Proceedings of The National Academy of Sciences, 1996
cagA, a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori str... more cagA, a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori strains that are associated with severe forms of gastroduodenal disease (type I strains). We found that the genetic locus that contains cagA (cag) is part of a 40-kb DNA insertion that likely was acquired horizontally and integrated into the chromosomal glutamate racemase gene. This pathogenicity island is f lanked by direct repeats of 31 bp. In some strains, cag is split into a right segment (cagI) and a left segment (cagII) by a novel insertion sequence (IS605). In a minority of H. pylori strains, cagI and cagII are separated by an intervening chromosomal sequence. Nucleotide sequencing of the 23,508 base pairs that form the cagI region and the extreme 3 end of the cagII region reveals the presence of 19 ORFs that code for proteins predicted to be mostly membrane associated with one gene (cagE), which is similar to the toxin-secretion gene of Bordetella pertussis, ptlC, and the transport systems required for plasmid transfer, including the virB4 gene of Agrobacterium tumefaciens. Transposon inactivation of several of the cagI genes abolishes induction of IL-8 expression in gastric epithelial cell lines. Thus, we believe the cag region may encode a novel H. pylori secretion system for the export of virulence determinants.
International Journal of Medical Microbiology, Mar 1, 2003
In order to investigate the interrelation between immunogenetic host and bacterial factors the T-... more In order to investigate the interrelation between immunogenetic host and bacterial factors the T-cell receptor (TCR) polymorphism TCRBV6S1 A/B, HLA-DRB1 alleles and cagA status was analyzed in 380 unrelated German individuals. H. pylori infection with cagA-positive bacterial strains was significantly associated with peptic ulcer disease in the German cohort. Patients homozygous for the non-functional TCRBV6S1B allele and presenting with peptic ulcer disease showed no CagA-specific antibodies in the majority of cases. There was no association between HLA-DRB1 alleles and the CagA status of infected individuals, although certain alleles show significant association to the infection status in different populations.
European Journal of Gastroenterology Hepatology, 2008
To investigate IL-18 mRNA expression in the gastric mucosa in Helicobacter pylori-infected childr... more To investigate IL-18 mRNA expression in the gastric mucosa in Helicobacter pylori-infected children and its association with macrophage infiltration, IL-8, and IL-1 beta mRNA expression. From 39 children, blood samples were taken for IL-1 beta gene polymorphism analysis and antral biopsies were obtained for histology (including macrophage immunostaining), culture and semiquantitative analysis of IL-18, IL-8, IL-1 beta, and CD14 mRNA expression by reverse transcription-PCR (RT-PCR). RT-PCR was used for H. pylori ureA and cagA mRNA detection in gastric tissue. H. pylori-infected patients had significantly higher IL-18, IL-8, and IL-1 beta transcript levels and macrophage numbers in the antral mucosa than H. pylori-negative children. IL-1 beta-511/31 gene polymorphism had no impact on gastric IL-1 beta mRNA levels. IL-18 mRNA expression correlated with mRNA expression of IL-8 and IL-1 beta, and transcript levels of all three cytokines were associated with macrophage infiltration and CD14 mRNA expression in the gastric tissue. Significant correlation was also observed between macrophage numbers and histological parameters of gastritis. These results suggest that interleukin(IL)-18 and macrophages may have an important function in gastric inflammatory response to H. pylori infection in children. IL-18, and possibly CD14 receptor signalling pathway, may be involved in macrophage activation and subsequent IL-8 and IL-1 beta release.
