TY - JOUR AB - Purpose of Review Regulatory T cells (Tregs) are critical contributors to immune homeostasis and their dysregulation can lead to the loss of immune tolerance and autoimmune diseases like type 1 diabetes (T1D). Recent studies have highlighted microRNAs (miRNAs) as important regulators of the immune system, by fine-tuning relevant genes in various immune cell types. In this review article, we discuss recent insights into miRNA regulation of immune tolerance and activation. Specifically, we discuss how the dysregulation of miRNAs in T cells contributes to their aberrant function and the onset of islet autoimmunity, as well as their potential as targets of novel intervention strategies to interfere with autoimmune activation. Recent Findings Several studies have shown that the dysregulation of individual miRNAs in T cells can contribute to impaired immune tolerance, contributing to onset and progression of islet autoimmunity. Importantly, the targeting of these miRNAs, including miR-92a, miR-142-3p and miR-181a, resulted in relevant effects on downstream pathways, improved Treg function and reduced islet autoimmunity in murine models. miRNAs are critical regulators of immune homeostasis and the dysregulation of individual miRNAs in T cells contributes to aberrant T cell function and autoimmunity. The specific targeting of individual miRNAs could improve Treg homeostasis and therefore limit overshooting T cell activation and islet autoimmunity. AU - Scherm, M.G. AU - Daniel, C. C1 - 59799 C2 - 49049 CY - 400 Market Street, Ste 700, Philadelphia, Pa 19106 Usa TI - miRNA regulation of T cells in islet autoimmunity and type 1 diabetes. JO - Curr. Diab. Rep. VL - 20 IS - 9 PB - Current Medicine Group PY - 2020 SN - 1534-4827 ER - TY - JOUR AB - PurposeThe measurement and estimation of diabetes in populations guides resource allocation, health priorities, and can influence practice and future research. To provide a critical reflection on current diabetes surveillance, we provide in-depth discussion about how upstream determinants, prevalence, incidence, and downstream impacts of diabetes are measured in the USA, and the challenges in obtaining valid, accurate, and precise estimates.FindingsCurrent estimates of the burden of diabetes risk are obtained through national surveys, health systems data, registries, and administrative data. Several methodological nuances influence accurate estimates of the population-level burden of diabetes, including biases in selection and response rates, representation of population subgroups, accuracy of reporting of diabetes status, variation in biochemical testing, and definitions of diabetes used by investigators. Technological innovations and analytical approaches (e.g., data linkage to outcomes data like the National Death Index) may help address some, but not all, of these concerns, and additional methodological advances and validation are still needed.SummaryCurrent surveillance efforts are imperfect, but measures consistently collected and analyzed over several decades enable useful comparisons over time. In addition, we proposed that focused subsampling, use of technology, data linkages, and innovative sensitivity analyses can substantially advance population-level estimation. AU - Ali, M.K.* AU - Siegel, K.R.* AU - Laxy, M. AU - Gregg, E.W.* C1 - 54399 C2 - 45550 CY - 400 Market Street, Ste 700, Philadelphia, Pa 19106 Usa TI - Advancing measurement of diabetes at the population level. JO - Curr. Diab. Rep. VL - 18 IS - 11 PB - Current Medicine Group PY - 2018 SN - 1534-4827 ER - TY - JOUR AB - Purpose of ReviewThe environmental triggers of islet autoimmunity leading to type 1 diabetes (T1D) need to be elucidated to inform primary prevention. The Environmental Determinants of Diabetes in the Young (TEDDY) Study follows from birth 8676 children with T1D risk HLA-DR-DQ genotypes in the USA, Finland, Germany, and Sweden. Most study participants (89%) have no first-degree relative with T1D. The primary outcomes include the appearance of one or more persistent islet autoantibodies (islet autoimmunity, IA) and clinical T1D.Recent FindingsAs of February 28, 2018, 769 children had developed IA and 310 have progressed to T1D. Secondary outcomes include celiac disease and autoimmune thyroid disease. While the follow-up continues, TEDDY has already evaluated a number of candidate environmental triggers, including infections, probiotics, micronutrient, and microbiome.SummaryTEDDY results suggest that there are multiple pathways leading to the destruction of pancreatic beta-cells. Ongoing measurements of further specific exposures, gene variants, and gene-environment interactions and detailed omics studies will provide novel information on the pathogenesis of T1D. AU - Rewers, M.