Helicobacter pylori induction of eosinophil migration is mediated by the cag pathogenicity island via microbial-epithelial interactions.

The host immune response directed against Helicobacter pylori is ineffective in eliminating the organism and strains harboring the cag pathogenicity island augment disease risk. Because eosinophils are a prominent component of H. pylori-induced gastritis, we investigated microbial and host mechanisms through which H. pylori regulates eosinophil migration. Our results indicate that H. pylori increases production of the chemokines CCL2, CCL5, and granulocyte-macrophage colony-stimulating factor by gastric epithelial cells and that these molecules induce eosinophil migration. These events are mediated by the cag pathogenicity island and by mitogen-activated protein kinases, suggesting that eosinophil migration orchestrated by H. pylori is regulated by a virulence-related locus.

Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses.

BACKGROUND: Sarcoidosis is an idiopathic granulomatous disease with pathologic and immunologic features similar to tuberculosis. Routine histologic staining and culture fail to identify infectious agents. An alternative means for investigating a role of infectious agents in human pathogenesis involves molecular analysis of pathologic tissues for microbial nucleic acids, as well as recognition of microbial antigens by the host immune system. Molecular analysis for superoxide dismutase A (sodA) allows speciation of mycobacteria. SodA is an abundantly secreted virulence factor that generates cellular immune responses in infected hosts. The purpose of this study is to investigate if target antigens of the sarcoidosis immune response can be identified by molecular analysis of sarcoidosis granulomas. METHODS: We detected sodA amplicons in 12 of 17 sarcoidosis specimens, compared to 2 of 16 controls (p = 0.001, two-tailed Fisher's exact test), and 3 of 3 tuberculosis specimens (p = 0.54). Analysis of the amplicons revealed sequences identical to M. tuberculosis (MTB) complex, as well as sequences which were genetically divergent. Using peripheral blood mononuclear cells (PBMC) from 12 of the 17 sarcoidosis subjects, we performed enzyme-linked immunospot assay (ELISPOT) to assess for immune recognition of MTB sodA peptides, along with PBMC from 26 PPD- healthy volunteers, and 11 latent tuberculosis subjects. RESULTS: Six of 12 sarcoidosis subjects recognized the sodA peptides, compared to one of 26 PPD- controls (p = 0.002), and 6/11 PPD+ subjects (p = .68). Overall, 10 of the 12 sarcoidosis subjects from whom we obtained PBMC and archival tissue possessed molecular or immunologic evidence for sodA. CONCLUSION: Dual molecular and immunologic analysis increases the ability to find infectious antigens. The detection of Th-1 immune responses to sodA peptides derived from molecular analysis of sarcoidosis granulomas reveals that these are among the target antigens contributing to sarcoidosis granulomatous inflammation.

Sex differences in the contribution of nicotine and nonpharmacological stimuli to nicotine self-administration in rats.

RATIONALE: Sex differences have been reported for the impact of nicotine and nonpharmacological cues on smoking. While nonpharmacological environmental stimuli have also been shown to influence nicotine self-administration in rats, there have been no attempts to examine the impact of sex differences in the contributions of nicotine and nondrug stimuli to this behavior. OBJECTIVES: This experiment investigated sex differences in operant responding for nicotine in rats when drug infusions were delivered either in the absence of, or in combination with, a nonpharmacological stimulus. METHODS: Initially, male and female rats acquired self-administration for nicotine alone across a range of doses (0.03, 0.06, and 0.15 mg kg(-1) inf(-1), freebase). After stable acquisition, nicotine infusions were combined with a weakly reinforcing, compound visual stimulus. RESULTS: While there was no overall effect of dose on active lever responding for nicotine in the absence of the visual stimulus, female rats responded more on the reinforced lever than males at 0.06 and 0.15 mg kg(-1) inf(-1) on an FR5 schedule. However, they also showed increased responding on the nonreinforced lever compared to males at the same doses. Combining nicotine infusions with the visual stimulus doubled responding compared to nicotine alone at 0.03 and 0.06, but not at 0.15 mg kg(-1) inf(-1): this effect was significantly greater for female rats. CONCLUSIONS: These data highlight the prominent contribution of nonpharmacological stimuli to nicotine-reinforced behavior across a range of doses in both male and female rats. They also reveal sex differences in operant responding for nicotine under conditions where a nonpharmacological stimulus is either absent, or combined with drug delivery.

Matrix metalloproteinase-7 and premalignant host responses in Helicobacter pylori-infected mice.

Helicobacter pylori-induced gastritis is the strongest singular risk factor for gastric adenocarcinoma. Matrix metalloproteinase-7 (MMP-7) is a proteolytic enzyme that can modify the intestinal microbial replicative niche as well as affect tumorigenesis, and H. pylori stimulates expression of MMP-7 in gastric epithelial cells in vitro. Utilizing a transgenic murine model of H. pylori-mediated injury, our experiments now show that gastric inflammation is increased within the context of MMP-7 deficiency, which involves both Th1- and Th17-mediated pathways. Enhanced gastritis in H. pylori-infected mmp-7-/- mice is strongly linked to accelerated epithelial cellular turnover. However, more severe inflammation and heightened proliferation and apoptosis are not dependent on MMP-7-mediated bacterial eradication. Collectively, these studies indicate that H. pylori-mediated induction of MMP-7 may serve to protect the gastric mucosa from pathophysiologic processes that promote carcinogenesis.