ABSTRACT Introduction: Epidemiological studies suggest epigallocatechin-3-gallate (EGCG), a natur... more ABSTRACT Introduction: Epidemiological studies suggest epigallocatechin-3-gallate (EGCG), a natural product from green tea, may have a role in prevention of gastric atrophy and gastric cancer in Asian populations. Cox-2 signaling pathway in gastric epithelial cells is of relevance to gastric carcinogenesis. The aim of this study was to investigate if H. pylori-induced Cox-2 upregulation in conditionally immortalized mouse gastric epithelial cells (MGEC) was inhibited by EGCG. Methods: H. pylori (NCTC11637, cag PAI+) were co-cultured with MGEC gastric epithelial cells for 12 hrs. MGEC cells were pre-incubated for 1 hr with EGCG (1-100 µM) (concentrations which did not affect bacterial or cell viability) before co-culture with H. pylori. At 12 hrs post-infection when maximum expression of Cox-2 transcript levels was evident, RNA was extracted form MGEC cells and evaluated by Northern blotting. Gapdh transcript levels were measured as a control. Results: At 12 hrs post-infection, EGCG (50-100 µM) significantly inhibited both basal and H. pylori-induced Cox-2 transcript levels in MGEC cells (n=3, p<0.05 and p<0.01, respectively). Conclusions: H. pylori-induced Cox-2 transcript levels in MGEC cells are significantly inhibited by EGCG in a dose dependent fashion. Green tea consumption as an inhibitor for H. pylori-induced gastric cancer, via COX-2 signaling pathway, might have a role in prevention of gastric carcinogenesis.
Childhood growth is a cornerstone of pediatric research. Statistical models need to consider indi... more Childhood growth is a cornerstone of pediatric research. Statistical models need to consider individual trajectories to adequately describe growth outcomes. Specifically, well-defined longitudinal models are essential to characterize both population and subject-specific growth. Linear mixed-effect models with cubic regression splines can account for the nonlinearity of growth curves and provide reasonable estimators of population and subject-specific growth, velocity and acceleration. We provide a stepwise approach that builds from simple to complex models, and account for the intrinsic complexity of the data. We start with standard cubic splines regression models and build up to a model that includes subject-specific random intercepts and slopes and residual autocorrelation. We then compared cubic regression splines vis-à-vis linear piecewise splines, and with varying number of knots and positions. Statistical code is provided to ensure reproducibility and improve dissemination of methods. Models are applied to longitudinal height measurements in a cohort of 215 Peruvian children followed from birth until their fourth year of life. Unexplained variability, as measured by the variance of the regression model, was reduced from 7.34 when using ordinary least squares to 0.81 (p < 0.001) when using a linear mixed-effect models with random slopes and a first order continuous autoregressive error term. There was substantial heterogeneity in both the intercept (p < 0.001) and slopes (p < 0.001) of the individual growth trajectories. We also identified important serial correlation within the structure of the data (ρ = 0.66; 95 % CI 0.64 to 0.68; p < 0.001), which we modeled with a first order continuous autoregressive error term as evidenced by the variogram of the residuals and by a lack of association among residuals. The final model provides a parametric linear regression equation for both estimation and prediction of population- and individual-level growth in height. We show that cubic regression splines are superior to linear regression splines for the case of a small number of knots in both estimation and prediction with the full linear mixed effect model (AIC 19,352 vs. 19,598, respectively). While the regression parameters are more complex to interpret in the former, we argue that inference for any problem depends more on the estimated curve or differences in curves rather than the coefficients. Moreover, use of cubic regression splines provides biological meaningful growth velocity and acceleration curves despite increased complexity in coefficient interpretation. Through this stepwise approach, we provide a set of tools to model longitudinal childhood data for non-statisticians using linear mixed-effect models.
We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in develo... more We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in developing countries is the initiator of a vicious cycle of events that result ultimately in malnutrition and growth impairment. Acute infection with H. pylori is accompanied by hypochlorhydria, which facilitates the acquisition of other enteropathogens because of removal of the gastric acid barrier, which then results in diarrheal disease and iron-deficiency anemia. This is likely to occur most frequently in developing regions where the prevalence of H. pylori infection is disproportionately high and multiple enteric coinfections are common. The consequent synergistic impact of diarrheal disease and micronutrient deficiency on growth and cognitive function in children has significant public health implications for socioeconomic development in these countries.
To assess the relationship between density determined by quantitative culture, status, and gastri... more To assess the relationship between density determined by quantitative culture, status, and gastric histology in children. Children with clinical symptoms indicating pathology in the upper gastrointestinal tract were referred for endoscopy. From each child blood was taken for serology, and antral biopsies were obtained for quantitative culture of and histology. Histological assessment was performed according to the updated Sydney System. The status of cultured was determined by polymerase chain reaction (PCR) and serum IgG response to CagA by western blotting. Adequate antral biopsies were obtained from 41 children with positive cultures. CagA IgG antibodies were found in 27 patients (66%), 25 of whom were also positive by the PCR. Two children infected with + strains as determined by the PCR were CagA seronegative. Infection with + strains was associated with significantly higher activity of inflammation and denser bacterial colonization in the antrum compared to negative strains. No correlation was observed between the density of colonization and chronic antral inflammation. This study shows that infection of children with + strains of is associated with enhanced activity of antral inflammation and higher density of colonization. There is a good correlation between serum western blot and bacterial PCR positivity in determining status and a positive relationship between histology and quantitative culture in assessing density in paediatric patients.
The murine Helicobacter felis model has been extensively used to investigate the importance of ho... more The murine Helicobacter felis model has been extensively used to investigate the importance of host factors in the development of chronic gastritis. The effect of gender in this murine model is unknown. Male and female C57BL/6J mice were infected with H felis for up to 1 year. At 4, 8, 19, 36, and 52 weeks post-infection, gastric histopathology, epithelial cell proliferation, and apoptosis were examined and compared with age-and gender-matched controls. In female mice, infection with H felis resulted in an earlier onset of chronic gastric inflammation, epithelial hyperplasia, and oxyntic cell loss than males. In females, there was a trend towards increased gastric pathology compared with males, with long-term-infected female mice having significantly greater (p < 0.05) chronic inflammation than male mice.
Concentrations of the soluble interleukin-2 receptor (sIL-2R) in the serum of 33 patients with co... more Concentrations of the soluble interleukin-2 receptor (sIL-2R) in the serum of 33 patients with coeliac disease were measured by ELISA. The levels of sIL-2R were significantly raised in 15 patients with untreated coeliac disease compared with treated patients and age-and sex-matched symptomatic and non-symptomatic control groups. Longitudinal studies in individual coeliac patients showed that serum sIL-2R fell following commencement of a gluten-free diet. Gluten challenge of 16 treated coeliac patients for 1 week resulted in a significant increase in serum sIL-2R, which returned to prechallenge levels within 4 weeks of recommencement of a gluten-free diet. We suggest that serum sIL-2R levels in patients with coeliac disease reflect specific immunological activation in response to gluten ingestion. Measurement ofserum sIL-2R may therefore be useful in the assessment ofresponse to treatment in patients with coeliac disease.
The specificity of the tumor cell immunoglobulin in three cases of low grade B cell gastrointesti... more The specificity of the tumor cell immunoglobulin in three cases of low grade B cell gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma has been studied. Using anti-idiotypic antibodies to detect the reactivity of tumor immunoglobulin in tissue sections from the patients and other individuals, we observed specificity for normal tissue components in all three cases studied. Reactivity in one case was with follicular dendritic cells, in the second case with a novel antigen on mucosal post capillary venules, and, in the third case, a broad pattern of reactivity was observed. This study suggests that autoimmunity may play a role in the pathogenesis of gastric lymphoma.
Full text is available as a scanned copy of the original print version. Get a printable copy (PDF... more Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1016K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by ... more We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by anti-inflammatory agents in inflammatory bowel disease. In vitro secretion of IL-6 by biopsy specimens from patients with active ulcerative colitis was investigated in the presence of cyclosporin-A (CsA) and drugs that have other anti-inflammatory actions. Biopsy specimens from patients with quiescent ulcerative colitis or controls were stimulated with anti-CD3 antibody to activate mucosal T cells. Stimulation of control specimens increased IL-6 secretion (median increase, 147%; p &amp;amp;lt; 0.003), which was prevented by CsA. In quiescent ulcerative colitis there was enhanced spontaneous secretion of IL-6 but a smaller, non-significant increase after T-cell activation (125%). Dexamethasone inhibited secretion in active ulcerative colitis (p &amp;amp;lt; 0.006). 5-Aminosalicylic acid, 6-mercaptopurine, methotrexate, and indomethacin had no effect. There also tended to be a small reduction with CsA, but this just failed to reach statistical significance. In quiescent ulcerative colitis the enhanced spontaneous secretion of IL-6 may be a consequence of mucosal T-cell or macrophage activation: the smaller increase after T-cell stimulation suggests that one or both of these two cell types are already pre-activated.
