scholarly journals Detection of enterovirus protein and RNA in multiple tissues from nPOD organ donors with type 1 diabetes

2018 ◽  
Author(s):  
Maarit Oikarinen ◽  
Jutta E Laiho ◽  
Sami Oikarinen ◽  
Sarah J Richardson ◽  
Irina Kusmartseva ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Pancreatic Islets ◽  
Lymphoid Tissues ◽  
Small Intestinal Mucosa ◽  
Organ Donors ◽  
Tissue Samples ◽  
Multiple Organs ◽  
Pancreatic Lymph Nodes

AbstractEpidemiological studies have shown an association between enterovirus (EV) infections and type 1 diabetes (T1D), and EV protein has been detected in the pancreatic islets of T1D patients. Here we correlated the detection of EVs in lymphoid tissues (spleen and pancreatic lymph nodes) and small intestinal mucosa to the virus detection in the pancreas of T1D, autoantibody-positive (aab+) and non-diabetic control organ donors of the Network for Pancreatic Organ Donors with Diabetes (nPOD) study. Formalin-fixed paraffin-embedded tissue samples were screened for insulin and EV protein using immunohistochemistry, and frozen tissue for EV genome using RT-PCR. The presence of EV protein in the pancreatic islets correlated with the presence of insulin-positive cells. Altogether 62 % of T1D and aab+ donors were positive for EV protein in pancreatic islets (only insulin-positive donors included), 40 % in duodenum and 32 % in spleen, compared to 33 %, 14 %, and 27 % of non-diabetic controls. Pancreatic lymph nodes were positive for EV protein in 60 % of T1D and aab+ cases. T1D and aab+ donors were more frequently VP1-positive in multiple organs than control donors (39 % vs. 11 %; including only insulin-positive donors). EV RNA was found in selected donors and from multiple tissue types except for duodenum, and individual T1D and aab+ donors were EV RNA-positive in multiple organs. The role of extra-pancreatic organs and their interplay with EV in T1D pathogenesis remains to be solved, but we hypothesize that these organs may serve as a reservoir for the virus which may reside in these tissues in a slow-replicating persistent form.

scholarly journals Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

Diabetes ◽  
2021 ◽  
pp. db210091
Author(s):  
Andrea Vecchione ◽  
Tatiana Jofra ◽  
Jolanda Gerosa ◽  
Kimberly Shankwitz ◽  
Roberta Di Fonte ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Pancreatic Lymph Nodes

scholarly journals Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Eric Marietta ◽  
Irina Horwath ◽  
Stephanie Meyer ◽  
Shahryar Khaleghi-Rostamkolaei ◽  
Eric Norman ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Nod Mice ◽  
Histopathological Analysis ◽  
Microbial Composition ◽  
Time Points ◽  
Pancreatic Lymph Nodes

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5–8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. Results Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. Conclusions These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

scholarly journals Inflammation and Hyperglycemia MediateDeaf1Splicing in the Pancreatic Lymph Nodes via Distinct Pathways During Type 1 Diabetes

Diabetes ◽  
2014 ◽  
Vol 64 (2) ◽  
pp. 604-617 ◽  
Author(s):  
Linda Yip ◽  
Rebecca Fuhlbrigge ◽  
Cariel Taylor ◽  
Remi J. Creusot ◽  
Teppei Nishikawa-Matsumura ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Pancreatic Lymph Nodes

scholarly journals Expansion of Th17 Cells and Functional Defects in T Regulatory Cells Are Key Features of the Pancreatic Lymph Nodes in Patients With Type 1 Diabetes

Diabetes ◽  
2011 ◽  
Vol 60 (11) ◽  
pp. 2903-2913 ◽  
Author(s):  
Alessandra Ferraro ◽  
Carlo Socci ◽  
Angela Stabilini ◽  
Andrea Valle ◽  
Paolo Monti ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Th17 Cells ◽  
T Regulatory Cells ◽  
Regulatory Cells ◽  
Pancreatic Lymph Nodes ◽  
Key Features ◽  
Functional Defects

scholarly journals Insulitis in the pancreas of non-diabetic organ donors under age 25 years with multiple circulating autoantibodies against islet cell antigens

2021 ◽  
Author(s):  
Silke Smeets ◽  
Diedert Luc De Paep ◽  
Geert Stangé ◽  
Katrijn Verhaeghen ◽  
Bart Van der Auwera ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
High Risk ◽  
Islet Cell ◽  
Age Groups ◽  
Pancreatic Tissue ◽  
Organ Donors ◽  
Tissue Samples ◽  
Increased Risk ◽  
Islet Cell Antigens

AbstractAutoantibodies against islet cell antigens are routinely used to identify subjects at increased risk of symptomatic type 1 diabetes, but their relation to the intra-islet pathogenetic process that leads to positivity for these markers is poorly understood. We screened 556 non-diabetic organ donors (3 months to 24 years) for five different autoantibodies and found positivity in 27 subjects, 25 single- and two double autoantibody-positive donors. Histopathological screening of pancreatic tissue samples showed lesion characteristic for recent-onset type 1 diabetes in the two organ donors with a high-risk profile, due to their positivity for multiple autoantibodies and HLA-inferred risk. Inflammatory infiltrates (insulitis) were found in a small fraction of islets (<5%) and consisted predominantly of CD3+CD8+ T-cells. Islets with insulitis were found in close proximity to islets devoid of insulin-positivity; such pseudo-atrophic islets were present in multiple small foci scattered throughout the pancreatic tissue or were found to be distributed with a lobular pattern. Relative beta cell area in both single and multiple autoantibody-positive donors was comparable to that in autoantibody-negative controls. In conclusion, in organ donors under age 25 years, insulitis and pseudo-atrophic islets were restricted to multiple autoantibody-positive individuals allegedly at high risk of developing symptomatic type 1 diabetes, in line with reports in older age groups. These observations may give further insight into the early pathogenetic events that may culminate in clinically overt disease.

