Department of Pathology
The University of Chicago
Gordon Center for Integrative Science (GCIS)
929 East 57th Street, Room W-506
Chicago, IL 60637
Immunological niches in the digestive system
We study how immune homeostasis is maintained in the digestive system, and how its failure can lead to diseases such as food allergies, inflammatory bowel diseases (IBD), autoimmune diseases and cancer. In particular the lab explores the possibility that there exist multiple immunologically distinct niches within the digestive system, studies how they are created by dietary, commensal colonization and infection history in the course of a lifetime, and what the systemic impact of each niche may be. We are analyzing the impact on the innate and adaptive immune system at the physiological, cellular and molecular level.
Gastrointestinal lymphatic system
One key aspect we are studying is the gastrointestinal lymphatic system and how compartmentalized lymphatic drainage along the gut helps create different immunological environment. For example, we have found previously that gut segment specific infection (helminths in the upper small intestine versus bacteria in the colon) leads to dysfunction of only selective lymph nodes. We are currently expanding our studies to other pathogens and members of the commensal microbiome, but also to different dietary regimes, as nutrients are taken up in a site-selective manner as well. Most notably, the lymphatics of the upper small intestine are responsible for the absorption of dietary lipids and other hydrophobic nutrients and molecules. Both lymph fluid composition but also lymphatic architecture are influenced by these environmental factors, and likely help create distinct milieus. This may help sustain homeostatic conditions, but also support the chronicity of pathological conditions such as the metabolic syndrome, cancers or IBD.
Pancreas and other branches of the digestive system
The digestive system also includes the pancreas, mesentery, and by extension liver, gall bladder, and the draining lymph nodes, of which several happen to be shared by these organs. We are exploring how the immune system of all these branches is influenced by gut luminal contents, and how it may communicate. This may occur via deliberate or inappropriate leakage of migratory immune cells, macro- and micro-molecules traveling through the interstitial space, common lymphatics or blood vessels. Through our studies we hope to better understand how for example gastrointestinal infections may trigger pathologies such as type 1 diabetes.
Techniques used in the laboratory
We used a wide range of techniques including microsurgery, lymphatic vessel cannulation, pancreatic islet isolation, live and light sheet imaging of the vascular and immune systems, single cell analysis, mass spectrometry, and genetic manipulation of mice.
In sum, our studies help define how tissue environments are created and influence the local immune system. While we focus on the digestive system, the concept that the concerted action of site specific exogenous factors, inherent tissue properties and connectivity to other organs determines the immunological output is likely relevant for other parts of the body as well. A more differentiated understanding of what shapes an immunological niche may help us devise more refined and effective therapeutic strategies to target organ-specific diseases.
Daria Esterházy, Maria CC Canesso, Paul A Muller, Ainsley Lockhart, Luka Mesin, Ana MC Faria and Daniel Mucida. Compartmentalized lymph node drainage dictates intestinal adaptive immune responses. https://www.biorxiv.org/content/early/2018/04/12/29962
Esterházy D, Loschko J, London M, Jove V, Oliveira TY, Mucida D. Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat Immunol. 2016 May;17(5):545-55. PubMed PMID: 27019226; PubMed Central PMCID: PMC4837106.
Esterházy D, Stützer I, Wang H, Rechsteiner MP, Beauchamp J, Döbeli H, Hilpert H, Matile H, Prummer M, Schmidt A, Lieske N, Boehm B, Marselli L, Bosco D, Kerr-Conte J, Aebersold R, Spinas GA, Moch H, Migliorini C, Stoffel M. Bace2 is a β cell-enriched protease that regulates pancreatic β cell function and mass. Cell Metab. 2011 Sep 7;14(3):365-77. PubMed PMID: 21907142.