Infection of the human gastric mucosa with Helicobacter pylori induces the development of mucosa-... more Infection of the human gastric mucosa with Helicobacter pylori induces the development of mucosa-associated lymphoid tissue (MALT), and H pylori-specific local humoral and T-cell responses. H pylori infection also results in the mucosal production of proinflammatory cytokines, which are important in stimulating neutrophil infiltration. Strains of H pylori expressing the cytotoxin associated protein A (CagA) induce gastric epithelial cells to secrete interleukin-8, the neutrophil chemotactic and activating peptide. Variation in the extent of mucosal injury may be a consequence of H pylori strain variability. Gastric B-cell lymphomas of MALT arise from a background of lymphoid follicles, which are acquired in response to H pylori infection. In many cases, eradication of H pylori from patients with low-grade gastric lymphoma results in lymphoma regression, including large tumor masses, implying a causal relationship between H pylori infection and lymphoma growth. Experiments studying the properties of tumor cell and tumor infiltrating T cells in vitro have suggested that rather than stimulating the tumor cells directly, H pylori stimulates tumor infiltrating T cells, which provide help for lymphoma growth. Unlike the active inflammatory response associated with infection with CagA positive strains, but consistent with the acquisition of lymphoid follicles in all infected individuals, the development of MALT lymphomas is independent of bacterial CagA status.
Proceedings of The National Academy of Sciences, 1996
cagA, a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori str... more cagA, a gene that codes for an immunodominant antigen, is present only in Helicobacter pylori strains that are associated with severe forms of gastroduodenal disease (type I strains). We found that the genetic locus that contains cagA (cag) is part of a 40-kb DNA insertion that likely was acquired horizontally and integrated into the chromosomal glutamate racemase gene. This pathogenicity island is f lanked by direct repeats of 31 bp. In some strains, cag is split into a right segment (cagI) and a left segment (cagII) by a novel insertion sequence (IS605). In a minority of H. pylori strains, cagI and cagII are separated by an intervening chromosomal sequence. Nucleotide sequencing of the 23,508 base pairs that form the cagI region and the extreme 3 end of the cagII region reveals the presence of 19 ORFs that code for proteins predicted to be mostly membrane associated with one gene (cagE), which is similar to the toxin-secretion gene of Bordetella pertussis, ptlC, and the transport systems required for plasmid transfer, including the virB4 gene of Agrobacterium tumefaciens. Transposon inactivation of several of the cagI genes abolishes induction of IL-8 expression in gastric epithelial cell lines. Thus, we believe the cag region may encode a novel H. pylori secretion system for the export of virulence determinants.
International Journal of Medical Microbiology, Mar 1, 2003
In order to investigate the interrelation between immunogenetic host and bacterial factors the T-... more In order to investigate the interrelation between immunogenetic host and bacterial factors the T-cell receptor (TCR) polymorphism TCRBV6S1 A/B, HLA-DRB1 alleles and cagA status was analyzed in 380 unrelated German individuals. H. pylori infection with cagA-positive bacterial strains was significantly associated with peptic ulcer disease in the German cohort. Patients homozygous for the non-functional TCRBV6S1B allele and presenting with peptic ulcer disease showed no CagA-specific antibodies in the majority of cases. There was no association between HLA-DRB1 alleles and the CagA status of infected individuals, although certain alleles show significant association to the infection status in different populations.
