in abomasal tissues of several effector cells as well as a progressive presence of specific antibodies against parasitic antigens in the gastric mucus. Cellular responses were evidenced from 1 wpi onward, showing an increase in antigen-presenting cells and various lymphocyte subsets in the gastric mucosa. CONCLUSIONS: The complexity of the host response was evidenced by statistically significant changes in the number of all these subpopulations (MHCII+, CD4+, CD8+, γδ+, CD45R+, IgA+, and IgG+), as well as in the evolution of the relative cytokine gene expression. From a functional point of view, negative associations were observed between the number of most of the immune cells (CD4, IgA, IgG, and CD45R cells) and parameters that could be related to the fecundity of worms, a phenomenon that was especially evident when the number of IgG and CD45R cells or the specific IgA levels of the gastric mucus were compared with parasitological parameters such as the female worm length or fecal egg counts at 8 wpi.
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Enfermedades de las Cabras/inmunología , Enfermedades de las Cabras/parasitología , Trichostrongyloidea/inmunología , Tricostrongiloidiasis/veterinaria , Abomaso/inmunología , Abomaso/parasitología , Animales , Heces/parasitología , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/parasitología , Cabras , Recuento de Huevos de Parásitos/veterinaria , España , Tricostrongiloidiasis/inmunología , Tricostrongiloidiasis/parasitologíaRESUMEN
BACKGROUND: Artemisia capillaris is among the most abundantly used traditional medicines, utilized in East Asia to treat diverse illnesses, including gastrointestinal tract diseases. We previously reported that an aqueous extract of A. capillaris (AEAC) inhibited gastric inflammation induced by HCl/ethanol via reactive oxygen species scavenging and NF-κB downregulation. To date, the pharmacological potential of AEAC for promoting mucosal integrity has not been studied. RESULTS: Here, we report that a single treatment with AEAC increased mucus production, and repeated administration of AEAC abolished HCl/ethanol-induced mucosal injury in vivo. Single- and multiple-dose AEAC treatments measurably increased the expression of mucosal stabilizing factors in vivo, including mucin (MUC) 5 AC, MUC6, and trefoil factor (TFF) 1 and TFF2 (but not TFF3). AEAC also induced mucosal stabilizing factors in both SNU-601 cells and RGM cells through phosphorylation of extracellular signal-regulated kinases. CONCLUSION: Taken together, our results suggest that AEAC protects against HCl/ethanol-induced gastritis by upregulating MUCs and TFFs and stabilizing the mucosal epithelium. © 2021 Society of Chemical Industry.
Asunto(s)
Artemisia/química , Medicamentos Herbarios Chinos/farmacología , Mucosa Gástrica/efectos de los fármacos , Gastropatías/tratamiento farmacológico , Animales , Mucosa Gástrica/inmunología , Mucosa Gástrica/lesiones , Humanos , Masculino , Mucinas/genética , Mucinas/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Hojas de la Planta/química , Ratas , Ratas Sprague-Dawley , Gastropatías/genética , Gastropatías/inmunología , Factor Trefoil-1/genética , Factor Trefoil-1/inmunologíaRESUMEN
Immune checkpoint blockade using PD-1 inhibition is an effective approach for treating a wide variety of cancer subtypes. While lower gastrointestinal (GI) side effects are more common, upper gastrointestinal adverse events are rarely reported. Here, we present a case of nivolumab-associated autoimmune gastritis. To elucidate the immunology underlying this condition, we leverage multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to identify the presence and proportion of infiltrating immune cells from a single section of biopsy specimen. Using MIBI-TOF, we analyze formalin-fixed, paraffin-embedded human gastric tissue with 28 labels simultaneously. Our analyses reveal a gastritis characterized by severe mucosal injury, interferon gamma (IFN-γ)-producing gastric epithelial cells, and mixed inflammation that includes CD8 and CD4 T cell infiltrates with reduced expression of granzyme B and FOXP3, respectively. Here, we provide a comprehensive multiplexed histopathological mapping of gastric tissue, which identifies IFN-γ-producing epithelial cells as possible contributors to the nivolumab-associated gastritis.
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Antineoplásicos Inmunológicos/efectos adversos , Gastritis/inducido químicamente , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Interferón gamma/inmunología , Nivolumab/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Biopsia , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/patología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Gastritis/genética , Gastritis/inmunología , Gastritis/patología , Expresión Génica , Granzimas/genética , Granzimas/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Interferón gamma/genética , Persona de Mediana Edad , Nivolumab/administración & dosificación , Estómago/efectos de los fármacos , Estómago/inmunología , Estómago/patología , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/inmunología , Neoplasias Uterinas/patologíaRESUMEN
OBJECTIVE: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. APPROACH: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1-/- and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. RESULTS: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1-/- mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. CONCLUSIONS: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.
