Rodney D. Newberry, MD
My research expertise is in basic cellular immunology related to the mucosal immune system. Throughout my career I have been interested in the mechanisms maintaining immunological tolerance to luminal antigens. Approximately ten years ago my laboratory initiated a new line of investigation to address a simple question of how lamina propria dendritic cells acquire luminal antigens to induce adaptive immune responses. Using an in vivo two photon imaging approach we observed that in the steady state small intestine lamina propria dendritic cells largely acquire luminal antigen via a previously undescribed mechanism in which goblet cells take up antigens from the lumen and pass them off to underlying dendritic cells, a process we have termed goblet cell associated antigen passages (GAPs; McDole et al. Nature 2012). Over the ensuing time we investigated the stimuli inducing and regulating GAP formation in adult mice (Knoop et al., Mucosal Immunology, 2014), the capacity for GAPs to translocate commensal and pathogenic bacteria (Knoop et al. Gut, 2016, Knoop et al. Gut Microbes, 2017, Kulkarni et al, Mucosal Immunology, 2018), and the role of GAPs in tolerance to dietary antigens (Kulkarni et al, Mucosal Immunology, 2019). In addition we have been investigating a role for GAPs during the pre-weaning period for establishing tolerance to commensal bacteria and as a portal for gut resident pathogens to induce disease in a mouse model of late onset sepsis (Knoop et al. Science Immunology, 2107, Knoop et al. Proceedings of the National Academy of Sciences, 2020). More recently my laboratory, in collaboration with Dr. Hsieh's group in the Division of Rheumatology, have been investigating how the gut microbiome and mucosal immune responses induced by these microbes impact diseases at distant sites including autoimmune diseases.
The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed to trillions of microbes and innocuous substances from the diet. The largest collection of immune cells in the body underlies this single layer epithelium and monitors the luminal contents to maintain tolerance to dietary and commensal antigens in the steady-state while retaining the ability to rapidly induce immunity to pathogens during infection. While great progress has been made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17 responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a physiologic response to enteric infection, which in and of itself, promotes the generation of Th17 cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance toward immunity. By studying this process in the absence of enteric infection or injury we can disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state. Understanding intrinsic properties of the gut that allows the rapid generation of protective responses could provide new approaches to treat enteric infections and provide insight into the pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs are inhibited, other pathways take over driving the development and/or expansion of Th17 cells specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to provide enhanced protection during enteric infection and/or injury.
Current Grant Support
|Host-environment interactions in the pathophysiology of digestive disease|
|Goblet Cells in Intestinal Immune Homeostasis|
|The Role of Route of Entry by Bacterial Antigens on colonic T Cell Responses|
|Gut Intrinsic Inflammatory Responses|
Rodney D. Newberry, M.D.
Udayan S, Stamou P, Crispie F, Hickey A, Floyd AN, Hsieh CS, Cotter PD, O'Sullivan O, Melgar S, O'Toole PW, Newberry RD, Rossini V, Nally K. Identification of Gut Bacteria such as Lactobacillus johnsonii that Disseminate to Systemic Tissues of Wild Type and MyD88-/- Mice. Gut microbes. 2022;14(1):2007743. doi: 10.1080/19490976.2021.2007743. PubMed PMID: 35023810; PMCID: PMC8765072.
