Project 1. Avoidance of autoimmunity relies on carefully regulated and appropriate interplay between genetics, the environment, and components of both the innate and adaptive (acquired) immune systems;a central hypothesis to this P01. Given the innate immune system's role in monitoring the microbiologic and biochemical environments, and providing rapid protective acquired immune responses, it is well positioned to break tolerance in response to environmental signals. Dendritic Cells [DC] provide this linkage, in part, through pattern recognition receptors [e.g., toll like receptors [TLR], and retinoic acid-induced gene 1-likereceptors [RLR] that "detect" bacterial/viral/biochemical and "self" molecular signatures leading td DC activation and inflammation. DC activation by TLR/RLR results in Type 1 interferons [IFN?/?] that drive DC maturation, THI, antibody, and CTL responses. Project 1 poses an interdigitating hypothesis;the conjoint defects in type 1 IFN biology, hyperactive IFN?/? responses and increased plasmacytoid DC (PDC)/IFN?/? production in the islet microenvironment play a critical role in T1D pathogenesis. These defects, investigated with Project 2, promote;a) loss of B cell function, b) immunogenic DC, c) pro-inflammatory macrophages [MF], d) THI responses, e) enhanced CTL and p cell killing and f) downgrading of protective Treg and iNKT cell responses. As a corollary, the defects reach full potential when PDC or other immune cells are activated by exogenous or endogenous factors that stimulate IFN?/? production, linking environment and immunogenetics. In addition, a major emphasis will be to evaluate the effect of specific candidate genotypes, (Ifihl,Tyk2) identified in genome wide association studies (GWAS) and affecting IFN?/? biology, on specific immune cell function and p cell function. We believe Project 1 finds marked significance and innovation through the integrative approach afforded by the P01 mechanism (with Project 2), and quite importantly, our ability to explore lymphoid and pancreatic tissues from the nPOD program.
In sum, patients with type 1 diabetes, as well as those at risk for developing the disease, would benefit from this translational research effort. In addition. Project 1 holds the promise of providing detailed mechanistic information on disease pathogenesis of human TID, as well as novel therapeutics for preventing and/or reversing the disorder.
|Creusot, Remi J; Giannoukakis, Nick; Trucco, Massimo et al. (2014) It's time to bring dendritic cell therapy to type 1 diabetes. Diabetes 63:20-30|
|Zheng, Shuyao; Mathews, Clayton E (2014) Metabolic abnormalities in the pathogenesis of type 1 diabetes. Curr Diab Rep 14:519|
|Atkinson, Mark A (2014) Losing a grip on the notion of ?-cell specificity for immune responses in type 1 diabetes: can we handle the truth? Diabetes 63:3572-4|
|Chen, Jing; Mathews, Clayton E (2014) Use of chemical probes to detect mitochondrial ROS by flow cytometry and spectrofluorometry. Methods Enzymol 542:223-41|
|Lantow, Margareta; Sivakumar, Ramya; Zeumer, Leilani et al. (2013) The granulocyte colony stimulating factor pathway regulates autoantibody production in a murine induced model of systemic lupus erythematosus. Arthritis Res Ther 15:R49|
|Myhr, Courtney B; Hulme, Maigan A; Wasserfall, Clive H et al. (2013) The autoimmune disease-associated SNP rs917997 of IL18RAP controls IFNýý production by PBMC. J Autoimmun 44:8-12|
|Hulme, Maigan A; Wasserfall, Clive H; Atkinson, Mark A et al. (2012) Central role for interleukin-2 in type 1 diabetes. Diabetes 61:14-22|
|Brusko, Todd M; Wasserfall, Clive H; Hulme, Maigan A et al. (2009) Influence of membrane CD25 stability on T lymphocyte activity: implications for immunoregulation. PLoS One 4:e7980|
|Matangkasombut, Ponpan; Marigowda, Gautham; Ervine, Aaron et al. (2009) Natural killer T cells in the lungs of patients with asthma. J Allergy Clin Immunol 123:1181-5|
|Atkinson, Mark A; Gianani, Roberto (2009) The pancreas in human type 1 diabetes: providing new answers to age-old questions. Curr Opin Endocrinol Diabetes Obes 16:279-85|
Showing the most recent 10 out of 63 publications