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Citocinas/metabolismo , Mucosa Gástrica/microbiología , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Células Th17/microbiología , Factores de Transcripción/metabolismo , Animales , Antígenos Bacterianos/metabolismo , Proteínas Bacterianas/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Mucosa Gástrica/inmunología , Mucosa Gástrica/metabolismo , Gastritis/inmunología , Gastritis/metabolismo , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/inmunología , Helicobacter pylori/metabolismo , Interacciones Huésped-Patógeno , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , FN-kappa B/metabolismo , Fenotipo , Fosforilación , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción/genética , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Gastric CD4+T cells contribute to Helicobacter pylori (H. pylori)-induced gastritis by amplifying mucosal inflammation and exacerbating mucosal injuries. However, the pathogenic CD4+ T cell subset involved in gastritis and the potential regulators are still unclear. Here we identified an IL-21-producing gastric CD4+T cell subset, which exhibited tissue-resident CXCR5-BTLA-PD-1hi TFH-like phenotype in H. pylori-positive gastritis patients. Meanwhile, we identified glucocorticoid-induced tumor necrosis factor receptor (GITR) as an important regulator to facilitate IL-21 production by CD4+T cells and accelerate mucosal inflammation in gastritis patients with H. pylori infection. Moreover, GITR expression was increased in gastric CD4+T cells of gastritis patients compared to healthy controls, along with the upregulated expression of its ligand GITRL in mucosal macrophages (MÏ) of gastritis patients. Further observations showed that the activation of GITR/GITRL signal promoted the IL-21 production of CD4+T cells via the STAT3 pathway. Besides this, IL-21 from CD4+T cells induced the proliferation of B cell and promoted the production of inflammatory cytokines IL-1ß and IL-6 and chemokines MIP-3α and CCL-25 as well as matrix metalloproteinase (MMP)-3 and MMP-9 by human gastric epithelial cells, suggesting the facilitating effect of IL-21-producing CD4+T cells on mucosal inflammation and injuries. Taking these data together, we revealed that GITR/GITRL signal promoted the polarization of mucosal IL-21-producing CD4+T cells in H. pylori-positive gastritis, which may provide therapeutic strategies for the clinical treatment of H. pylori-induced gastritis.
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Mucosa Gástrica/metabolismo , Gastritis/metabolismo , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori/patogenicidad , Inmunidad Mucosa , Interleucinas/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/diagnóstico , Gastritis/inmunología , Gastritis/microbiología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Interacciones Huésped-Patógeno , Humanos , Mediadores de Inflamación/metabolismo , Ligandos , Fenotipo , Transducción de Señal , Células T Auxiliares Foliculares/inmunología , Factores de Necrosis Tumoral/metabolismoRESUMEN
BACKGROUND: The progression to gastric cancer has been linked to chronic infection with Helicobacter pylori (H. pylori). Immune checkpoint inhibitors (programmed cell death -1, PD-1; programmed cell death -ligand 1, PD-L1) have a role in cancer immune escape. The relationship between H. pylori virulence factors with PD-1, PD-L1 T helper 1 (Th1), T helper 17 (Th17), and regulatory T cell (Treg) response genes, has not been thoroughly investigated in the development of gastric cancer. Therefore, we evaluated how H. pylori virulence factors influence the expression levels of immune-related genes in the development of gastric immunopathology. METHODS: A total of 92 gastric tissues of normal controls and patients with gastritis, gastric ulcer, and gastric cancer were examined for the expression of immune-checkpoint inhibitor genes (PD-1 PD-L1), Th1 (interferon- γ, IFN-γ), Th17 (interleukin- 17, IL-17, Retinoic-acid-receptor- related orphan nuclear receptor gamma t, RORγ-t), and Treg (Forkhead box P3, FOXP3) response genes with quantitative real-time PCR (qRT-PCR). Furthermore, correlation of H. pylori virulence factors' (cytotoxin-associated gene A, cagA; vacuolating cytotoxin gene A, vacA (s1,s2,m1,m2); blood group antigen-binding adhesin gene A, babA, duodenal ulcer promoting gene A, dupA; the putative neuraminyllactose-binding hemagglutinin homolog, hpaA; neutrophil-activating protein A napA; outer inflammatory protein A, oipA; urease A, ureA; and urease B, ureB) genotypes with a degree of inflammation and density of H. pylori were investigated. Next, the relationship between H. pylori virulence factors and immune-checkpoint inhibitor genes, and T-cell response genes was evaluated. Eventually, a decision tree model was developed to determine the clinical outcome of patients using expression data. RESULTS: The intensity of PD-1 and PD-L1 mRNA expression was increased significantly in gastric tissue of patients with gastric ulcer (PD-1: 2.3 fold, p=0.01; PD-L1: 2.1 fold, p=0.004), and gastric cancer (PD-1: 2 fold, p= 0.04; PD-L1: 1.8 fold, p=0.05) compared with control subjects. Also, PD-1: PD-L1 expression was significantly higher in patients with gastritis, who were infected with a marked density of H. pylori compared with its mildly infected counterparts. Furthermore, a novel negative correlation was found between PD-1 (r= -0.43) and PD-L1 (r= -0.42) with FOXP3 in patients with gastritis. CagA-positive H. pylori strain's negative association with PD-L1 expression (r=-0.34) was detected in patients with gastritis. Interestingly, PD-1 mRNA expression correlated positively with vacA s2/m2, in gastritis (r=0.43) and ulcer (r=0.43) patients. Furthermore, PD-1: PDL1 expression negatively correlated with vacA m1/m2 (r=-0.43 for PD-1; r=-0.38 for PD-L1) in gastritis patients. Moreover, an inverse correlation of PDL1 was present with vacA m1 (r=0.52) and vacA s1/m1 (r=0.46) versus vacA m2 (r=-0.44) and vacA m1 (r=0.52) and vacA s1/m2 (r=-0.14) in ulcer patients, respectively. Also, a correlation of vacA m2 (r=-0.47) and vacA s1/s2 (r= 0.45) with PD-1 was detected in ulcer patients. In addition, a novel negative correlation between FOXP3 mRNA levels and napA was shown in patients with gastritis and ulcer (r=-0.59). Finally, a computer-based model that was developed showed that knowing the expression levels of PD-L1, RORγ-t, and vacA s1/m2 would be useful to detect the clinical outcome of a patient. CONCLUSION: Our results suggested that PD-1:PD-L1 immune checkpoint inhibitors were increased in gastric pre-cancerous lesions that progress to gastric cancer. Herein, we report the relationship between H. pylori virulence factors and expression of host immune checkpoint inhibitors for diagnostic prediction of gastric malignancies using computer-based models.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Infecciones por Helicobacter/patología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Gástricas/diagnóstico , Factores de Virulencia/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Biomarcadores de Tumor/análisis , Biopsia , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Progresión de la Enfermedad , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/inmunología , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/análisis , Transducción de Señal/inmunología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Úlcera Gástrica/inmunología , Úlcera Gástrica/microbiología , Úlcera Gástrica/patología , Factores de Virulencia/metabolismo , Adulto JovenRESUMEN
Helicobacter pylori is a Gram-negative bacterium found on the luminal surface of the gastric mucosa in at least 50% of the world's human population. The protective effect of breastfeeding against H. pylori infection has been extensively reported; however, the mechanisms behind this protection remain poorly understood. Human IgA from colostrum has reactivity against H. pylori antigens. Despite that IgA1 and IgA2 display structural and functional differences, their reactivity against H. pylori had not been previously determined. We attested titers and reactivity of human colostrum-IgA subclasses by ELISA, immunoblot, and flow cytometry. Colostrum samples from healthy mothers had higher titers of IgA; and IgA1 mostly recognized H. pylori antigens. Moreover, we found a correlation between IgA1 reactivity and their neutralizing effect determined by inhibition of cytoskeletal changes in AGS cells infected with H. pylori. In conclusion, colostrum-IgA reduces H. pylori infection of epithelial gastric cells, suggesting an important role in preventing the bacteria establishment during the first months of life. As a whole, these results suggest that IgA1 from human colostrum provides protection that may help in the development of the mucosal immune system of newborn children.
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Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Calostro/inmunología , Helicobacter pylori/inmunología , Inmunoglobulina A Secretora/inmunología , Citoesqueleto , Células Epiteliales , Femenino , Mucosa Gástrica/inmunología , Infecciones por Helicobacter/inmunología , Humanos , EmbarazoRESUMEN
The aim of this study was to investigate the immunomodulatory effect and mechanism of the glycopeptides from Paecilomyces sinensis (CPS-II) on ethanol induced ulcers in mice. In this study, histopathological evaluation (H&E staining) and the gastric ulcer score, ulcer index, total acid secretion and gastric pH value were used to determine the anti-ulcer activity. The expression levels of interleukin (IL)-6, interleukin (IL)-10 and tumor necrosis factor-α (TNF-α) were detected by ELISA. The contents of superoxide dismutase (SOD), malondialdehyde (MDA) and epidermal growth factor (PEG2) in serum were measured according to the instructions for the reagents. Western blotting was used to detect the effect of CPS-II on the MEK/ERK pathway. The results showed that CPS-II could inhibit the ulcer score and ulcer index compared with the disease control group. CPS-II could significantly increase gastric pH and decrease gastric acid secretion in mice. The ELISA analysis showed that the expression levels of IL-6 and TNF-α in the CPS-II treatment group were significantly decreased, while the expression levels of IL-10 were significantly increased in the CPS-II treatment group. In the resveratrol treatment group, the content of MDA in serum was decreased, and the level of PEG2 and the activity of SOD in serum were significantly increased, which indicated that CPS-II has immunoregulation and anti-ulcer properties. The CPS-II treatment group could reduce the expression level of miR-9-5p in gastric tissue. pEGFR had been identified as a potential target of miR-9-5p. Western blot analysis showed that CPS-II could up-regulate the relative protein expression of pEGFR/EGFR, pRaf/Raf, pMEK/MEK, pERK/ERK, and ZO-1. The results showed that CPS-II could reduce oxidative stress and inflammatory response by regulating the miR-9-5p-MEK/ERK signaling pathway, thus protecting the gastric mucosa and improving stress gastric ulcers.