Sazonovs A, Stevens CR, Venkataraman GR, Yuan K, Avila B, Abreu MT, Ahmad T, Allez M, Ananthakrishnan AN, Atzmon G, Baras A, Barrett JC, Barzilai N, Beaugerie L, Beecham A, Bernstein CN, Bitton A, Bokemeyer B, Chan A, Chung D, Cleynen I, Cosnes J, Cutler DJ, Daly A, Damas OM, Datta LW, Dawany N, Devoto M, Dodge S, Ellinghaus E, Fachal L, Farkkila M, Faubion W, Ferreira M, Franchimont D, Gabriel SB, Ge T, Georges M, Gettler K, Giri M, Glaser B, Goerg S, Goyette P, Graham D, Hämäläinen E, Haritunians T, Heap GA, Hiltunen M, Hoeppner M, Horowitz JE, Irving P, Iyer V, Jalas C, Kelsen J, Khalili H, Kirschner BS, Kontula K, Koskela JT, Kugathasan S, Kupcinskas J, Lamb CA, Laudes M, Lévesque C, Levine AP, Lewis JD, Liefferinckx C, Loescher BS, Louis E, Mansfield J, May S, McCauley JL, Mengesha E, Mni M, Moayyedi P, Moran CJ, Newberry RD, O'Charoen S, Okou DT, Oldenburg B, Ostrer H, Palotie A, Paquette J, Pekow J, Peter I, Pierik MJ, Ponsioen CY, Pontikos N, Prescott N, Pulver AE, Rahmouni S, Rice DL, Saavalainen P, Sands B, Sartor RB, Schiff ER, Schreiber S, Schumm LP, Segal AW, Seksik P, Shawky R, Sheikh SZ, Silverberg MS, Simmons A, Skeiceviciene J, Sokol H, Solomonson M, Somineni H, Sun D, Targan S, Turner D, Uhlig HH, van der Meulen AE, Vermeire S, Verstockt S, Voskuil MD, Winter HS, Young J, Duerr RH, Franke A, Brant SR, Cho J, Weersma RK, Parkes M, Xavier RJ, Rivas MA, Rioux JD, McGovern DPB, Huang H, Anderson CA, Daly MJ. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility. Nat Genet. 2022. Epub 20220829. doi: 10.1038/s41588-022-01156-2. PubMed PMID: 36038634.
Yokanovich LT, Newberry RD, Knoop KA. Regulation of oral antigen delivery early in life: Implications for oral tolerance and food allergy. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2021. Epub 2021/01/07. doi: 10.1111/cea.13823. PubMed PMID: 33403739.
Wang MH, Friton JJ, Raffals LE, Leighton JA, Pasha SF, Picco MF, Monroe K, Nix BD, Newberry RD, Faubion WA. Novel Genetic Variant Predicts Surgical Recurrence Risk in Crohn's Disease Patients. Inflamm Bowel Dis. 2021. Epub 2021/03/17. doi: 10.1093/ibd/izaa362. PubMed PMID: 33724339.
Somineni HK, Nagpal S, Venkateswaran S, Cutler DJ, Okou DT, Haritunians T, Simpson CL, Begum F, Datta LW, Quiros AJ, Seminerio J, Mengesha E, Alexander JS, Baldassano RN, Dudley-Brown S, Cross RK, Dassopoulos T, Denson LA, Dhere TA, Iskandar H, Dryden GW, Hou JK, Hussain SZ, Hyams JS, Isaacs KL, Kader H, Kappelman MD, Katz J, Kellermayer R, Kuemmerle JF, Lazarev M, Li E, Mannon P, Moulton DE, Newberry RD, Patel AS, Pekow J, Saeed SA, Valentine JF, Wang MH, McCauley JL, Abreu MT, Jester T, Molle-Rios Z, Palle S, Scherl EJ, Kwon J, Rioux JD, Duerr RH, Silverberg MS, Zwick ME, Stevens C, Daly MJ, Cho JH, Gibson G, McGovern DPB, Brant SR, Kugathasan S. Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease. Am J Hum Genet. 2021;108(3):431-45. Epub 2021/02/19. doi: 10.1016/j.ajhg.2021.02.001. PubMed PMID: 33600772; PMCID: PMC8008495.
Secca C, Bando JK, Fachi JL, Gilfillan S, Peng V, Di Luccia B, Cella M, McDonald KG, Newberry RD, Colonna M. Spatial distribution of LTi-like cells in intestinal mucosa regulates type 3 innate immunity. Proc Natl Acad Sci U S A. 2021;118(23). Epub 2021/06/05. doi: 10.1073/pnas.2101668118. PubMed PMID: 34083442; PMCID: PMC8201890.
