Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin‐dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM

Kobayashi, Tetsuro; Nishida, Yoriko; Tanaka, Shoichiro; Aida, Kaoru

doi:10.1002/dmrr.1237

Cited by 21 publications

(18 citation statements)

References 43 publications

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“…Studies of gene-deficient mice indicate that RLRs play an important role in antiviral response [22][23][24]. We have demonstrated significant hyper-expression of RLRs in islet cells of patients with fulminant type 1 diabetes [8,9]. MDA5 was strongly expressed in islet cells (including β-and α-cells) of fulminant type 1 diabetic pancreata.…”

Section: Enterovirus In the Pancreasmentioning

confidence: 81%

“…The human TLR multigene family comprises 10 members, with TLR2, -3, -4, -7, and -8 considered to be of importance in the recognition of structural components of RNA viruses, including viral doublestranded RNA, single-stranded RNA, and surface glycoproteins [30]. We showed that both TLR3 and TLR4 were expressed in MNCs that had infiltrated islets of fulminant type 1 diabetic pancreata, but not SPIDDM patients or non-diabetic controls [8,9]. The frequencies of islets with infiltrating MNCs expressing TLR3 and TLR4 were 11.7% and 4.3%, respectively, although almost no islet with MNCs expressing TLR3 or TLR4 was recognized in pancreata of non-diabetic controls or SPIDDM patients.…”

Section: Enterovirus In the Pancreasmentioning

confidence: 82%

“…LGP2 also was preferentially hyper-expressed in islet β-cells of pancreas with fulminat type 1 diabetic patients [9]. In non-diabetic and SPIDDM pancreata, weak basal expression of LGP2 was observed in β-cells.…”

Section: Enterovirus In the Pancreasmentioning

confidence: 90%

“…NOD2 also recogfulminant type 1 diabetes [7][8][9]. A proportion of islet cells and acinar cells were positive for VP1.…”

Section: Enterovirus In the Pancreasmentioning

confidence: 99%

“…Endogenous insulin secretion is completely abolished over time and diabetic microangiopathies develop within a short duration [5,6]. Remarkable severe insulitis was recognized in autopsied pancreata of patients who died shortly after the onset of fulminant type 1 diabetes [3,[7][8][9][10]. The mechanisms underlying aggressive and rapid destruction of β-cells remain some of the key issues in question regarding this subtype of type 1 diabetes.…”

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confidence: 99%

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Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

et al. 2013

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Abstract. Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes.

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Section: Enterovirus In the Pancreasmentioning

confidence: 81%

Section: Enterovirus In the Pancreasmentioning

confidence: 82%

Section: Enterovirus In the Pancreasmentioning

confidence: 90%

“…NOD2 also recogfulminant type 1 diabetes [7][8][9]. A proportion of islet cells and acinar cells were positive for VP1.…”

Section: Enterovirus In the Pancreasmentioning

confidence: 99%

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confidence: 99%

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Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

et al. 2013

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Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition

Luo

et al. 2020

Diabetes Metabolism Res

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Summary Fulminant type 1 diabetes (FT1D) is a subset of type 1 diabetes characterized by extremely rapid pancreatic β‐cell destruction with aggressive progression of hyperglycaemia and ketoacidosis. It was initially classified as idiopathic type 1 diabetes due to the absence of autoimmune markers. However, subsequent studies provide evidences supporting the involvement of autoimmunity in rapid β‐cell loss in FT1D pathogenesis, which are crucial for FT1D being an autoimmune disease. This article highlights the role of immunological aspects in FT1D according to the autoimmune‐associated genetic background, viral infection, innate immunity, adaptive immunity, and pancreas histology.

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Enteroviruses and the pathogenesis of type 1 diabetes revisited: cross‐reactivity of enterovirus capsid protein (VP1) antibodies with human mitochondrial proteins

Hansson

Korsgren

Pontén

et al. 2013

The Journal of Pathology

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Current or recent enteroviral infections show an association with type 1 diabetes. However, evidence for this has mainly been generated using a particular mouse monoclonal antibody (clone 5-D8/1) which binds the viral capsid protein VP1. Difficulty in confirming these findings using other independent methods has led to the concern that this might be artefactual. To address this, we examined the potential cross-reactivity of clone 5-D8/1 with normal islet proteins. Western blotting, two-dimensional gel electrophoresis, and mass spectrometry were used to identify human islet proteins bound by the clone 5-D8/1. We found a distinct reactivity with two mitochondrial proteins, creatine kinase B-type and ATP synthase beta subunit. Immunohistochemistry using the clone 5-D8/1 revealed a granular cytoplasmic staining pattern in mitochondria-rich cells, ie hepatocytes, ductal epithelial cells, vascular endothelial cells, skeletal muscle cells, and the neoplastic salivary gland oncocytoma cells, whereas connective tissue and infiltrating immune cells were negative. Staining on islets of Langerhans from subjects with recent-onset type 1 diabetes, but not on isolated human islets infected in vitro with enteroviruses, could be blocked after mixing the clone 5-D8/1 with the mitochondrial proteins. Collectively, our data show that the clone 5-D8/1 detects two human mitochondrial enzymes in addition to enteroviral VP1. The notion that the previously reported VP1 positivity in islets of recent-onset type 1 diabetes patients could reflect cross-reactivity to native islet proteins and not the presence of EV is supported by difficulties in demonstrating EV infection by independent techniques such as PCR or in situ hybridization. These findings call for revisiting the presence of enteroviruses in pancreatic islets of patients with type 1 diabetes.

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Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin‐dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM

Abstract: These findings demonstrate that retinoic acid-inducible protein I (RIG-I)-like helicases and TLRs play a crucial role on beta-cell destruction in enterovirus-induced FT1D. The presence of distinct mechanism(s) of slowly progressive beta-cell failure in SPIDDM was suggested.

Cited by 21 publications

References 43 publications

Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]

Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition

Enteroviruses and the pathogenesis of type 1 diabetes revisited: cross‐reactivity of enterovirus capsid protein (VP1) antibodies with human mitochondrial proteins

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