Toll-Like Receptor 7 Is Required for Lacrimal Gland Autoimmunity and Type 1 Diabetes Development in Male Nonobese Diabetic Mice

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands. Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands. The innate immune signals driving lymphocytic infiltration of these glands are not well-defined. Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice. We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development. TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation. Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice. RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands. Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.

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Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice

Frontiers in Immunology ◽

10.3389/fimmu.2018.01565 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 5

Author(s):

Marcos Iglesias ◽

Anirudh Arun ◽

Maria Chicco ◽

Brandon Lam ◽

C. Conover Talbot ◽

...

Keyword(s):

Type 1 Diabetes ◽

Interleukin 10 ◽

Type I Interferons ◽

Type I ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Diabetes Development ◽

Nonobese Diabetic Mice

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Rotavirus Infection of Infant and Young Adult Nonobese Diabetic Mice Involves Extraintestinal Spread and Delays Diabetes Onset

Journal of Virology ◽

10.1128/jvi.00205-07 ◽

2007 ◽

Vol 81 (12) ◽

pp. 6446-6458 ◽

Cited By ~ 36

Author(s):

Kate L. Graham ◽

Joanne A. O'Donnell ◽

Yan Tan ◽

Natalie Sanders ◽

Emma M. Carrington ◽

...

Keyword(s):

Type 1 Diabetes ◽

Young Adult ◽

Infectious Virus ◽

Nod Mice ◽

Islet Autoimmunity ◽

Adult Mice ◽

Nonobese Diabetic ◽

Diabetes Development ◽

Nonobese Diabetic Mice

ABSTRACT Rotaviruses have been implicated as a possible viral trigger for exacerbations in islet autoimmunity, suggesting they might modulate type 1 diabetes development. In this study, the ability of rotavirus strain RRV to infect the pancreas and affect insulitis and diabetes was examined in nonobese diabetic (NOD) mice, an experimental model of type 1 diabetes. Mice were inoculated either orally or intraperitoneally as infants or young adults. In infant mice inoculated orally, rotavirus antigen was detected in pancreatic macrophages outside islets and infectious virus was found in blood cells, pancreas, spleen, and liver. Extraintestinal RRV spread and pancreatic presence of infectious virus also occurred in intraperitoneally inoculated infant and adult mice. The initiation of insulitis was unaltered by infection. The onset of diabetes was delayed in infant mice inoculated orally and infant and adult mice inoculated intraperitoneally. In contrast, adult mice inoculated orally showed no evidence of pancreatic RRV, the lowest rate of detectable RRV replication, and no diabetes modulation. Thus, the ability of RRV infection to modulate diabetes development in infant and young adult NOD mice was related to the overall extent of detectable virus replication and the presence of infectious virus extraintestinally, including in the pancreas. These studies show that RRV infection of infant and young adult NOD mice provides significant protection against diabetes. As these findings do not support the hypothesis that rotavirus triggers autoimmunity related to type 1 diabetes, further research is needed to resolve this issue.

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Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

10.1101/258525 ◽

2018 ◽

Author(s):

Marcos Iglesias ◽

Anirudh Arun ◽

Maria Chicco ◽

Brandon Lam ◽

Conover Talbot ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Nod Mice ◽

Interleukin 10 ◽

Type I Interferons ◽

Type I ◽

Diabetes Development

AbstractDestruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in NOD mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.AbbreviationsALNaxillary lymph nodesIL-10interleukin-10MFImean fluorescence intensityMLNmesentheric lymph nodesNODnonobese diabetic micePLNpancreatic lymph nodesTI-IFNtype-1 InterferonsTmemmemory T cellsTregregulatory T cells

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Toll-Like Receptor 3 Is Critical for Coxsackievirus B4-Induced Type 1 Diabetes in Female NOD Mice

Endocrinology ◽

10.1210/en.2013-2006 ◽

2014 ◽

Vol 156 (2) ◽

pp. 453-461 ◽

Cited By ~ 16

Author(s):

Kelly D. McCall ◽

Jean R. Thuma ◽

Maria C. Courreges ◽

Fabian Benencia ◽

Calvin B.L. James ◽

...