European Journal of Gastroenterology Hepatology, 2008
To investigate IL-18 mRNA expression in the gastric mucosa in Helicobacter pylori-infected childr... more To investigate IL-18 mRNA expression in the gastric mucosa in Helicobacter pylori-infected children and its association with macrophage infiltration, IL-8, and IL-1 beta mRNA expression. From 39 children, blood samples were taken for IL-1 beta gene polymorphism analysis and antral biopsies were obtained for histology (including macrophage immunostaining), culture and semiquantitative analysis of IL-18, IL-8, IL-1 beta, and CD14 mRNA expression by reverse transcription-PCR (RT-PCR). RT-PCR was used for H. pylori ureA and cagA mRNA detection in gastric tissue. H. pylori-infected patients had significantly higher IL-18, IL-8, and IL-1 beta transcript levels and macrophage numbers in the antral mucosa than H. pylori-negative children. IL-1 beta-511/31 gene polymorphism had no impact on gastric IL-1 beta mRNA levels. IL-18 mRNA expression correlated with mRNA expression of IL-8 and IL-1 beta, and transcript levels of all three cytokines were associated with macrophage infiltration and CD14 mRNA expression in the gastric tissue. Significant correlation was also observed between macrophage numbers and histological parameters of gastritis. These results suggest that interleukin(IL)-18 and macrophages may have an important function in gastric inflammatory response to H. pylori infection in children. IL-18, and possibly CD14 receptor signalling pathway, may be involved in macrophage activation and subsequent IL-8 and IL-1 beta release.
ABSTRACT Introduction: Epidemiological studies suggest epigallocatechin-3-gallate (EGCG), a natur... more ABSTRACT Introduction: Epidemiological studies suggest epigallocatechin-3-gallate (EGCG), a natural product from green tea, may have a role in prevention of gastric atrophy and gastric cancer in Asian populations. Cox-2 signaling pathway in gastric epithelial cells is of relevance to gastric carcinogenesis. The aim of this study was to investigate if H. pylori-induced Cox-2 upregulation in conditionally immortalized mouse gastric epithelial cells (MGEC) was inhibited by EGCG. Methods: H. pylori (NCTC11637, cag PAI+) were co-cultured with MGEC gastric epithelial cells for 12 hrs. MGEC cells were pre-incubated for 1 hr with EGCG (1-100 µM) (concentrations which did not affect bacterial or cell viability) before co-culture with H. pylori. At 12 hrs post-infection when maximum expression of Cox-2 transcript levels was evident, RNA was extracted form MGEC cells and evaluated by Northern blotting. Gapdh transcript levels were measured as a control. Results: At 12 hrs post-infection, EGCG (50-100 µM) significantly inhibited both basal and H. pylori-induced Cox-2 transcript levels in MGEC cells (n=3, p&lt;0.05 and p&lt;0.01, respectively). Conclusions: H. pylori-induced Cox-2 transcript levels in MGEC cells are significantly inhibited by EGCG in a dose dependent fashion. Green tea consumption as an inhibitor for H. pylori-induced gastric cancer, via COX-2 signaling pathway, might have a role in prevention of gastric carcinogenesis.
