Singh, Bhagirath - University of Western Ontario - Department of Microbiology and Immunology

研究领域

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.

近期论文

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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.