Expression of Toll-like Receptors in the Pancreas of Recent-onset Fulminant Type 1 Diabetes

Shibasaki, Saeko; Imagawa, Akihisa; Tauriainen, Sisko; Iino, Morio; Oikarinen, Maarit; Abiru, Hitoshi; Tamaki, Keiji; Seino, Hiroaki; Nishi, Katsuhiro; Takase, Izumi; Okada, Yoshinori; Uno, Shigeyuki; Murase-Mishiba, Yuko; Terasaki, Jungo; Makino, Hideichi; Shimomura, Iichiro; Hyöty, Heikki; Hanafusa, Toshiaki

doi:10.1507/endocrj.k09e-291

Cited by 78 publications

(64 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, there is evidence that the innate immune response, particularly macrophages, also plays a role in autoimmune diabetes (58). Intriguingly, high numbers of monocytes/macrophages are present in the pancreatic infiltrates of patients suffering from fulminant diabetes (33,34), which is noted for its aggressive and rapid disease progression. The pathogenic monocyte response in Tgfbr2 −/− OT-II RIP-mOva mice is in part dependent on GM-CSF, a cytokine with established roles in myeloid cell homeostasis and monocyte activation (40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

“…4H). Intriguingly, high numbers of monocytes/macrophages are present in the pancreatic infiltrates of patients suffering from an aggressive subtype of type I diabetes termed "fulminant diabetes," in which hyperglycemia occurs over the course of a few days (33,34). Indeed the course of diabetes development is far more acute in Tgfbr2 −/− than in Foxp3sf OT-II RIP-mOva mice (Fig.…”

Section: Enhanced Priming Of Pancreas Draining Lymph Node T Cells In Thementioning

confidence: 99%

See 1 more Smart Citation

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Liu

Nixon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Enhanced Priming Of Pancreas Draining Lymph Node T Cells In Thementioning

confidence: 99%

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Liu

Nixon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that islet cells infected with human enterovirus activate DCs via an endosomal acidification-dependent mechanism [39], suggesting a role for TLR7 or TLR9 activation. The presence of TLR7 on antigen-presenting cells within islets of individuals with recent-onset diabetes has also been demonstrated [40].…”

Section: Tlr7/9 Agonists Activate Nod-derived Bmdcs and Cause The Secmentioning

confidence: 98%

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8 + T cells. Methods We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8 + T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice). Results TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. Conclusions/interpretation TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis.

show abstract

“…In ;1% of infected individuals, the virus spreads to the motoneurons and causes paralytic disease. Similarly, some other enteroviruses, including the six coxsackievirus B (CVB) serotypes, seem to have a tropism for human pancreatic islets in vitro (4)(5)(6)(7) and in vivo (8)(9)(10), possibly because islet cells express the coxsackie-adenovirus receptor (CAR), which is the major receptor for CVBs (11).…”

mentioning

confidence: 99%

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Laitinen¹,

Honkanen

Pakkanen³

et al. 2014

Diabetes

Self Cite

227

221

View full text Add to dashboard Cite

The rapidly increasing incidence of type 1 diabetes implies that environmental factors are involved in the pathogenesis. Enteroviruses are among the suspected environmental triggers of the disease, and the interest in exploring the possibilities to develop vaccines against these viruses has increased. Our objective was to identify enterovirus serotypes that could be involved in the initiation of the disease process by screening neutralizing antibodies against 41 different enterovirus types in a unique longitudinal sample series from a large prospective birth-cohort study. The study participants comprised 183 case children testing persistently positive for at least two diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. Coxsackievirus B1 was associated with an increased risk of β-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and was attenuated by the presence of maternal antibodies against the virus. Two other coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern, suggesting immunological cross-protection against coxsackievirus B1. These results support previous observations suggesting that the group B coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon.

show abstract

Expression of Toll-like Receptors in the Pancreas of Recent-onset Fulminant Type 1 Diabetes

Cited by 78 publications

References 27 publications

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Toll-like receptor 7 stimulation promotes autoimmune diabetes in the NOD mouse

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes

Contact Info

Product

Resources

About