Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third... more Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third of the general population and is responsible for common and serious diseases. These diseases include food poisoning and toxic shock syndrome, which are caused by exotoxins produced by S. aureus. Of the more than 20 Staphylococcal enterotoxins, SEA and SEB are the best characterized and are also regarded as superantigens because of their ability to bind to class II MHC molecules on antigen presenting cells and stimulate large populations of T cells that share variable regions on the chain of the T cell receptor. The result of this massive T cell activation is a cytokine bolus leading to an acute toxic shock. These proteins are highly resistant to denaturation, which allows them to remain intact in contaminated food and trigger disease outbreaks. A recognized problem is the emergence of multi-drug resistant strains of S. aureus and these are a concern in the clinical setting as they are a common cause of antibiotic-associated diarrhea in hospitalized patients. In this review, we provide an overview of the current understanding of these proteins.
Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thous... more Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3-to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.
The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithel... more The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; th...
Helicobacter pylori (H. pylori) infects >50% of the world’s population and is linked to peptic... more Helicobacter pylori (H. pylori) infects >50% of the world’s population and is linked to peptic ulcers and gastric cancer. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation and induction of Treg cells in vitro, but the mechanism was unknown. Herein, we investigated the underlying mechanisms behind H. pylori-mediated upregulation of B7-H1 expression by GEC and its functional relevance to chronic infection. Using H. pylori wild type and isogenic mutant strains we showed that H. pylori requires its type 4 secretion system (T4SS) component cytotoxin associated gene A (CagA) and peptidoglycan for B7-H1 upregulation in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, containing a functional T4SS, but not with H. pylori SS1 strain lacking this delivery system, led to upregulation of B7-H1 expression, increased bacterial load, induction of Treg cell in the stomach and increased IL-10 in the serum. Interestingly, B7-H1 knock out mice showed less Treg cells and reduced bacterial loads. We also showed that H. pylori uses p38 MAPK pathway to upregulate B7-H1 expression in GEC. Our observations suggest that H. pylori T4SS contributes to the ability to evade immune-mediated clearance by modulating expression of B7-H1 in GEC. These observations may have important implications in vaccine efforts directed at H. pylori.
Purpose: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal dis... more Purpose: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal disease in premature infants. While all the events that lead to NEC remain elusive, concurrent administration of hydrocortisone (HC) and indomethacin ( IND) is associated with increased incidence of NEC as these agents disrupt cell migration and proliferation. Goal/Hypothesis: Intestinal epithelial cell migration and proliferation are key elements in recovery from intestinal injury. We hypothesized administration of Rat Amniotic Fluid (rAF) and specifically one of the key components in rAF, hepatocyte growth factor (HGF) may improve cell migration and proliferation disrupted by concurrent administration of HC and/or IND. Methods: After 24 hours exposure, proliferation and migration of IEC-6 rat intestinal epithelial cells (IEC) was measured in vitro in the presence/absence of rAF, mouse HGF, HC and/or IND, and a PI3-K inhibitor. Prostaglandin concentrations in the supernatants were analyzed...
The development of accurate classification models depends upon the methods used to identify the m... more The development of accurate classification models depends upon the methods used to identify the most relevant variables. The aim of this article is to evaluate variable selection methods to identify important variables in predicting a binary response using nonlinear statistical models. Our goals in model selection include producing non-overfitting stable models that are interpretable, that generate accurate predictions and have minimum bias. This work was motivated by data on clinical and laboratory features of Helicobacter pylori infections obtained from 60 individuals enrolled in a prospective observational study. We carried out a comprehensive performance comparison of several nonlinear classification models over the H. pylori data set. We compared variable selection results by Multivariate Adaptive Regression Splines (MARS), Logistic Regression with regularization, Generalized Additive Models (GAMs) and Bayesian Variable Selection in GAMs. We found that the MARS model approach h...
