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About the Lab
In the two major forms of IBD, Crohn’s disease and ulcerative colitis, the underlying etiological factors and the pathogenesis remain poorly defined. It is generally believed that exaggerated immune responses to luminal normal enteric flora are involved in the initiation and perpetuation of the disease process.
The availability of a wide variety of experimental models of intestinal inflammation has helped provide important clues about the pathogenesis of IBD. The commonly used models include chemically induced mucosal injury and colitis induced by the transfer of selected populations of T cells into immunodeficient mice. The spontaneous development of colitis in genetically engineered animal models has provided excellent experimental models to study the pathogenesis of IBD. One important lesson learned from IBD models is that many different immunologic and mucosal defects can lead to similar pathologic findings.
For the last several years, our laboratory has focused on defining the pathogenesis of chronic intestinal inflammation using TCR alpha KO mice as a model of human IBD. TCR alpha KO mice develop spontaneously chronic colitis with many features of ulcerative colitis. We have identified a regulatory B cell subset, which appears under chronic intestinal inflammatory conditions and suppresses the progression of intestinal inflammation by secreting IL-10. TCR alpha KO mice deficient in both IL-4 and B cells, but not in IL-4 alone, develop granulomatous colitis with features of Crohn’s disease. This suggests that differences in the two major forms of IBD may reflect different immunological responses to similar initiating events.
The laboratory is closely associated with the Center for the Study of Inflammatory Bowel Disease at Mass General and collaborates with the other members of the Center; Dr. Bhan is an Associate Director of the Center. In collaboration with Dr. Terhorst and Dr. Xavier we have studied the role of Th-1 and Th-17 pathways, innate immune system and autophagy in the development of intestinal inflammation. Collaborative studies with Dr. Scott Snapper’s laboratory have shown that interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function. The studies with Dr. Richard Hodin’s laboratory indicate that administration of intestinal alkaline phosphatase may have a beneficial effect in intestinal inflammatory conditions and metabolic syndromes. Dr. Bhan’s consultant role in the newly established Harvard Institute of Translational Immunology-Helmsley Pilot Program in Crohn’s Disease has led to his collaboration with Dr. Vijay Yajnik at Mass General and Dr. Matthew Myerson at DFCI to identify microorganisms in Crohn’s disease lesions.
For the last several years, our laboratory has focused on defining the pathogenesis of chronic intestinal inflammation using TCR alpha KO mice as a model of human IBD. TCR alpha KO mice develop spontaneously chronic colitis with many features of ulcerative colitis. These features include restriction of inflammation to the colon and the mucosa, presence of autoantibodies, the protective role of appendectomy and pathogenic role of Th-2 pathway in the development of colitis. We have identified a regulatory B cell subset, which appears under chronic intestinal inflammatory conditions and suppresses the progression of intestinal inflammation by secreting IL-10. Recently, we have identified an IL-12-producing regulatory B cell subset. TCR alpha KO mice deficient in both IL-4 and B cells, but not in IL-4 alone, develop granulomatous colitis with features of Crohn’s disease. This suggests that differences in the two major forms of IBD may reflect different immunological responses to similar initiating events.
- Atul K. Bhan, MBBS, MD
Lassen KG, McKenzie CI, Mari M, et al. Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity. 2016; 44:1392-405.
Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Kara G. Lassen, Petric Kuballa, Kara L. Conway, Khushbu K. Patel, Christine E. Becker, Joanna M. Peloquin, Eduardo J. Villablanca, Jason M. Norman, Ta-Chiang Liu, Robert J. Heath, Morgan L. Becker, Lola Fagbami, Heiko Horn, Johnathan Mercer, Omer H. Yilmaz, Jacob D. Jaffe, Alykhan F. Shamji, Atul K. Bhan, Steven A. Carr, Mark J. Daly, Herbert W. Virgin, Stuart L. Schreiber, Thaddeus S. Stappenbeck, Ramnik J. Xavier. Proc Natl Acad Sci U S A. 2014 May 27; 111(21): 7741–7746.
Interleukin-10 Receptor Signaling in Innate Immune Cells Regulates Mucosal Immune Tolerance and Anti-Inflammatory Macrophage Function. Dror S. Shouval, Amlan Biswas, Jeremy A. Goettel, Katelyn McCann, Evan Conaway, Naresh S. Redhu, Ivan D. Mascanfroni, Ziad Al Adham, Sydney Lavoie, Mouna Ibourk, Deanna D. Nguyen, Janneke N. Samsom, Johanna C. Escher, Raz Somech, Batia Weiss, Rita Beier, Laurie Conklin, Christen L. Ebens, Fernanda GMS Santos, Alexandre R. Ferreira, Mary Sherlock,Atul K. Bhan, Werner Müller, J. Rodrigo Mora, Francisco J. Quintana, Christoph Klein, Aleixo M. Muise, Bruce H. Horwitz, Scott B. Snapper. Immunity. 2014 May 15; 40(5): 706–719.
Intestinal alkaline phosphatase prevents metabolic syndrome in mice. Kanakaraju Kaliannan, Sulaiman R. Hamarneh, Konstantinos P. Economopoulos, Sayeda Nasrin Alam, Omeed Moaven, Palak Patel, Nondita S. Malo, Madhury Ray, Seyed M. Abtahi, Nur Muhammad, Atri Raychowdhury, Abeba Teshager, Mussa M. Rafat Mohamed, Angela K. Moss, Rizwan Ahmed, Shahrad Hakimian, Sonoko Narisawa, José Luis Millán, Elizabeth Hohmann, H. Shaw Warren, Atul K. Bhan, Madhu S. Malo, Richard A. Hodin. Proc Natl Acad Sci U S A. 2013 Apr 23; 110(17): 7003–7008.
Intestinal dendritic cells survey circulatory antigens prior to induction of CD8+ T cells. Sun Young Chang, Joo-Hye Song, Bayasi Guleng, Carmen Alonso Cotoner, Seiji Arihiro, Yun Zhao, Hao-Sen Chiang, Michael O'Keeffe, Gongxian Liao, Christopher L. Karp, Mi-Na Kweon, Arlene H. Sharpe, Atul Bhan, Cox Terhorst, Hans-Christian Reinecker. Immunity. 2013 Jan 24; 38(1): 10.
mTORC1 in the Paneth cell niche couples intestinal stem cell function to calorie intake. Ömer H. Yilmaz, Pekka Katajisto, Dudley W. Lamming, Yetis Gültekin, Khristian E. Bauer-Rowe, Shomit Sengupta, Kivanc Birsoy, Abdulmetin Dursun, V. Onur Yilmaz, Martin Selig, G. Petur Nielson, Mari Mino-Kenudson, Lawrence Zukerberg, Atul Bhan, Vikram Deshpande, David M. Sabatini. Nature. 2012 Jun 28; 486(7404): 490–495.
Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation. Sugimoto K, Ogawa A, Shimomura Y, Nagahama K, Mizoguchi A, Bhan AK. Gastroenterology. 2007 Jul;133(1):124-36.
Dependence of intestinal granuloma formation on unique myeloid DC-like cells. Atsushi Mizoguchi, Atsushiro Ogawa, Hidetoshi Takedatsu, Ken Sugimoto, Yasuyo Shimomura, Katsunori Shirane, Kiyotaka Nagahama, Takashi Nagaishi, Emiko Mizoguchi, Richard S. Blumberg, Atul K. Bhan. J Clin Invest. 2007 Mar 1; 117(3): 605–615.
- Pathologist, Massachusetts General Hospital
- Professor of Pathology, Harvard Medical School