* AU - Hyöty, H.* AU - Lernmark, Å.* AU - Hagopian, W.* AU - She, J.X.* AU - Schatz, D.* AU - Ziegler, A.-G. AU - Toppari, J.* AU - Akolkar, B.* AU - Krischer, J.* C1 - 54648 C2 - 45719 CY - 400 Market Street, Ste 700, Philadelphia, Pa 19106 Usa TI - The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update. JO - Curr. Diab. Rep. VL - 18 IS - 12 PB - Current Medicine Group PY - 2018 SN - 1534-4827 ER - TY - JOUR AB - Purpose of ReviewTo provide an overview of studies that have detected enteroviruses (EV) in samples from people with type 1 diabetes (T1D), the techniques they have used, and which challenges they have encountered.Recent FindingsRecent studies have detected EVs in serum, blood, stools, nasal swabs, and pancreas of people with T1D before or around clinical onset of disease, indicating that an association between EV infections and T1D exists. However, definitive evidence for its role as disease triggers is lacking. Recent access to human samples is starting to provide the necessary tools to define their role in disease pathogenesis. Emerging evidence suggests that chronic infections take place in the pancreas of diabetic donors. However, the development of sensitive techniques able to detect low amounts of viral protein and RNA still constitute a major challenge for the field.SummaryNew evidence at the protein, RNA, and host immune response level suggests a role for EV infections in the development of autoimmunity. In the upcoming years, new technologies, collaborative efforts, and therapeutic interventions are likely to find a definitive answer for their role in disease pathogenesis. AU - Rodriguez-Calvo, T. C1 - 54372 C2 - 45535 CY - 400 Market Street, Ste 700, Philadelphia, Pa 19106 Usa TI - Enteroviral infections as a trigger for type 1 diabetes. JO - Curr. Diab. Rep. VL - 18 IS - 11 PB - Current Medicine Group PY - 2018 SN - 1534-4827 ER - TY - JOUR AB - Purpose of review We provide an overview of pancreas pathology in type 1 diabetes (T1D) in the context of its clinical stages.Recent findings Recent studies of pancreata from organ donors with T1D and non-diabetic donors expressing T1D-associated autoantibodies reveal pathological changes/disease mechanisms beyond the well-known loss of beta cells and lymphocytic infiltrates of the islets (insulitis), including beta-cell stress, dysfunction, and viral infections. Pancreas pathology evolves through disease stages, is asynchronous, and demonstrates a chronic disease that remains active years after diagnosis. Critically, beta-cell loss is not complete at onset, although young age is associated with increased severity.SummaryThe recognition of multiple pathogenic alterations and the chronic nature of disease mechanisms during and after the development of T1D inform improved clinical trial design and reveal additional targets for therapeutic manipulation, in the context of an expanded time window for intervention. AU - Rodriguez-Calvo, T. AU - Richardson, S.J.* AU - Pugliese, A.* C1 - 54477 C2 - 45610 CY - 400 Market Street, Ste 700, Philadelphia, Pa 19106 Usa TI - Pancreas pathology during the natural history of type 1 diabetes. JO - Curr. Diab. Rep. VL - 18 IS - 11 PB - Current Medicine Group PY - 2018 SN - 1534-4827 ER - TY - JOUR AB - Type 1 diabetes (T1D) is a complex autoimmune disease, and first stages of the disease typically develop early in life. Genetic as well as environmental factors are thought to contribute to the risk of developing autoimmunity against pancreatic beta cells. Several environmental factors, such as breastfeeding or early introduction of solid food, have been associated with increased risk for developing T1D. During the first years of life, the gut microbial community is shaped by the environment, in particular by dietary factors. Moreover, the gut microbiome has been described for its role in shaping the immune system early in life and early data suggest associations between T1D risk and alterations in gut microbial communities. In this article, we discuss environmental factors influencing the colonization process of the gut microbial community. Furthermore, we review possible interactions between the microbiome and the host that might contribute to the risk of developing T1D. AU - Endesfelder, D. AU - Engel, M. AU - zu Castell, W. C1 - 48548 C2 - 41163 CY - Philadelphia TI - Gut