CD74, or the class II MHC-associated invariant chain, is best known for the regulation of Ag pres... more CD74, or the class II MHC-associated invariant chain, is best known for the regulation of Ag presentation. However, recent studies have suggested other important roles for this protein in inflammation and cancer studies. We have shown that CD74 is expressed on the surface of gastric cells, and Helicobacter pylori can use this receptor as a point of attachment to gastric epithelial cells, which lead to IL-8 production. This study investigates the ability of H. pylori to up-regulate one of its receptors in vivo and with a variety of gastric epithelial cell lines during infection with H. pylori. CD74 expression was increased dramatically on gastric biopsies from H. pylori-positive patients and gastric cell lines exposed to the bacteria. Gastric cells exposed to H. pylori-conditioned medium revealed that the host cell response was responsible for the up-regulation of CD74. IL-8 was found to up-regulate CD74 cell surface expression because blocking IL-8Rs or neutralizing IL-8 with Abs counteracted the increased expression of CD74 observed during infection with H. pylori. These studies demonstrate how H. pylori up-regulates one of its own receptors via an autocrine mechanism involving one of the products induced from host cells.
CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (... more CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) that regulates the cell biology and functions of MHC class II molecules. Class II MHC and Ii expression was believed to be restricted to classical antigen-presenting cells (APC); however, during inflammation, other cell types, including mucosal epithelial cells, have also been reported to express class II MHC molecules. Given the importance of Ii in the biology of class II MHC, we sought to examine the expression of Ii by gastric epithelial cells (GEC) to determine whether class II MHC molecules in these nonconventional APC cells were under the control of Ii and to further support the role that these cells may play in local immune and inflammatory responses during Helicobacter pylori infection. Thus we examined the expression of Ii on GEC from human biopsy samples and then confirmed this observation using independent methods on several GEC lines. The mRNA for Ii was detected by RT-PC...
reduction of IFN-c and IL-17 levels. Inhibition was partly dependent on nitric oxide and superoxi... more reduction of IFN-c and IL-17 levels. Inhibition was partly dependent on nitric oxide and superoxide generated by monocytes. This effect was not due to increased T cell apoptosis; on the contrary, they showed better viability than those cultured with neutrophils. Taken together, our results demonstrate that different populations of myeloid cells isolated from the chronically inflamed mouse colon have the potential to enhance and/or suppress T cell activation, viability and/or function. A better understanding of how these complex interactions contribute to disease pathogenesis may reveal novel therapeutic strategies for the treatment of patients with IBD.
Stromal cells, such as myofibroblasts and fibroblasts, represent a significant fraction of MHC cl... more Stromal cells, such as myofibroblasts and fibroblasts, represent a significant fraction of MHC class II-positive cells in the normal human colonic lamina propria, suggesting they may play an important role in CD4(+) T cell regulation in a tolerogenic environment. The aim of this study was to examine whether human colonic myofibroblasts (CMFs) phenotypically and functionally resemble conventional antigen-presenting cells (APCs). Our results support the hypothesis that intestinal myofibroblasts are a novel, nonprofessional APC phenotype important in modulating mucosal T cell responses. Given their strategic location, we propose that intestinal myofibroblasts play a critical role in mediating tolerance to luminal antigens.
World journal of gastroenterology : WJG, Jan 28, 2014
Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, sin... more Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immu...
Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thous... more Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3-to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.
Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection... more Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection, which leads to clinically significant gastric diseases including chronic gastritis, peptic ulcer disease (PUD), and gastric cancer (GC). H. pylori is able to produce a persistent infection due in large part to its ability to hijack the host immune response. The host adaptive immune response is activated to strategically and specifically attack pathogens and normally clears them from the infected host. Since B and T lymphocytes are central mediators of adaptive immunity, in this chapter we review their development and the fundamental mechanisms regulating their activation in order to understand how some of the normal processes are subverted by H. pylori. In this review, we place particular emphasis on the CD4+ T cell responses, their subtypes, and regulatory mechanisms because of the expanding literature in this area related to H. pylori. T lymphocyte differentiation and function are finely orchestrated through a series of cell-cell interactions, which include immune checkpoint receptors. Among the immune checkpoint receptor family, there are some with inhibitory properties that are exploited by tumor cells to facilitate their immune evasion. Gastric epithelial cells (GECs), which act as antigen-presenting cells (APCs) in the gastric mucosa, are induced by H. pylori to express immune checkpoint receptors known to sway T lymphocyte function and thus circumvent effective T effector lymphocyte responses. This chapter reviews these and other mechanisms used by H. pylori to interfere with host immunity in order to persist.
Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third... more Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third of the general population and is responsible for common and serious diseases. These diseases include food poisoning and toxic shock syndrome, which are caused by exotoxins produced by S. aureus. Of the more than 20 Staphylococcal enterotoxins, SEA and SEB are the best characterized and are also regarded as superantigens because of their ability to bind to class II MHC molecules on antigen presenting cells and stimulate large populations of T cells that share variable regions on the chain of the T cell receptor. The result of this massive T cell activation is a cytokine bolus leading to an acute toxic shock. These proteins are highly resistant to denaturation, which allows them to remain intact in contaminated food and trigger disease outbreaks. A recognized problem is the emergence of multi-drug resistant strains of S. aureus and these are a concern in the clinical setting as they are a common cause of antibiotic-associated diarrhea in hospitalized patients. In this review, we provide an overview of the current understanding of these proteins.
Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thous... more Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3-to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.
The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithel... more The accumulation of Helicobacter pylori infection-induced oxidative DNA damage in gastric epithelial cells is a risk factor for developing gastric cancer (GC); however, the underlying mechanisms remain poorly understood. Here we report that the suppression of NEIL2, an oxidized base-specific mammalian DNA glycosylase, is one such mechanism via which H. pylori infection may fuel the accumulation of DNA damage during the initiation and progression of GC. Using a combination of cultured cell lines and primary cells, we show that expression of NEIL2 is significantly down-regulated after H. pylori infection; such down-regulation was also seen in human gastric biopsies. The H. pylori infection-induced down-regulation of NEIL2 is specific, as Campylobacter jejuni has no such effect. Using gastric organoids isolated from the murine stomach in co-culture studies with live bacteria mimicking the infected stomach lining, we found that H. pylori infection was associated with IL-8 production; th...
Helicobacter pylori (H. pylori) infects >50% of the world’s population and is linked to peptic... more Helicobacter pylori (H. pylori) infects >50% of the world’s population and is linked to peptic ulcers and gastric cancer. We have previously shown that H. pylori upregulates B7-H1 expression on GEC, which, in turn, suppress T cell proliferation and induction of Treg cells in vitro, but the mechanism was unknown. Herein, we investigated the underlying mechanisms behind H. pylori-mediated upregulation of B7-H1 expression by GEC and its functional relevance to chronic infection. Using H. pylori wild type and isogenic mutant strains we showed that H. pylori requires its type 4 secretion system (T4SS) component cytotoxin associated gene A (CagA) and peptidoglycan for B7-H1 upregulation in GEC. In vivo confirmation was obtained when infection of C57BL/6 mice with H. pylori PMSS1 strain, containing a functional T4SS, but not with H. pylori SS1 strain lacking this delivery system, led to upregulation of B7-H1 expression, increased bacterial load, induction of Treg cell in the stomach and increased IL-10 in the serum. Interestingly, B7-H1 knock out mice showed less Treg cells and reduced bacterial loads. We also showed that H. pylori uses p38 MAPK pathway to upregulate B7-H1 expression in GEC. Our observations suggest that H. pylori T4SS contributes to the ability to evade immune-mediated clearance by modulating expression of B7-H1 in GEC. These observations may have important implications in vaccine efforts directed at H. pylori.