scholarly journals N-terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes

2015 ◽  
Vol 112 (43) ◽  
pp. 13318-13323 ◽  
Author(s):  
Niyun Jin ◽  
Yang Wang ◽  
Frances Crawford ◽  
Janice White ◽  
Philippa Marrack ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Lymph Nodes ◽  
Chromogranin A ◽  
Cell Clones ◽  
T Cell Stimulation ◽  
N Terminus ◽  
Pancreatic Lymph Nodes

Chromogranin A (ChgA) is an autoantigen for CD4+ T cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). The natural ChgA-processed peptide, WE14, is a weak agonist for the prototypical T cell, BDC-2.5, and other ChgA-specific T-cell clones. Mimotope peptides with much higher activity share a C-terminal motif, WXRM(D/E), that is predicted to lie in the p5 to p9 position in the mouse MHC class II, IAg7 binding groove. This motif is also present in WE14 (WSRMD), but at its N terminus. Therefore, to place the WE14 motif into the same position as seen in the mimotopes, we added the amino acids RLGL to its N terminus. Like the other mimotopes, RLGL-WE14, is much more potent than WE14 in T-cell stimulation and activates a diverse population of CD4+ T cells, which also respond to WE14 as well as islets from WT, but not ChgA−/− mice. The crystal structure of the IAg7–RLGL–WE14 complex confirmed the predicted placement of the peptide within the IAg7 groove. Fluorescent IAg7–RLGL–WE14 tetramers bind to ChgA-specific T-cell clones and easily detect ChgA-specific T cells in the pancreas and pancreatic lymph nodes of NOD mice. The prediction that many different N-terminal amino acid extensions to the WXRM(D/E) motif are sufficient to greatly improve T-cell stimulation leads us to propose that such a posttranslational modification may occur uniquely in the pancreas or pancreatic lymph nodes, perhaps via the mechanism of transpeptidation. This modification could account for the escape of these T cells from thymic negative selection.

scholarly journals Abnormal Cannabidiol protects pancreatic beta cells in mouse models of experimental Type 1 diabetes

2020 ◽  
Author(s):  
Isabel Gonzalez-Mariscal ◽  
Macarena Pozo Morales ◽  
Silvana Yanina Romero-Zerbo ◽  
Vanesa Espinosa-Jimenez ◽  
Alejandro Escamilla ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Beta Cell ◽  
Mouse Models ◽  
Nod Mice ◽  
List Type ◽  
Pancreatic Lymph Nodes ◽  
Islet Inflammation

ABSTRACTBackground and PurposeThe atypical cannabinoid Abn-CBD was reported to improve the inflammatory status in preclinical models of several pathologies including autoimmune diseases. However, its potential for autoimmune diabetes, i.e. type 1 diabetes (T1D), is unknown.Experimental ApproachWe used two mouse models of T1D, streptozotocin (STZ)-injected and non-obese diabetic (NOD) mice. Eight-to-ten-week-old male C57Bl6/J mice were pre-treated with Abn-CBD (1mg/kg of body weight) or vehicle for 1 week, following STZ treatment, and euthanized 1 week later. Six-week-old female NOD mice were treated with Abn-CBD (0.1-1mg/kg) or vehicle for 12 weeks and then euthanized. Blood, pancreas, pancreatic lymph nodes and circulating T cells were collected and processed for analysis. Glycemia was also monitored.Key ResultsAbn-CBD decreased circulating proinflammatory cytokines, ameliorated islet inflammation and the autoimmune attack, showing a 2-fold decrease in CD8+ T cells infiltration and reduced Th1/Th2 ratio in pancreatic lymph nodes of STZ-injected mice. Mechanistically, Abn-CBD reduced intra-islet phospho-NF-κB and TXNIP. Concomitant reduction of islet cell apoptosis and intra-islet fibrosis were observed in Abn-CBD pre-treated mice compared to vehicle. In NOD mice, Abn-CBD reduced the expression of Ifng, Il21, Tnfa and Il10 while increased Il4 in circulating CD4+ T cells compared to vehicle, reducing the severity of insulitis and improving glucose tolerance.Conclusion and ImplicationsAltogether, we found that Abn-CBD reduces intra-islet inflammation and delays the progression of insulitis in mouse models of T1D, preserving healthy functional islets. Hence, Abn-CBD and related compounds emerge as new candidates to develop pharmacological strategies to treat early stages of T1D.WHAT IS ALREADY KNOWN-Phytocannabinoids such as cannabidiol (CBD) have anti-inflammatory and glucose-lowering properties-The CBD derivative Abn-CBD ameliorates inflammation in various diseases and modulates beta cell functionWHAT THIS STUDY ADDS-Abn-CBD reduces systemic and pancreatic inflammation in mice models of type 1 diabetes-Abn-CBD prevents beta cell damage and loss during type 1 diabetes onsetCLINICAL SIGNIFICANCE-Synthetic cannabinoids emerge as potential treatment for type 1 diabetes

scholarly journals Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes

2009 ◽  
Vol 10 (9) ◽  
pp. 1026-1033 ◽  
Author(s):  
Linda Yip ◽  
Leon Su ◽  
Deqiao Sheng ◽  
Pearl Chang ◽  
Mark Atkinson ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Lymph Nodes ◽  
Peripheral Tissue ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Tissue Antigens ◽  
Pancreatic Lymph Nodes
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