Russler-Germain EV, Jung J, Miller AT, Young S, Yi J, Wehmeier A, Fox LE, Monte KJ, Chai JN, Kulkarni DH, Funkhouser-Jones LJ, Wilke G, Durai V, Zinselmeyer BH, Czepielewski RS, Greco S, Murphy KM, Newberry RD, Sibley LD, Hsieh CS. Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections. Immunity. 2021;54(11):2547-64.e7. Epub 2021/10/30. doi: 10.1016/j.immuni.2021.10.002. PubMed PMID: 34715017; PMCID: PMC8716016.
Rusconi BA, Newberry RD. The microbial one-hit wonder. J Exp Med. 2021;218(9). Epub 2021/08/20. doi: 10.1084/jem.20211382. PubMed PMID: 34410326; PMCID: PMC8383817.
Noah TK, Lee JB, Brown CA, Yamani A, Tomar S, Ganesan V, Newberry RD, Huffnagle GB, Divanovic S, Hogan SP. Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning and Predisposes to Oral Antigen Sensitization in Mice. Frontiers in immunology. 2021;12:636198. Epub 2021/04/13. doi: 10.3389/fimmu.2021.636198. PubMed PMID: 33841417; PMCID: PMC8034294.
Newberry RD, Hogan SP. Intestinal epithelial cells in tolerance and allergy to dietary antigens. The Journal of allergy and clinical immunology. 2021;147(1):45-8. Epub 2020/11/05. doi: 10.1016/j.jaci.2020.10.030. PubMed PMID: 33144143.
Kulkarni DH, Newberry RD. A Novel Role of Circular RNA in Intestinal Epithelial Repair. Gastroenterology. 2021;161(4):1108-10. Epub 2021/07/26. doi: 10.1053/j.gastro.2021.07.031. PubMed PMID: 34303659.
Kosinsky RL, Zerche M, Kutschat AP, Nair A, Ye Z, Saul D, von Heesen M, Friton JJ, Schwarzer AC, Paglilla N, Sheikh SZ, Wegwitz F, Sun Z, Ghadimi M, Newberry RD, Sartor RB, Faubion WA, Johnsen SA. RNF20 and RNF40 regulate vitamin D receptor-dependent signaling in inflammatory bowel disease. Cell Death Differ. 2021. Epub 2021/06/06. doi: 10.1038/s41418-021-00808-w. PubMed PMID: 34088983.
Ingle H, Hassan E, Gawron J, Mihi B, Li Y, Kennedy EA, Kalugotla G, Makimaa H, Lee S, Desai P, McDonald KG, Diamond MS, Newberry RD, Good M, Baldridge MT. Murine astrovirus tropism for goblet cells and enterocytes facilitates an IFN-lambda response in vivo and in enteroid cultures. Mucosal Immunol. 2021;14(3):751-61. Epub 2021/03/07. doi: 10.1038/s41385-021-00387-6. PubMed PMID: 33674763; PMCID: PMC8085034.
Gustafsson JK, Davis JE, Rappai T, McDonald KG, Kulkarni DH, Knoop KA, Hogan SP, Fitzpatrick JA, Lencer WI, Newberry RD. Intestinal goblet cells sample and deliver lumenal antigens by regulated endocytic uptake and transcytosis. Elife. 2021;10. Epub 2021/10/23. doi: 10.7554/eLife.67292. PubMed PMID: 34677124; PMCID: PMC8594945.
Courtney CM, Onufer EJ, McDonald KG, Steinberger AE, Sescleifer AM, Seiler KM, Tecos ME, Newberry RD, Warner BW. Small Bowel Resection Increases Paracellular Gut Barrier Permeability via Alterations of Tight Junction Complexes Mediated by Intestinal TLR4. J Surg Res. 2021;258:73-81. Epub 20200928. doi: 10.1016/j.jss.2020.08.049. PubMed PMID: 33002664; PMCID: PMC7937530.