Childhood growth is a cornerstone of pediatric research. Statistical models need to consider indi... more Childhood growth is a cornerstone of pediatric research. Statistical models need to consider individual trajectories to adequately describe growth outcomes. Specifically, well-defined longitudinal models are essential to characterize both population and subject-specific growth. Linear mixed-effect models with cubic regression splines can account for the nonlinearity of growth curves and provide reasonable estimators of population and subject-specific growth, velocity and acceleration. We provide a stepwise approach that builds from simple to complex models, and account for the intrinsic complexity of the data. We start with standard cubic splines regression models and build up to a model that includes subject-specific random intercepts and slopes and residual autocorrelation. We then compared cubic regression splines vis-à-vis linear piecewise splines, and with varying number of knots and positions. Statistical code is provided to ensure reproducibility and improve dissemination of methods. Models are applied to longitudinal height measurements in a cohort of 215 Peruvian children followed from birth until their fourth year of life. Unexplained variability, as measured by the variance of the regression model, was reduced from 7.34 when using ordinary least squares to 0.81 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) when using a linear mixed-effect models with random slopes and a first order continuous autoregressive error term. There was substantial heterogeneity in both the intercept (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and slopes (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) of the individual growth trajectories. We also identified important serial correlation within the structure of the data (ρ = 0.66; 95 % CI 0.64 to 0.68; p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001), which we modeled with a first order continuous autoregressive error term as evidenced by the variogram of the residuals and by a lack of association among residuals. The final model provides a parametric linear regression equation for both estimation and prediction of population- and individual-level growth in height. We show that cubic regression splines are superior to linear regression splines for the case of a small number of knots in both estimation and prediction with the full linear mixed effect model (AIC 19,352 vs. 19,598, respectively). While the regression parameters are more complex to interpret in the former, we argue that inference for any problem depends more on the estimated curve or differences in curves rather than the coefficients. Moreover, use of cubic regression splines provides biological meaningful growth velocity and acceleration curves despite increased complexity in coefficient interpretation. Through this stepwise approach, we provide a set of tools to model longitudinal childhood data for non-statisticians using linear mixed-effect models.
We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in develo... more We hypothesize that infection with the gastric pathogen Helicobacter pylori in children in developing countries is the initiator of a vicious cycle of events that result ultimately in malnutrition and growth impairment. Acute infection with H. pylori is accompanied by hypochlorhydria, which facilitates the acquisition of other enteropathogens because of removal of the gastric acid barrier, which then results in diarrheal disease and iron-deficiency anemia. This is likely to occur most frequently in developing regions where the prevalence of H. pylori infection is disproportionately high and multiple enteric coinfections are common. The consequent synergistic impact of diarrheal disease and micronutrient deficiency on growth and cognitive function in children has significant public health implications for socioeconomic development in these countries.
To assess the relationship between density determined by quantitative culture, status, and gastri... more To assess the relationship between density determined by quantitative culture, status, and gastric histology in children. Children with clinical symptoms indicating pathology in the upper gastrointestinal tract were referred for endoscopy. From each child blood was taken for serology, and antral biopsies were obtained for quantitative culture of and histology. Histological assessment was performed according to the updated Sydney System. The status of cultured was determined by polymerase chain reaction (PCR) and serum IgG response to CagA by western blotting. Adequate antral biopsies were obtained from 41 children with positive cultures. CagA IgG antibodies were found in 27 patients (66%), 25 of whom were also positive by the PCR. Two children infected with + strains as determined by the PCR were CagA seronegative. Infection with + strains was associated with significantly higher activity of inflammation and denser bacterial colonization in the antrum compared to negative strains. No correlation was observed between the density of colonization and chronic antral inflammation. This study shows that infection of children with + strains of is associated with enhanced activity of antral inflammation and higher density of colonization. There is a good correlation between serum western blot and bacterial PCR positivity in determining status and a positive relationship between histology and quantitative culture in assessing density in paediatric patients.
The murine Helicobacter felis model has been extensively used to investigate the importance of ho... more The murine Helicobacter felis model has been extensively used to investigate the importance of host factors in the development of chronic gastritis. The effect of gender in this murine model is unknown. Male and female C57BL/6J mice were infected with H felis for up to 1 year. At 4, 8, 19, 36, and 52 weeks post-infection, gastric histopathology, epithelial cell proliferation, and apoptosis were examined and compared with age-and gender-matched controls. In female mice, infection with H felis resulted in an earlier onset of chronic gastric inflammation, epithelial hyperplasia, and oxyntic cell loss than males. In females, there was a trend towards increased gastric pathology compared with males, with long-term-infected female mice having significantly greater (p < 0.05) chronic inflammation than male mice.
