"The most important genetic determinant of T1D incidence in both humans and mice is the major histocompatibility complex (MHC) , . Despite the strong genetic component of predisposition to disease, concordance between monozygotic twins is approximately 50% , . Beside the interplay of genes and environment in the induction of T1D, there are complex interactions between different immune system cells that determine the outcome of disease . "
[Show abstract][Hide abstract] ABSTRACT: Our ability to successfully intervene in disease processes is dependent on definitive diagnosis. In the case of autoimmune disease, this is particularly challenging because progression of disease is lengthy and multifactorial. Here we show the first chronological compendium of transcriptional and cellular signatures of diabetes in the non-obese diabetic mouse. Our data relates the immunological environment of the islets of Langerhans with the transcriptional profile at discrete times. Based on these data, we have parsed diabetes into several discrete phases. First, there is a type I interferon signature that precedes T cell activation. Second, there is synchronous infiltration of all immunological cellular subsets and a period of control. Finally, there is the killing phase of the diabetogenic process that is correlated with an NF-kB signature. Our data provides a framework for future examination of autoimmune diabetes and its disease progression markers.
PLoS ONE 03/2013; 8(3):e59701. DOI:10.1371/journal.pone.0059701 · 3.23 Impact Factor
"Precipitating from a loss of self-tolerance, adaptive immune lymphocytes, such as CD4+ and CD8+ T cells, in addition to B cells, play a prominent role in β-cell destruction.1–5 With disease incidence climbing steadily at a rate of 3% per year and a concordance rate of 40–60% for monozygotic twins, genetics cannot be the only contributing factor to disease onset.6–8 Until insulin was discovered as the hormone responsible for maintaining glucose homeostasis in the 1920s, T1D was a lethal disease; but despite the current widespread use of exogenous insulin to maintain normal blood glucose, insulin insufficiency in vital organs leads to numerous life-threatening complications, including nephrophathy, neuropathy, and retinopathy.9 "
[Show abstract][Hide abstract] ABSTRACT: Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of insulin-secreting pancreatic β cells. In humans with T1D and in nonobese diabetic (NOD) mice (a murine model for human T1D), autoreactive T cells cause β-cell destruction, as transfer or deletion of these cells induces or prevents disease, respectively. CD4(+) and CD8(+) T cells use distinct effector mechanisms and act at different stages throughout T1D to fuel pancreatic β-cell destruction and disease pathogenesis. While these adaptive immune cells employ distinct mechanisms for β-cell destruction, one central means for enhancing their autoreactivity is by the secretion of proinflammatory cytokines, such as IFN-γ, TNF-α, and IL-1. In addition to their production by diabetogenic T cells, proinflammatory cytokines are induced by reactive oxygen species (ROS) via redox-dependent signaling pathways. Highly reactive molecules, proinflammatory cytokines are produced upon lymphocyte infiltration into pancreatic islets and induce disease pathogenicity by directly killing β cells, which characteristically possess low levels of antioxidant defense enzymes. In addition to β-cell destruction, proinflammatory cytokines are necessary for efficient adaptive immune maturation, and in the context of T1D they exacerbate autoimmunity by intensifying adaptive immune responses. The first half of this review discusses the mechanisms by which autoreactive T cells induce T1D pathogenesis and the importance of ROS for efficient adaptive immune activation, which, in the context of T1D, exacerbates autoimmunity. The second half provides a comprehensive and detailed analysis of (1) the mechanisms by which cytokines such as IL-1 and IFN-γ influence islet insulin secretion and apoptosis and (2) the key free radicals and transcription factors that control these processes.
Annals of the New York Academy of Sciences 01/2013; 1281(1). DOI:10.1111/j.1749-6632.2012.06826.x · 4.31 Impact Factor
"Both serum CML and diabetes-associated autoantibodies are likely to be only surrogate markers of putative destructive innate and adaptive immune changes, respectively. A twin study should ideally be performed prospectively in a population-based cohort from birth to determine the rate of induction of autoantibodies and diabetes, and because our twins were initially disease discordant, disease concordance rate is underestimated (26), but our analysis limits bias from the strong disease association with these autoantibodies (2). If autoantibodies were genetically determined, even nondiabetic MZ twins would eventually show them, which, in general, they did not. "
[Show abstract][Hide abstract] ABSTRACT: In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum N(ε)-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA(+) and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA(+) and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA(+) children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target.
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