scholarly journals Parabacteroides distasonis enhances Type 1 Diabetes autoimmunity via molecular mimicry

2020 ◽  
Author(s):  
Qian Huang ◽  
I-Ting Chow ◽  
Claudia Brady ◽  
Amol Raisingani ◽  
Danmeng Li ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Molecular Mimicry ◽  
Nod Mice ◽  
Cross Reactivity ◽  
Nod Mouse ◽  
Human Gut ◽  
Human T Cell

ABSTRACTType 1 Diabetes (T1D) is an autoimmune disease characterized by destruction of pancreatic β-cells. Focusing on the main insulin epitope, insulin B-chain 9-23 (insB:9-23), we explored whether a microbial insB:9-23 mimic could modulate T1D. We now demonstrate that a microbial insB:9-23 mimic of Parabacteroides distasonis, a human gut commensal, exclusively stimulates non-obese diabetic (NOD) mouse T cells specific to insB:9-23. Indeed, immunization of NOD mice with either the bacterial mimic peptide or insB:9-23 further verified the cross-reactivity in vivo. Modeling P. distasonis peptide revealed a potential pathogenic register 3 binding. P. distasonis colonization of the female NOD mice gut accelerated T1D onset. In addition, adoptive transfer of splenocytes from NOD mice colonized with P. distasonis to NOD.SCID recipients conferred the enhanced disease phenotype. Integration analysis of published infant T1D gut microbiome data revealed that P. distasonis peptide is not present in the gut microbiota in the first year of life of infants that eventually develop T1D. Furthermore, P. distasonis peptide can stimulate human T cell clones specific to insB:9-23 and T1D patients demonstrated a strong humoral immune response to P. distasonis than controls. Taken together, our studies define a potential molecular mimicry link between T1D pathogenesis and the gut microbiota.One Sentence SummaryThe human gut commensal bacterium, Parabacteroides distasonis, accelerates type 1 diabetes in the NOD mouse model of the disease and involves expression of an insulin B:9-23 epitope mimic, supporting a potential disease mechanism involving molecular mimicry.

scholarly journals Human gut microbiota transferred to germ-free NOD mice modulate the progression towards type 1 diabetes regardless of the pace of beta cell function loss in the donor

Diabetologia ◽  
2019 ◽  
Vol 62 (7) ◽  
pp. 1291-1296 ◽  
Author(s):  
Vit Neuman ◽  
Ondrej Cinek ◽  
David P. Funda ◽  
Tomas Hudcovic ◽  
Jaroslav Golias ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Nod Mice ◽  
Human Gut ◽  
Germ Free ◽  
Function Loss

scholarly journals The DNA Sensor AIM2 Protects against Streptozotocin-Induced Type 1 Diabetes by Regulating Intestinal Homeostasis via the IL-18 Pathway

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 959 ◽  
Author(s):  
Jefferson Antônio Leite ◽  
Gabriela Pessenda ◽  
Isabel C. Guerra-Gomes ◽  
Alynne Karen Mendonça de Santana ◽  
Camila André Pereira ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Bacterial Translocation ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Dna Sensor ◽  
Proinflammatory Response

Pattern recognition receptors (PRRs), such as Nod2, Nlrp3, Tlr2, Trl4, and Tlr9, are directly involved in type 1 diabetes (T1D) susceptibility. However, the role of the cytosolic DNA sensor, AIM2, in T1D pathogenesis is still unknown. Here, we demonstrate that C57BL/6 mice lacking AIM2 (AIM2−/−) are prone to streptozotocin (STZ)-induced T1D, compared to WT C57BL/6 mice. The AIM2−/− mice phenotype is associated with a greater proinflammatory response in pancreatic tissues, alterations in gut microbiota and bacterial translocation to pancreatic lymph nodes (PLNs). These alterations are related to an increased intestinal permeability mediated by tight-junction disruption. Notably, AIM2−/− mice treated with broad-spectrum antibiotics (ABX) are protected from STZ-induced T1D and display a lower pancreatic proinflammatory response. Mechanistically, the AIM2 inflammasome is activated in vivo, leading to an IL-18 release in the ileum at 15 days after an STZ injection. IL-18 favors RegIIIγ production, thus mitigating gut microbiota alterations and reinforcing the intestinal barrier function. Together, our findings show a regulatory role of AIM2, mediated by IL-18, in shaping gut microbiota and reducing bacterial translocation and proinflammatory response against insulin-producing β cells, which ultimately results in protection against T1D onset in an STZ-induced diabetes model.