Keyword(s):

Type 1 Diabetes ◽

Knockout Mice ◽

Nod Mice ◽

Toll Like Receptor ◽

Wild Type ◽

Infected Female ◽

Coxsackievirus B4 ◽

Nonobese Diabetic ◽

Group B

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3+/+) and TLR3 knockout (TLR3−/−) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.

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Rodent Models for Investigating the Dysregulation of Immune Responses in Type 1 Diabetes

Journal of Diabetes Research ◽

10.1155/2013/138412 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Feng-Cheng Chou ◽

Heng-Yi Chen ◽

Shyi-Jou Chen ◽

Mei-Cho Fang ◽

Huey-Kang Sytwu

Keyword(s):

Type 1 Diabetes ◽

Animal Studies ◽

Genetic Manipulation ◽

Nod Mice ◽

Environmental Parameters ◽

Conditional Knockout ◽

Therapeutic Approaches ◽

Nonobese Diabetic ◽

Genetically Manipulated

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producingβcells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches.

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Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Diabetes ◽

10.2337/db05-0810 ◽

2006 ◽

Vol 55 (7) ◽

pp. 2098-2105 ◽

Cited By ~ 50

Author(s):

P. Alard ◽

J. N. Manirarora ◽

S. A. Parnell ◽

J. L. Hudkins ◽

S. L. Clark ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Function ◽

Nod Mice ◽

Antigen Presenting Cell ◽

Diabetes Development ◽

Antigen Presenting

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Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

PLoS Genetics ◽

10.1371/journal.pgen.1008178 ◽

2019 ◽

Vol 15 (6) ◽

pp. e1008178 ◽

Cited By ~ 1

Author(s):

Jochen Mattner ◽

Javid P. Mohammed ◽

Michael E. Fusakio ◽

Claudia Giessler ◽

Carl-Philipp Hackstein ◽

...

Keyword(s):

Type 1 Diabetes ◽

Functional Data ◽

Susceptibility Gene ◽

Nod Mice ◽

Nonobese Diabetic

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Spatial variations in gut permeability are linked to type 1 diabetes development in non-obese diabetic mice

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000793 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000793

Author(s):

William C Joesten ◽

Audrey H Short ◽

Michael A Kennedy

Keyword(s):

Type 1 Diabetes ◽

Large Intestine ◽

Nod Mice ◽

Spatial Variations ◽

Gut Permeability ◽

Spatially Resolved ◽

Diabetes Development ◽

End Stage ◽

Design And Methods

ObjectivesTo determine if spatial variations in gut permeability play a role in regulating type 1 diabetes (T1D) progression.Research design and methodsSpatially resolved duodenum, jejunum, ileum, and large intestine sections from end-stage T1D non-obese diabetic (NOD) mice were probed by immunohistochemistry to quantify zonulin levels as a measure of gut permeability in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR/LtJ control mice.ResultsZonulin levels were elevated in the small and large intestines in early-progressor and late-progressor NOD mice in comparison with non-progressor NOD mice and healthy NOR control mice. In early-onset mice, elevated zonulin levels were maximum in the duodenum and jejunum and decreased in the ileum and large intestine. In late-progressor mice, zonulin levels were elevated almost evenly along the small and large intestines. In non-progressor NOD mice, zonulin levels were comparable with NOR control levels in both the small and large intestines.ConclusionsElevated zonulin expression levels indicated that gut permeability was increased both in the small and large intestines in NOD mice that progressed to end-stage T1D in comparison with non-progressor NOD mice and healthy NOR control mice. Highest elevations in zonulin levels were observed in the duodenum and jejunum followed by the ileum and large intestines. Spatial variations in gut permeability appeared to play a role in regulating the rate and severity of T1D progression in NOD mice indicating that spatial variations in gut permeability should be investigated as a potentially important factor in human T1D progression.

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Large Gliadin Peptides Detected in the Pancreas of NOD and Healthy Mice following Oral Administration

Journal of Diabetes Research ◽

10.1155/2016/2424306 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Susanne W. Bruun ◽

Knud Josefsen ◽

Julia T. Tanassi ◽

Aleš Marek ◽

Martin H. F. Pedersen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cells ◽

Degradation Products ◽

Intestinal Barrier ◽

Nod Mice ◽

Radioactive Label ◽

Nonobese Diabetic ◽

Gliadin Peptide ◽

Gliadin Peptides

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

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