Purpose: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal dis... more Purpose: Necrotizing enterocolitis (NEC) is the most common life-threatening gastrointestinal disease in premature infants. While all the events that lead to NEC remain elusive, concurrent administration of hydrocortisone (HC) and indomethacin ( IND) is associated with increased incidence of NEC as these agents disrupt cell migration and proliferation. Goal/Hypothesis: Intestinal epithelial cell migration and proliferation are key elements in recovery from intestinal injury. We hypothesized administration of Rat Amniotic Fluid (rAF) and specifically one of the key components in rAF, hepatocyte growth factor (HGF) may improve cell migration and proliferation disrupted by concurrent administration of HC and/or IND. Methods: After 24 hours exposure, proliferation and migration of IEC-6 rat intestinal epithelial cells (IEC) was measured in vitro in the presence/absence of rAF, mouse HGF, HC and/or IND, and a PI3-K inhibitor. Prostaglandin concentrations in the supernatants were analyzed...
The development of accurate classification models depends upon the methods used to identify the m... more The development of accurate classification models depends upon the methods used to identify the most relevant variables. The aim of this article is to evaluate variable selection methods to identify important variables in predicting a binary response using nonlinear statistical models. Our goals in model selection include producing non-overfitting stable models that are interpretable, that generate accurate predictions and have minimum bias. This work was motivated by data on clinical and laboratory features of Helicobacter pylori infections obtained from 60 individuals enrolled in a prospective observational study. We carried out a comprehensive performance comparison of several nonlinear classification models over the H. pylori data set. We compared variable selection results by Multivariate Adaptive Regression Splines (MARS), Logistic Regression with regularization, Generalized Additive Models (GAMs) and Bayesian Variable Selection in GAMs. We found that the MARS model approach h...
CD74, or the class II MHC-associated invariant chain, is best known for the regulation of Ag pres... more CD74, or the class II MHC-associated invariant chain, is best known for the regulation of Ag presentation. However, recent studies have suggested other important roles for this protein in inflammation and cancer studies. We have shown that CD74 is expressed on the surface of gastric cells, and Helicobacter pylori can use this receptor as a point of attachment to gastric epithelial cells, which lead to IL-8 production. This study investigates the ability of H. pylori to up-regulate one of its receptors in vivo and with a variety of gastric epithelial cell lines during infection with H. pylori. CD74 expression was increased dramatically on gastric biopsies from H. pylori-positive patients and gastric cell lines exposed to the bacteria. Gastric cells exposed to H. pylori-conditioned medium revealed that the host cell response was responsible for the up-regulation of CD74. IL-8 was found to up-regulate CD74 cell surface expression because blocking IL-8Rs or neutralizing IL-8 with Abs counteracted the increased expression of CD74 observed during infection with H. pylori. These studies demonstrate how H. pylori up-regulates one of its own receptors via an autocrine mechanism involving one of the products induced from host cells.
CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (... more CD74 is known as the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) that regulates the cell biology and functions of MHC class II molecules. Class II MHC and Ii expression was believed to be restricted to classical antigen-presenting cells (APC); however, during inflammation, other cell types, including mucosal epithelial cells, have also been reported to express class II MHC molecules. Given the importance of Ii in the biology of class II MHC, we sought to examine the expression of Ii by gastric epithelial cells (GEC) to determine whether class II MHC molecules in these nonconventional APC cells were under the control of Ii and to further support the role that these cells may play in local immune and inflammatory responses during Helicobacter pylori infection. Thus we examined the expression of Ii on GEC from human biopsy samples and then confirmed this observation using independent methods on several GEC lines. The mRNA for Ii was detected by RT-PC...
reduction of IFN-c and IL-17 levels. Inhibition was partly dependent on nitric oxide and superoxi... more reduction of IFN-c and IL-17 levels. Inhibition was partly dependent on nitric oxide and superoxide generated by monocytes. This effect was not due to increased T cell apoptosis; on the contrary, they showed better viability than those cultured with neutrophils. Taken together, our results demonstrate that different populations of myeloid cells isolated from the chronically inflamed mouse colon have the potential to enhance and/or suppress T cell activation, viability and/or function. A better understanding of how these complex interactions contribute to disease pathogenesis may reveal novel therapeutic strategies for the treatment of patients with IBD.
