Inflammatory bowel disease (IBD) encompasses Crohn's disease and Ulcerative colitis, diseases the cause of which is currently unknown. In recent years, tremendous progress has been made towards understanding the pathogenesis of IBD. The evidence strongly points to a role for both a microbial and an immune component. Several species of pathogenic bacteria residing within the gut lumen have been implicated, and these include invasive Escherichia coli, Helicobacter, Clostridium and Enterococcus species. Furthermore, increased levels of the inflammatory cytokines interleukin (IL)-17 and IL-23 have been reported within the intestinal mucosa. These two cytokines are critical for the function and maintenance of T helper type 17 (TH17) cells, a recently identified subset of helper T cells that play important roles in host defense and organ specific autoimmune inflammation. Genome wide array analyses have identified prominent IBD susceptibility genes involved in the IL-23-TH17 immune response pathway, immune suppression, and innate immunity to microbial pathogens. Collectively, these studies point to an imbalance in the symbiotic relationship between host and microbe, such that loss in tolerance to the intestinal microbiota and increased TH17 related inflammation are now considered to be responsible for the pathogenesis of IBD. The exact mechanisms for why and how this occurs in patients with IBD is unclear. Our recent identification of one physiological trigger that drives THI 7 responses within the intestinal lamina propria provides a clue. We found that innate immune recognition of apoptotic intestinal epithelial cells dying during an infection induces differentiation of naive CD4 T cells into effector TH17 cells. Here we aim to test our hypothesis that an inability to protect the intestinal epithelium during infections with damaging and invasive enteric pathogens serves as an instigator of IBD. We will characterize the antigen specificities of infection-induced THI 7 response to self and non-self antigens, and define the regulatory mechanisms that control self-specific populations. We will ask whether an absence or a dysfunction of these regulatory populations within a genetic susceptibility background for IBD, leads to failure in protecting and repairing the epithelium damaged from infection, progressive loss of barrier functions against luminal bacteria, and an inability to suppress the aggravated inflammatory response.

Public Health Relevance

T helper 17 cells have been associated with inflammatory bowel disease. This proposal seeks to characterize the self and non-self specificities of T helper 17 cells induced in response to an enteric infection, and define the regulatory mechanisms that control self-specific populations. The new knowledge we gain should lead to an improved understanding of the causative defects in inflammatory bowel disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
New York
United States
Zip Code
Meisel, Marlies; Hinterleitner, Reinhard; Pacis, Alain et al. (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580-584
Blander, J Magarian (2018) Regulation of the Cell Biology of Antigen Cross-Presentation. Annu Rev Immunol 36:717-753
Blander, J Magarian; Barbet, Gaetan (2018) Exploiting vita-PAMPs in vaccines. Curr Opin Pharmacol 41:128-136
Barbet, Gaetan; Sander, Leif E; Geswell, Matthew et al. (2018) Sensing Microbial Viability through Bacterial RNA Augments T Follicular Helper Cell and Antibody Responses. Immunity 48:584-598.e5
Moretti, Julien; Roy, Soumit; Bozec, Dominique et al. (2017) STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy of the Endoplasmic Reticulum. Cell 171:809-823.e13
Moretti, Julien; Blander, J Magarian (2017) Cell-autonomous stress responses in innate immunity. J Leukoc Biol 101:77-86
Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860
Blander, J Magarian (2017) The many ways tissue phagocytes respond to dying cells. Immunol Rev 277:158-173
Tang, Mei San; Bowcutt, Rowann; Leung, Jacqueline M et al. (2017) Integrated Analysis of Biopsies from Inflammatory Bowel Disease Patients Identifies SAA1 as a Link Between Mucosal Microbes with TH17 and TH22 Cells. Inflamm Bowel Dis 23:1544-1554
Campisi, Laura; Barbet, Gaetan; Ding, Yi et al. (2016) Apoptosis in response to microbial infection induces autoreactive TH17 cells. Nat Immunol 17:1084-92

Showing the most recent 10 out of 105 publications