immunity and type 1 diabetes: A mélange of microbes, diet, and host interactions? JO - Curr. Diab. Rep. VL - 16 IS - 7 PB - Current Medicine Group PY - 2016 SN - 1534-4827 ER - TY - JOUR AB - The development of multiple disease-relevant autoantibodies is a hallmark of autoimmune diseases. In autoimmune type 1 diabetes (T1D), a variable time frame of autoimmunity precedes the clinically overt disease. The relevance of T follicular helper (TFH) cells for the immune system is increasingly recognized. Their pivotal contribution to antibody production by providing help to germinal center (GC) B cells facilitates the development of a long-lived humoral immunity. Their complex differentiation process, involving various stages and factors like B cell lymphoma 6 (Bcl6), is strictly controlled, as anomalous regulation of TFH cells is connected with immunopathologies. While the adverse effects of a TFH cell-related insufficient humoral immunity are obvious, the role of increased TFH frequencies in autoimmune diseases like T1D is currently highlighted. High levels of autoantigen trigger an excessive induction of TFH cells, consequently resulting in the production of autoantibodies. Therefore, TFH cells might provide promising approaches for novel therapeutic strategies. AU - Scherm, M.G. AU - Ott, V. AU - Daniel, C. C1 - 48925 C2 - 41498 CY - Philadelphia TI - Follicular helper T cells in autoimmunity. JO - Curr. Diab. Rep. VL - 16 IS - 8 PB - Current Medicine Group PY - 2016 SN - 1534-4827 ER - TY - JOUR AB - Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D. AU - Petzold, A. AU - Solimena, M. AU - Knoch, K.-P. C1 - 46586 C2 - 37697 TI - Mechanisms of beta cell dysfunction associated with viral infection. JO - Curr. Diab. Rep. VL - 15 IS - 10 PY - 2015 SN - 1534-4827 ER - TY - JOUR AB - The lack or dysfunction of insulin-producing beta-cells is the cause of all forms of diabetes. In vitro generation of beta-cells from pluripotent stem cells for cell-replacement therapy or triggering endogenous mechanisms of beta-cell repair have great potential in the field of regenerative medicine. Both approaches rely on a thorough understanding of beta-cell development and homeostasis. Here, we briefly summarize the current knowledge of beta-cell differentiation during pancreas development in the mouse. Furthermore, we describe how this knowledge is translated to instruct differentiation of both mouse and human pluripotent stem cells towards the beta-cell lineage. Finally, we shortly summarize the current efforts to identify stem or progenitor cells in the adult pancreatic organ and to harness the endogenous regenerative potential. Understanding development and regeneration of beta-cells already led to identification of molecular targets for therapy and informed on pathomechanisms of diabetes. In the future might lead to beta-cell repair and replacement therapies. AU - Raducanu, A. AU - Lickert, H. C1 - 8617 C2 - 30211 SP - 481-489 TI - Understanding pancreas development for β-cell repair and replacement therapies. JO - Curr. Diab. Rep. VL - 12 IS - 5 PB - Current Medicine Group PY - 2012 SN - 1534-4827 ER - TY - JOUR AB - Foxp3(+) regulatory T (Treg) cells serve as a vital mechanism of negative regulation to maintain immunological self-tolerance thereby suppressing immune-mediated inflammation. The identification of the transcription factor Foxp3 as the specification factor for the Treg cell lineage facilitated our understanding in the biology of Treg generation and function. In the past, we carefully studied the extrathymic conversion of naive CD4(+) T cells into Foxp3(+) expressing Treg cells and found that this process is most efficient upon subimmunogenic supply of strong-agonistic T cell receptor (TCR) ligands avoiding activation of antigen-presenting and T cells. In contrast, weak-agonistic antigens fail to efficiently induce stable Foxp3(+) Treg cells irrespective of the applied dose. Here, we discuss the specific requirements for the establishment of Treg vaccination protocols to interfere with autoimmunity such as Type 1 diabetes. AU - Weigmann, B.* AU - Daniel, C. C1 - 8614 C2 - 30415 SP - 463-470 TI - Treg vaccination with a strong-agonistic insulin mimetope. JO - Curr. Diab. Rep. VL - 12 IS - 5 PB - Current Medicine Group PY - 2012 SN - 1534-4827 ER - TY - JOUR AU - Ziegler, A.-G. AU - Walter, M.* C1 - 1275 C2 - 28071 SP - 323-325 TI - Loss and preservation of β-cell function: Two treatment regimes targeting T or B lymphocytes. JO - Curr. Diab. Rep. VL - 10 IS - 5 PB - Springer PY - 2010 SN - 1534-4827 ER -