Stromal cells, such as myofibroblasts and fibroblasts, represent a significant fraction of MHC cl... more Stromal cells, such as myofibroblasts and fibroblasts, represent a significant fraction of MHC class II-positive cells in the normal human colonic lamina propria, suggesting they may play an important role in CD4(+) T cell regulation in a tolerogenic environment. The aim of this study was to examine whether human colonic myofibroblasts (CMFs) phenotypically and functionally resemble conventional antigen-presenting cells (APCs). Our results support the hypothesis that intestinal myofibroblasts are a novel, nonprofessional APC phenotype important in modulating mucosal T cell responses. Given their strategic location, we propose that intestinal myofibroblasts play a critical role in mediating tolerance to luminal antigens.
World journal of gastroenterology : WJG, Jan 28, 2014
Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, sin... more Helicobacter pylori (H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immu...
Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thous... more Food poisoning due to staphylococcal enterotoxins A and B (SEA and SEB) affects hundreds of thousands of people annually. SEA and SEB induce massive intestinal cytokine production, which is believed to be the key factor in staphylococcal enterotoxin enteropathy. MHC class II molecules are the major receptors for staphylococcal enterotoxins. We recently demonstrated that normal human subepithelial intestinal myofibroblasts (IMFs) express MHC class II molecules. We hypothesized that IMFs are among the first cells to respond to staphylococcal enterotoxins and contribute to the cytokine production associated with staphylococcal enterotoxin pathogenesis. We demonstrated here that primary cultured IMFs bind staphylococcal enterotoxins in a MHC class II-dependent fashion in vitro. We also demonstrated that staphylococcal enterotoxins can cross a CaCo-2 epithelial monolayer in coculture with IMFs and bind to the MHC class II on IMFs. IMFs responded to SEA, but not SEB, exposure with 3-to 20-fold increases in the production of proinflammatory chemokines (MCP-1, IL-8), cytokines (IL-6), and growth factors (GM-CSF and G-CSF). The SEA induction of the proinflammatory mediators by IMFs resulted from the efficient cross-linking of MHC class II molecules because cross-linking of class II MHC by biotinylated anti-HLA-DR Abs induced similar cytokine patterns. The studies presented here show that MCP-1 is central to the production of other cytokines elicited by SEA in IMFs because its neutralization with specific Abs prevented the expression of IL-6 and IL-8 by IMFs. Thus, MCP-1 may play a leading role in initiation of inflammatory injury associated with staphylococcal enterotoxigenic disease.
Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection... more Helicobacter pylori is a prevalent human pathogen that successfully establishes chronic infection, which leads to clinically significant gastric diseases including chronic gastritis, peptic ulcer disease (PUD), and gastric cancer (GC). H. pylori is able to produce a persistent infection due in large part to its ability to hijack the host immune response. The host adaptive immune response is activated to strategically and specifically attack pathogens and normally clears them from the infected host. Since B and T lymphocytes are central mediators of adaptive immunity, in this chapter we review their development and the fundamental mechanisms regulating their activation in order to understand how some of the normal processes are subverted by H. pylori. In this review, we place particular emphasis on the CD4+ T cell responses, their subtypes, and regulatory mechanisms because of the expanding literature in this area related to H. pylori. T lymphocyte differentiation and function are finely orchestrated through a series of cell-cell interactions, which include immune checkpoint receptors. Among the immune checkpoint receptor family, there are some with inhibitory properties that are exploited by tumor cells to facilitate their immune evasion. Gastric epithelial cells (GECs), which act as antigen-presenting cells (APCs) in the gastric mucosa, are induced by H. pylori to express immune checkpoint receptors known to sway T lymphocyte function and thus circumvent effective T effector lymphocyte responses. This chapter reviews these and other mechanisms used by H. pylori to interfere with host immunity in order to persist.
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