Concentrations of the soluble interleukin-2 receptor (sIL-2R) in the serum of 33 patients with co... more Concentrations of the soluble interleukin-2 receptor (sIL-2R) in the serum of 33 patients with coeliac disease were measured by ELISA. The levels of sIL-2R were significantly raised in 15 patients with untreated coeliac disease compared with treated patients and age-and sex-matched symptomatic and non-symptomatic control groups. Longitudinal studies in individual coeliac patients showed that serum sIL-2R fell following commencement of a gluten-free diet. Gluten challenge of 16 treated coeliac patients for 1 week resulted in a significant increase in serum sIL-2R, which returned to prechallenge levels within 4 weeks of recommencement of a gluten-free diet. We suggest that serum sIL-2R levels in patients with coeliac disease reflect specific immunological activation in response to gluten ingestion. Measurement ofserum sIL-2R may therefore be useful in the assessment ofresponse to treatment in patients with coeliac disease.
The specificity of the tumor cell immunoglobulin in three cases of low grade B cell gastrointesti... more The specificity of the tumor cell immunoglobulin in three cases of low grade B cell gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma has been studied. Using anti-idiotypic antibodies to detect the reactivity of tumor immunoglobulin in tissue sections from the patients and other individuals, we observed specificity for normal tissue components in all three cases studied. Reactivity in one case was with follicular dendritic cells, in the second case with a novel antigen on mucosal post capillary venules, and, in the third case, a broad pattern of reactivity was observed. This study suggests that autoimmunity may play a role in the pathogenesis of gastric lymphoma.
Full text is available as a scanned copy of the original print version. Get a printable copy (PDF... more Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1016K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.
We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by ... more We have studied modulation of mucosal interleukin-6 (IL-6) secretion by T-cell activation and by anti-inflammatory agents in inflammatory bowel disease. In vitro secretion of IL-6 by biopsy specimens from patients with active ulcerative colitis was investigated in the presence of cyclosporin-A (CsA) and drugs that have other anti-inflammatory actions. Biopsy specimens from patients with quiescent ulcerative colitis or controls were stimulated with anti-CD3 antibody to activate mucosal T cells. Stimulation of control specimens increased IL-6 secretion (median increase, 147%; p &amp;amp;lt; 0.003), which was prevented by CsA. In quiescent ulcerative colitis there was enhanced spontaneous secretion of IL-6 but a smaller, non-significant increase after T-cell activation (125%). Dexamethasone inhibited secretion in active ulcerative colitis (p &amp;amp;lt; 0.006). 5-Aminosalicylic acid, 6-mercaptopurine, methotrexate, and indomethacin had no effect. There also tended to be a small reduction with CsA, but this just failed to reach statistical significance. In quiescent ulcerative colitis the enhanced spontaneous secretion of IL-6 may be a consequence of mucosal T-cell or macrophage activation: the smaller increase after T-cell stimulation suggests that one or both of these two cell types are already pre-activated.
Infection of the human gastric mucosa with Helicobacter pylori induces the development of mucosa-... more Infection of the human gastric mucosa with Helicobacter pylori induces the development of mucosa-associated lymphoid tissue (MALT), and H pylori-specific local humoral and T-cell responses. H pylori infection also results in the mucosal production of proinflammatory cytokines, which are important in stimulating neutrophil infiltration. Strains of H pylori expressing the cytotoxin associated protein A (CagA) induce gastric epithelial cells to secrete interleukin-8, the neutrophil chemotactic and activating peptide. Variation in the extent of mucosal injury may be a consequence of H pylori strain variability. Gastric B-cell lymphomas of MALT arise from a background of lymphoid follicles, which are acquired in response to H pylori infection. In many cases, eradication of H pylori from patients with low-grade gastric lymphoma results in lymphoma regression, including large tumor masses, implying a causal relationship between H pylori infection and lymphoma growth. Experiments studying the properties of tumor cell and tumor infiltrating T cells in vitro have suggested that rather than stimulating the tumor cells directly, H pylori stimulates tumor infiltrating T cells, which provide help for lymphoma growth. Unlike the active inflammatory response associated with infection with CagA positive strains, but consistent with the acquisition of lymphoid follicles in all infected individuals, the development of MALT lymphomas is independent of bacterial CagA status.
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