We hypothesize a critical factor for the immunopathogenesis of type 1 diabetes (T1D) is centered on dendritic cell (DC) maturation-based defects supporting the genesis of autoreactive T cells while impairing tolerance mechanisms requiring fully intact DC. Our studies in NOD mice provide a mechanism for DC maturation defects, heightened type 1 interferon (IFNa/(3) response. We find dysregulated IFNa/p signaling impacts maturation differentially. Working at the level of immature DC it blocks maturation while more mature cells DC become immunogenic. Our analysis of congenic mice demonstrates heightened IFNa/p signaling is present in the B6.NODc1c strain, suggesting /cfcf5 genes on chromosome 1 regulate this defect. We also find a second defect that compounds dysregulated IFNa/p responses. Our studies show both NOD and 11D subjects have significantly expanded plasmacytoid DC (PDC) that produce high levels of IFNa/p. Importantly, PDC are increased in NOD lymphoid tissues and are prominent in insulitis lesions. Furthermore, analysis of congenic mice suggests the PDC defect is regulated by genes within the chromosome 3 Idd10/17/18 region. To address this hypothesis and proposed mechanism for DCdysfunction we will;1.) Determine the relative roles of PDC and heightened IFNa/p signaling on DC maturation and function in vivo and their roles in the pathogenesis T1D using NOD, NOD.B6/dd5.7/5.2, NOD.IFNAR-/-, BQ.NODdc and NOD.Idd10/17/18 congenic mouse strains, 2.) Determine the effect of heightened IFNa/p signaling on NOD DC APC function, and assess the ldd5.1/5.2 contribution to this abnormality, 3.) Determine whether human T1D subjects manifest heightened IFNa/p signaling responses, further assess PDC numbers and PDC based-IFNa/p production, and in cooperation with Projects 1 &3, determine IFNa/p effects on immune function in vitro. The proposed studies may provide a mechanistic and immunogenetic basis for the association of viruses and with T1D pathogenesis and provide important new approaches to study environmental-immune interactions. Finally, these studies will potentially provide new methods to assess disease activity/susceptibility or risk e.g., PDC numbers in peripheral blood, levels of IFNa/p production, heightened IFNa/p signaling (increased phospho-STAT1/STAT2) and expression of IFNa/p target genes (MxA, IRF7) as well as new approaches to preventing T1D, e.g., blocking IFNa/p action

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI042288-13
Application #
8131062
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
13
Fiscal Year
2010
Total Cost
$286,084
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Chen, Yi-Guang; Mathews, Clayton E; Driver, John P (2018) The Role of NOD Mice in Type 1 Diabetes Research: Lessons from the Past and Recommendations for the Future. Front Endocrinol (Lausanne) 9:51
Kusmartseva, Irina; Beery, Maria; Philips, Tiffany et al. (2018) Hospital time prior to death and pancreas histopathology: implications for future studies. Diabetologia 61:954-958
Hu, Ronghua; Xia, Chang-Qing; Butfiloski, Edward et al. (2018) Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: Implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection. Clin Immunol 195:139-148
Smith, Mia J; Rihanek, Marynette; Wasserfall, Clive et al. (2018) Loss of B-Cell Anergy in Type 1 Diabetes Is Associated With High-Risk HLA and Non-HLA Disease Susceptibility Alleles. Diabetes 67:697-703
Perry, Daniel J; Wasserfall, Clive H; Oram, Richard A et al. (2018) Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling. Sci Rep 8:4529
Ratiu, Jeremy J; Racine, Jeremy J; Hasham, Muneer G et al. (2017) Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes. J Immunol 198:4255-4267
Delitto, Daniel; Delitto, Andrea E; DiVita, Bayli B et al. (2017) Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment. Cancer Res 77:672-683
Posgai, Amanda L; Wasserfall, Clive H; Kwon, Kwang-Chul et al. (2017) Plant-based vaccines for oral delivery of type 1 diabetes-related autoantigens: Evaluating oral tolerance mechanisms and disease prevention in NOD mice. Sci Rep 7:42372
Sebastiani, Guido; Ventriglia, Giuliana; Stabilini, Angela et al. (2017) Regulatory T-cells from pancreatic lymphnodes of patients with type-1 diabetes express increased levels of microRNA miR-125a-5p that limits CCR2 expression. Sci Rep 7:6897
O'Kell, Allison L; Wasserfall, Clive; Catchpole, Brian et al. (2017) Comparative Pathogenesis of Autoimmune Diabetes in Humans, NOD Mice, and Canines: Has a Valuable Animal Model of Type 1 Diabetes Been Overlooked? Diabetes 66:1443-1452

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