Type 1 diabetes (T1D) occurs as a result of interplay of genetic and environmental factors. Recent genome-wide scans have given much information about the genes that predispose to disease but much less is known of the environmental interaction that causes susceptible individuals to develop T1D. We have recently generated evidence in the Non Obese Diabetic mouse (NOD) that the innate immune response, mediated through the innate immune adaptor MyD88, may plays a critical role influencing development of disease. We showed that mice deficient in MyD88 did not develop diabetes when bred in a Specific Pathogen free (SPF) environment. There was evidence of increased T regulatory cell activity in the pancreatic lymph nodes of these MyD88-/- mice. However, when the mice were rederived into a germ free facility, they developed the same high incidence of diabetes as wild type mice in the same conditions. Re-introduction of a restricted set of gut commensal bacteria (Altered Schaedler's flora) again reduced diabetes. This indicated that the internal commensal environment was influencing the development of disease. Understanding how commensals interact with the internal mucosa to shape our immune system, both innate and adaptive immunity, is critical to explain how chronic inflammatory diseases, including autoimmune diseases, develop. In this project we will 1) investigate the critical time windows for the exposure to intestinal flora in influencing whether disease develops and the associated immune developmental changes;2) test the importance of expression of MyD88 in intestinal dendritic cells as the most potent antigen presenting cells and the critical link between innate and adaptive immune responses;3) investigate the importance of expression of MyD88 in intestinal epithelial cells in responding to and sensing the commensal flora. Our studies will enhance our understanding of how the internal environment may shape the immune response and lead to autoimmunity in a genetically susceptible autoimmune diabetes model. In turn, this may help to direct investigation in people genetically susceptible to diabetes and aid development of new strategies for prevention and treatment of type 1 diabetes.

Public Health Relevance

Type 1 diabetes (T1D) occurs in genetically susceptible individuals and it has been known for many years that environmental factors play an important role in determining whether these individuals develop diabetes. However, the identification of these environmental factors and their mechanisms in induction of autoimmune diabetes remains unclear. Viruses, toxins, dietary factors have all been implicated as triggers for clinical disease. The interaction between the organisms and environment is mediated principally through mucosal surfaces. The innate immune system is an evolutionarily conserved system that represents the first line of defense against environmental insults. Innate immunity is mediated primarily through Toll-like receptors (TLRs) that recognize the key pattern sequences of pathogens. Eleven TLRs have been found in mice and most of them are also expressed in humans. As part of our broader research program, we have generated several lines of single TLR deficient mice on the non-obese diabetic (NOD) background. NOD mice are the most widely used experimental model for type 1 diabetes. Our data generated using these animals suggest a TLR specific effect on disease expression in each TLR deficient NOD mouse strain. A common critical signaling molecule downstream of most TLRs is MyD88. In an attempt to clarify the role of TLRs in mediating the expression of diabetes, we have generated MyD88 deficient NOD mice. Surprisingly, these mice were found to be completely resistant to the development of diabetes when raised in a conventional specific pathogen free (SPF) environment. Most strikingly, when these animals were housed in germ free (GF) conditions, diabetes resistance was diminished. When the GF MyD88-/-NOD mice were recolonized with commensal flora, the incidence of diabetes was reduced. This suggests that exposure to commensal bacteria was an important part of the mechanism by which MyD88 deficient NOD mice were protected from development of T1D. In this application, we will test the hypothesis that the timing of exposure to commensal, non-pathogenic bacteria is important in protecting susceptible individuals from diabetes development and the expression of MyD88 in dendritic cells and gut epithelial cells shapes the composition of the commensal bacteria which in turn affects disease development. To test our hypothesis, we propose three specific aims.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088181-04
Application #
8478090
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$331,637
Indirect Cost
$131,252
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Tai, Ningwen; Peng, Jian; Liu, Fuqiang et al. (2016) Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice. J Exp Med 213:2129-46
Hu, Changyun; Ding, Heyuan; Li, Yangyang et al. (2015) NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proc Natl Acad Sci U S A 112:11318-23
Hu, Youjia; Peng, Jian; Tai, Ningwen et al. (2015) Maternal Antibiotic Treatment Protects Offspring from Diabetes Development in Nonobese Diabetic Mice by Generation of Tolerogenic APCs. J Immunol 195:4176-84
Kleffel, Sonja; Vergani, Andrea; Tezza, Sara et al. (2015) Interleukin-10+ regulatory B cells arise within antigen-experienced CD40+ B cells to maintain tolerance to islet autoantigens. Diabetes 64:158-71
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Hu, Changyun; Wong, F Susan; Wen, Li (2015) Type 1 diabetes and gut microbiota: Friend or foe? Pharmacol Res 98:9-15
Tai, Ningwen; Wong, F Susan; Wen, Li (2015) The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord 16:55-65
Yuksel, Muhammed; Wang, Yipeng; Tai, Ningwen et al. (2015) A novel "humanized mouse" model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 62:1536-50

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