scholarly journals Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Diabetologia ◽  
2019 ◽  
Vol 62 (8) ◽  
pp. 1517-1517
Author(s):  
Midhat H. Abdulreda ◽  
R. Damaris Molano ◽  
Gaetano Faleo ◽  
Maite Lopez-Cabezas ◽  
Alexander Shishido ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Vivo Imaging ◽  
Nod Mice

scholarly journals Evaluation of different mucosal microbiota leads to gut microbiota-based prediction of type 1 diabetes in NOD mice

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Youjia Hu ◽  
Jian Peng ◽  
Fangyong Li ◽  
F. Susan Wong ◽  
Li Wen
Keyword(s):  
Type 1 Diabetes ◽  
Gut Microbiota ◽  
Nod Mice

scholarly journals Antibodies from a Patient with Type 1 Diabetes and Celiac Disease Bind to Macrophages that Express the Scavenger Receptor CD163

2011 ◽  
Vol 25 (6) ◽  
pp. 327-329 ◽  
Author(s):  
Brigitte Sonier ◽  
Alexander Strom ◽  
Gen-Sheng Wang ◽  
Christopher Patrick ◽  
Jennifer A Crookshank ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Celiac Disease ◽  
Molecular Mimicry ◽  
Scavenger Receptor ◽  
Cross Reactivity ◽  
Rat Jejunum ◽  
The Novel ◽  
Blood Monocytes ◽  
Specific Subset

Antibodies against the wheat storage globulin Glo-3A from a patient with both type 1 diabetes (T1D) and celiac disease were enriched to identify potential molecular mimicry between wheat antigens and T1D target tissues. Recombinant Glo-3A was used to enrich anti-Glo-3A immunoglobulin G antibodies from plasma by batch affinity chromatography. Rat jejunum and pancreas, as well as human duodenum and monocytes were probed, and binding was evaluated by immunohistochemistry and confocal microscopy. Glo-3A-enriched antibodies bound to a specific subset of cells in the lamina propria of rat jejunum that co-localized mostly with a marker of resident, alternatively activated CD163-positive (CD163+) macrophages. Blood monocytes and macrophage-like cells in human duodenum were also labelled with the enriched antibodies. Blocking studies revealed that binding to CD163+macrophages was not due to cross-reactivity with anti-Glo-3A antibodies, but rather to non-Glo-3A antibodies co-purified during antibody enrichment. The novel finding of putative autoantibodies against tolerogenic intestinal CD163+macrophages suggests that regulatory macrophages were targeted in this patient with celiac disease and T1D.

scholarly journals In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Diabetologia ◽  
2019 ◽  
Vol 62 (7) ◽  
pp. 1237-1250 ◽  
Author(s):  
Midhat H. Abdulreda ◽  
R. Damaris Molano ◽  
Gaetano Faleo ◽  
Maite Lopez-Cabezas ◽  
Alexander Shishido ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
In Vivo Imaging ◽  
Nod Mice

scholarly journals C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

2017 ◽  
Vol 115 (1) ◽  
pp. 162-167 ◽  
Author(s):  
Yang Wang ◽  
Tomasz Sosinowski ◽  
Andrey Novikov ◽  
Frances Crawford ◽  
David B. Neau ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Posttranslational Modifications ◽  
Cell Activation ◽  
Nod Mice ◽  
Side Chain ◽  
C Terminus

A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

scholarly journals Regulatory T Cells Prevent Transfer of Type 1 Diabetes in NOD Mice Only When Their Antigen Is Present In Vivo

2008 ◽  
Vol 181 (7) ◽  
pp. 4516-4522 ◽  
Author(s):  
Daniel R. Tonkin ◽  
Jing He ◽  
Gene Barbour ◽  
Kathryn Haskins
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Nod Mice

scholarly journals Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5638-5646 ◽  
Author(s):  
Soojeong Kang ◽  
Eun-Jin Park ◽  
Yeonsoo Joe ◽  
Eunhui Seo ◽  
Mi-Kyoung Park ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Blood Glucose ◽  
Gelatin Zymography ◽  
Nod Mice ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Nonobese Diabetic ◽  
Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

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