Avoidance of autoimmunity appears to rely on a carefully orchestrated series of activities involving an appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems. When this process fails, a variety of autoimmune disorders can arise;including type 1 diabetes where insulin producing pancreatic p cells are destroyed. Adaptive CD4'^ T helper (TH) cells orchestrate the nature and duration of immune responses through distinct properties of lineage-specific cell subsets (e.g., THI, TH17, regulatory T cells (Treg), etc.). The overall objective of Project 2 is to characterize the interplay between antigen presenting cells (APC) and TH subsets, identify their mechanistic contribution to the pathogenesis of TID, evaluate the potential of these cells to serve as markers for autoimmune disease activity. In addition, a major emphasis will be given to evaluate the contributions of specific candidate genotypes previously identified in genome wide association studies (GWAS), for their contribution to immune regulation (Project 2 - ILISRAP, TLRS;Project 1 - IFIHI). This project emanates from literature suggesting that patients with TID exhibit a remarkable loss of immunoregulation whose cellular contributors include proinflammatory APC, unstable and functionally defective Treg, and persistent T effector cells (Teff) that are refractory to regulation. Project 2 will test the hypothesis that in TID, CD4^ T cells are functionally defective and that the molecular &cellular basis for this defect resides in interactions between the innate and adaptive immune response (including dendritic cells, natural killer (NK) cells, & iNKT cells) as well as the balance between Teff and Treg subsets. We believe Project 2 finds marked innovation through the integrative approach afforded by the POI mechanism, the use of novel methodologies to isolate the cellular source of defects, the study of genetic loci underrepresented in TID research and quite importantly, our ability to explore lymphoid and pancreatic tissues and cells from the nPOD program.
Patients with TID, as well as those at risk for developing the disease, would benefit from this research in it's provision of an improved understanding of how and why the disorder develops. In addition. Project 2 holds the promise of providing improved biomarkers that better identify risk for developing TID, as well as novel therapeutics capable of preventing and/or reversing the disease.
|Chen, Jing; Chernatynskaya, Anna V; Li, Jian-Wei et al. (2017) T cells display mitochondria hyperpolarization in human type 1 diabetes. Sci Rep 7:10835|
|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|
|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|
|Wang, Qiming; Racine, Jeremy J; Ratiu, Jeremy J et al. (2017) Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy. J Immunol 199:3757-3770|
|Jackson, Jessica; Posgai, Amanda; Campbell-Thompson, Martha et al. (2017) Insulitis in Autoantibody-Positive Pancreatic Donor With History of Gestational Diabetes Mellitus. Diabetes Care 40:723-725|
|Newman, Jeremy R B; Conesa, Ana; Mika, Matthew et al. (2017) Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes. Genome Res 27:1807-1815|
|Whitener, Robert L; Gallo Knight, Lisa; Li, Jianwei et al. (2017) The Type 1 Diabetes-Resistance Locus Idd22 Controls Trafficking of Autoreactive CTLs into the Pancreatic Islets of NOD Mice. J Immunol 199:3991-4000|
|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|
|Newby, Brittney N; Brusko, Todd M; Zou, Baiming et al. (2017) Type 1 Interferons Potentiate Human CD8+ T-Cell Cytotoxicity Through a STAT4- and Granzyme B-Dependent Pathway. Diabetes 66:3061-3071|
|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|
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