Case Western Reserve University




Alan D. Levine, Ph.D.


Intestinal Host Defense

Office Phone: 216-368-0342
Office Fax: 216.368.3055

Intestinal Host Defense: Toggling between immune tolerance and immune protection

The intestinal mucosa is the largest lymphoid organ, as assessed by the quantity of antibody produced, the number of resident leukocytes, and its surface area exposure to the environment (greater than that of a tennis court). Confounding the situation, the wall of the gut is continuously bathed by bacteria, parasites, fungi, amoebae, viruses, mitogens, toxins, and immunogenic food proteins. Therefore, a complex multi-tiered host defense system has evolved in the gut that can be divided into four interactive functions: (1) Barrier exclusion by an actively regenerating epithelial cell monolayer. (2) Innate inflammatory responses mediated by local synthesis of pro- and anti-inflammatory cytokines and antimicrobial peptides. (3) Acquired immune responses regulated by T lymphocytes. (4) Host-microbiome colonization and differentiation.

Our laboratory focuses on the mechanisms that regulate these systems. (1) Effects on intestinal permeability associated with HIV infection or inflammatory bowel disease (IBD), due to changes in the the structure, composition, and function of the tight junctional complex that regulates paracellular epithelial continuity. (2) In murine models of acute and chronic intestinal inflammation, we investigate the temporal expression and regulation of pro-inflammatory and anti-inflammatory cytokines in response to gut injury induced by ischemia associated with illicit drug abuse (opioids, methamphetamine, cocaine), and in a transgenic mouse that models human inflammatory bowel disease. (3) Dysbiosis in the HIV+, drug abuse, or IBD gut, and its consequent effect on host mucosal immune protection.  (4) Using transgenic murine models, we explore the mechanisms by which co-stimulatory and accessory molecules direct the development of immune tolerance as T cells migrate from the Peyer’s patch to the gut wall. (5) We characterize the biochemical, spatial, temporal, and structural organization of the signal transduction pathway initiating with the anti-specific T cell receptor, and differentially regulated in naïve, helper, effector, and mucosal T cells. (5) We research the regulation of integrin affinity/avidity, expression, and activation in both naïve and memory T cells by the interstitial extracellular matrix, and how matrix-induced T cell polarization modulates the partitioning of the TCR/CD3 signaling complex in the plasma membrane.


Selected Publications

Pandiyan, P., Younes, S. A., Ribeiro, S. P., Talla, A., McDonald, D., Bhaskaran, N., Levine, A. D., Weinberg, A., and Sekaly, R. P. “Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation.” Front Immunol (2016) 7, 228; doi: 10.3389/fimmu.2016.00228. [PubMed]

Pagano, M.E., Maietti, C.M., Levine, A.D. “Risk factors of repeated infectious disease incidence among substance-dependent girls and boys court-referred to treatment.” Am J Drug Alcohol Abuse (2015) 41(3). 230-236; Early Online: 1–7. DOI: 10.3109/00952990.2014.939753. [PubMed]

Chung C.Y., Alden S.L., Fu P., Funderburg N.T., Levine A.D. (2014). Progressive Proximal-to-Distal Reduction in Expression of the Tight Junction Complex in Colonic Epithelium of Virally-suppressed HIV+ Individuals. PLoS Pathog (2014) 10:e1004198; doi: 10.1371/journal.ppat.1004198. [PubMed]

Funderburg, N.T., Stubblefield Park, S.R., Sung, H.C., Hardy, G., Clagett, B., Ignatz-Hoover, J., Harding, C.V., Fu, P., Katz, J.A., Lederman, M.M., Levine, A.D.  (2013). Circulating CD4+ and CD8+ T cells are activated in IBD and are associated with plasma markers of inflammation. Immunology 140, 87–97.  doi: 10.1111/imm.12114. [PubMed]

Gill, T., Levine, A.D. (2013) Mitochondrial derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction. J. Biol Chem. 288, 26246-26255. doi:10.1074/jbc.M113.476895. [PubMed]

Klatt, N.R., Harris, L.D., Vinton, C.L., Sung, H., Briant, J.A., Tabb, B., Morcock, D., McGinty, J.W., Lifson, J.D., Lafont, B.A., Martin, M.A., Levine, A.D., Estes, J.D., Brenchley, J.M.  (2010). Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation and IL-17 production in the absence of SIV infection. Mucosal Immunology 3(4): 387–398. [PubMed]

Complete List of Published Work in MyBibliography: