Dr. Bhagirath Singh
Director, Centre for Human Immunology
Professor, Department of Microbiology & Immunology
Scientist, Robarts Research Institute
University of Western Ontario
London, Ontario, Canada
Contact information:
Room 214, Siebens Drake Medical Research Institute
1400 Western Road
London, Ontario N6G 2V4
Tel. (Office): (519) 661-3228
Tel. (Laboratory): (519) 661-3483
Fax: (519) 661-3499
E-mail: bsingh@uwo.ca
Cellular basis for the activation of regulatory T cells in autoimmune diabetes by microbial agents
CD4 helper T cells modulate both immunity and autoimmunity. We are exploring their role in the pathogenesis and prevention of type 1 autoimmune diabetes (T1D). There is a reciprocal relationship between regulatory Treg cells, which prevent tissue inflammation and promote self-tolerance, and proinflammatory T cells involved in the disease. In vivo helper T cells appear to have greater plasticity in switching from effector to regulatory phenotype. We are investigating Treg and IL-17 producing Th17 cell subsets following islet autoantigens and mycobacterial adjuvant immunization in prevention of T1D.
Dendritic cell in the modulation of autoimmunity in Type I diabetes
Induction and progression of type 1 diabetes (T1D) is dependent on antigen presenting cells, particularly dendritic cells (DC). Different subsets of DCs are critical for the induction and effector phase of the disease. The goal of this project is to use DCs to prevent and modulate T1D using the NOD mouse model of T1D. Further, to correlate the data from the mouse model of T1D with human subjects, we characterize and assess peripheral blood DCs from subjects with T1D. In line with our goals, our lab has discovered a novel peptide fragment of apolipoprotein E (ApoE), termed Ep1.B, which induces the differentiation of monocytes into DC subset. We are exploring the potential application of Ep1.B in modulating immunity.
Regeneration of insulin producing islet beta cells in pancreatic tissue
There is considerable evidence that insulin producing beta cells in the pancreatic islets can regenerate through formation of new islet-like cell clusters containing beta cells. We previously showed diabetes prevention and islet preservation in NOD mice by treatment with mycobacterial preparations such as complete Freund’s adjuvant (CFA) or BCG. Several recent studies have confirmed regeneration of beta cells in the islets and following prevention of autoimmunity. The specific aim of our work is to investigate the expression of various transcription factors particularly the regenerating (Reg) gene family in islet beta cell regeneration in the pancreas of NOD mice to functionally reverse T1D.
Current Lab Members:
Edwin Lee-Chan
Olga Krougly
Recent Publications
1. Summers KL and Singh B. 2012. Gut microbes and regulatory Th17 cells in Type 1 diabetes. Immunotherapy. 4: 363–364.
2. Bellemore SM; Nikoopour E; Au BC; Krougly O; Lee-Chan E; Haeryfar SM; Singh B. Anti-atherogenic peptide Ep1.B derived from Apolipoprotein E induces tolerogenic plasmacytoid dendritic cells. Clin Exp Immunol; 2014 May (in press); PubMed ID: 24784480
3. Nikoopour E, Singh B. Reciprocity in microbiome and immune system interactions and its implications in disease and health. Inflamm Allergy Drug Targets; 2014 Apr 13; 13(2):94-104. PubMed ID: 24678760
4. Singh B, Nikoopour E, Huszarik K, Elliott JF and Jevnikar AM. 2011. Immunomodulation and Regeneration of Islet Beta cells by Cytokines in Autoimmune Type 1 Diabetes. J Interferon Cytokine Res. 31: 711-719.
5. Nikoopour E, Sandrock C, Huszarik K, Krougly O, Lee-Chan E, Masteller EL, Bluestone JA and Singh B. 2011. Cutting edge: Vasostatin-1 derived peptide ChgA29-42 is Antigenic Epitope of diabetogenic BDC2.5 T cells in NOD mice. J. Immunol. 186:3831-3835.
6. Huszarik K, Wright B, Keller C, Nikoopour E, Krougly O, Lee-Chan E, Qin HY, Cameron MJ, Gurr WK, Hill DJ, Sherwin RS, Kelvin DJ, Singh B. Adjuvant Immunotherapy Increases {beta} Cell Regenerative Factor Reg 2 in the Pancreas of Diabetic Mice. Journal of Immunology 2010; 185: 5120-5129.
7. Nikoopour E, Schwartz J, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, Singh B. 2010. Th17 polarized cells from Nonobese Diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes. Journal of Immunology 2010; 184: 4779-4788.
8. Nikoopour E, Schwartz J, Huszarik K, Sandrock C, Krougly O, Lee-Chan E, Singh B. 2010. Th17 polarized cells from Nonobese Diabetic mice following mycobacterial adjuvant immunotherapy delay type 1 diabetes. J Immunol 184: 4779-4788.
9. Kilgannon P, Novak Z, Fotedar A, Singh B. 2010. Junctional diversity prevents negative selection of an antigen-specific T cell repertoire. Mol Immunol 47: 1154-1160.
10. French MB, Loeb MB, Richardson C, Singh B. Research preparedness paves the way to respond to pandemic H1N1 2009 influenza virus. Can J Infect Dis Med Microbiol. 20:e63-e66, 2009.
11. Zhang X, Alnaeeli M, Singh B, Teng YT. 2009. Involvement of SOCS3 in regulation of CD11c+ dendritic cell-derived osteoclastogenesis and severe alveolar bone loss. Infect Immun. 77: 2000-2009.
12. Stephens TA, Nikoopour E, Rider BJ, Leon-Ponte M, Chau TA, Mikolajczak S, Chaturvedi P, Lee-Chan E, Flavell RA, Haeryfar SM, Madrenas J, Singh B. 2008. Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E. J. Immunol. 181: 6859-6871.
13. Enayat Nikoopour, Jordan Ari Schwartz and Bhagirath Singh. 2008. Therapeutic Benefits of Regulating Inflammation in Autoimmunity. Inflammation & Allergy-Drug Targets, 7: 203-210
14. Mukherjee R, Chaturvedi P, E. Lee-Chan E, B. Singh B. 2008. Exogenous CLIP Localizes into endocytic compartment ofcells upon internalization: Implications for antigen presentation by MHC class II molecules. Mol Immunol 45: 2166-2176.
15. Marleau AM, Summers KL, Singh B. 2008. Differential contributions of APC subsets to T cell activation in non-obese diabetic mice. J Immunol. 180: 5235-5249.
16. Bocksch L, Rider BJ, Stephens T, Dai E, Liu L, Diao H, Viswanathan K, Munuswamy-Ramanujam G, Singh B, Lucas A. 2007. C-terminal apolipoprotein E-derived peptide, Ep1.B, displays anti-atherogenic activity. Atherosclerosis. 194: 116-124.
17. Summers KL, Marleau AM, Mahon JL, McManus R, Hramiak I, Singh B. 2006. Reduced IFN-a secretion by blood dendritic cells in human diabetes. Clin Immunol 121:81-89.
18. Qin HY, Mukherjee R, Lee-Chan E, Ewen C, Bleackley RC, Singh, B. 2006. A novel mechanism of regulatory T cell-mediated downregulation of autoimmunity. Int Immunol. 18:1001-15.
19. Mukherjee R, Wagar DA , Stephens TA, Lee-Chan E, Singh B. 2005. Identification of CD4+ T cell specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) – a novel β cell autoantigen in type 1 diabetes. J. Immunol. 174: 5306-15.
20. Qin HY, Chaturvedi P, Singh, B. 2004. In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-γ/TNF-α. Int Immunol. 16:1723-1732.
21. Rajput A, Singh B. 2004 Gene expression profiling in type 1 diabetes prone NOD mice immunized with a disease protective autoantigenic peptide. J. Autoimmun. 23: 311-321.
22. Young HY, Zucker P, Flavell RA, Jevnikar AM, Singh B. 2004. Characterization of the role of Major Histocompatibility Complex in type 1 diabetes recurrence after islet transplantation. Transplantation 78: 509-515.
23. Summers KL, Annette AM, Stephens TA, Mahon JL, Singh B. 2004. Dendritic cells and Immune regulation in the pathogenesis and prevention of Type 1 diabetes. Can. J. Diabetes 28: 20-29.
Past Lab Members
University of Western Ontario
Katrina Huszarik
Enayat Nikoopour
Christian Sandrock
Beverly Rider
Tracy Stephens
Marc Zechel
Sean Prange
Holly Young
Annette Marleau
Kelly Summers
Ashish Rajput
Rinee Mukherjee
Pratibha Chaturvedi
Hui-Yu Qin
Jordan A. Schwartz
Michael Krawitz
Rachel Delima
Henry Chou
Rakesh Verma
Tetyana Pelipyagina
QueendyYu
University of Alberta
Patrick D. Kilgannon
Zuzana Novak
Babita Agrawal
Arun Fotedar
Michel Boyer
Wallace Smart
Donna MacNeil
Jana Lauzon
Ester Fraga
M. Manickasundari,
William Cliffe
Tom Dillion
Career and Research Profile
Dr. Singh is the inaugural Director of the Centre for Human Immunology (CHI) at the University of Western Ontario (UWO) and Professor in the Department of Microbiology and Immunology and Scientist at the Robarts Research Institute. From 2001-2009 he served as the founding Scientific Director of the Institute of Infection and Immunity, one of 13 Institutes of the Canadian Institutes of Health Research (CIHR), the main public funding body for health research in Canada. . He served as Professor and Chair of the Department of Microbiology and Immunology at the University of Western Ontario from 1992-2001 and from 1997-2001 was also the Deputy Director of the Robarts Research Institute. He was a faculty member in the Department of Immunology at the University of Alberta, Edmonton from 1977-1992.
His laboratory has done seminal work in the immunology of peptides. Well before the crystal structure of MHC molecules was elucidated his laboratory identified that peptides of 9-12 amino acids were required for priming and triggering of humoral and helper T cell-mediated immune responses. His laboratory first described that immunomodulation induced by microbial adjuvants such as CFA or BCG prevented autoimmune type 1 diabetes and its recurrence and regulatory CD4 T cells played an important role in this process. This work had a major impact in our understanding of the role of microbial agents and in the formulation of the Hygiene hypothesis for protective immunity. He has published over 200 articles in peer-reviewed journals.
Honours and Awards
Dr. Singh is recognized as a leader in the field of immunology of peptides and the regulation of autoimmune responses in type 1 diabetes. In recognition of his significant contributions, Dr. Singh has been the recipient of numerous awards including the Alberta Heritage Medical Scientist Award and the Award of Excellence of the Faculty of Medicine of University of Western Ontario. In 2000 he was the Banting and Best Memorial Lecturer at the 17th International Diabetes Federation Congress and in 2001 he was Bernhard Cinader Award Lecturer at the Canadian Society for Immunology. He was elected fellow of the Royal Society of Canada (FRSC) in 2004 and of the Canadian Academy of Health Sciences (FCAHS) in 2005. He has served as a member of peer review grant panels of the Juvenile Diabetes Foundation International, the Canadian Diabetes Association, CIHR and the National Institute of Health. In 2010 he received the John D. Reynolds award of the Canadian Society for Immunology for his contributions to Canadian immunology.
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