Gastric immune responses interact with bacterial virulence factors to promote the pathogenesis of diseases associated with H. pylori infection. While helper T (Th) cells promote inflammation in response to H. pylori in both humans and mice, they are also essential for immunity in animal models. Effective immunity can be induced by vaccination although antibody responses are not necessary. Since/-/. pylori is a noninvasive pathogen, the """"""""protective"""""""" Th cells are believed to modify epithelial cell gone expression such that the niche favoring colonization is disrupted. Th1 cells can augment expression of receptors that bind H. pylori and favor the epithelial damage that ensues. As such, they act as a """"""""pathogenic"""""""" T cell. Either endogenous or exogenous ROS can regulate the expression of genes associated with Th1 cells. In contrast, Th2 cells, through the production ofIL-4, IL-5, IL-10, IL-13, IL-25 and TGF-Beta can antagonize the effects of Th1 cells. Tr1 cells, a recently described subset of Th cells, resemble Th2 cells by producing IL-5 and -10 but also produce IFN-gamma similar to Th1 cells. Importantly, Tr1 cells are present in the digestive tract and attenuate the host response to luminal antigen including the induction of colitis in animal models. Cytokines associated with Tr1 cells prevent the generation of ROS, the expression of genes associated with Th1 cells and their effects on bacterial binding and epithelial cell damage. These observations suggest that a """"""""protective"""""""" response to vaccines will induce Tr1 cells, or related regulatory Th cells, that are responsible for limiting inflammation. How these cells are derived is unknown and their role in host defense has yet to be defined. This background leads to our general hypothesis that a relative imbalance in helper T cell subsets favors the stimulation of inflammation and epithelial damage in response to persistent infection with H. pylori. More specifically, oxidative stress associated with H. pylori infection selects for """"""""pathogenic"""""""" Th1 responses that contribute to epithelial damage while a regulatory """"""""protective"""""""" Th1 cell will favor tissue integrity and immunity. The overall objective is to define the T cell response to natural infection with H. pylori or immunization and elucidate the mechanisms governing lymphoepithelial cell interactions in disease versus immunity. This will be achieved in the following Specific Aims: 1). Define the factors selecting for """"""""pathogenic"""""""" Th cells associated with H. pylori infection. 2). Identify T cell markers that are correlates of immunity. 3). Define mechanisms of host defense attributed to """"""""protective"""""""" Th cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK051677-06
Application #
6580940
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1997-09-01
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$284,900
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Das, Soumita; Sarkar, Arup; Choudhury, Sarmistha Sinha et al. (2015) ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome. Cell Mol Gastroenterol Hepatol 1:311-324
Ernst, P B; Erickson, L D; Loo, W M et al. (2012) Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice. Am J Physiol Gastrointest Liver Physiol 302:G105-15
O'Hara, Ann M; Bhattacharyya, Asima; Bai, Jie et al. (2009) Tumor necrosis factor (TNF)-alpha-induced IL-8 expression in gastric epithelial cells: role of reactive oxygen species and AP endonuclease-1/redox factor (Ref)-1. Cytokine 46:359-69
Minohara, Yutaka; Boyd, David K; Hawkins, Hal K et al. (2007) The effect of the cag pathogenicity island on binding of Helicobacter pylori to gastric epithelial cells and the subsequent induction of apoptosis. Helicobacter 12:583-90
Croxen, Matthew A; Ernst, Peter B; Hoffman, Paul S (2007) Antisense RNA modulation of alkyl hydroperoxide reductase levels in Helicobacter pylori correlates with organic peroxide toxicity but not infectivity. J Bacteriol 189:3359-68
Ding, Song-Ze; Minohara, Yutaka; Fan, Xue Jun et al. (2007) Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells. Infect Immun 75:4030-9
O'Hara, Ann M; Bhattacharyya, Asima; Mifflin, Randy C et al. (2006) Interleukin-8 induction by Helicobacter pylori in gastric epithelial cells is dependent on apurinic/apyrimidinic endonuclease-1/redox factor-1. J Immunol 177:7990-9
Ernst, Peter B; Peura, David A; Crowe, Sheila E (2006) The translation of Helicobacter pylori basic research to patient care. Gastroenterology 130:188-206; quiz 212-3
Wang, J; Brooks, E G; Bamford, K B et al. (2001) Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion. J Immunol 167:926-34
Fan, X; Gunasena, H; Cheng, Z et al. (2000) Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J Immunol 165:1918-24

Showing the most recent 10 out of 11 publications