Immunopathology of the human pancreas in type-I diabetes

Richardson, Sarah J.; Willcox, Abby; Bone, Adrian J.; Morgan, Noel G.; Foulis, Alan K.

doi:10.1007/s00281-010-0205-0

Cited by 80 publications

(75 citation statements)

References 90 publications

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“…IKK2-CA Pdx-1 animals develop severe hyperglycemia and hypoinsulinemia mirroring substantial b-cell loss that is associated with marked islet inflammation. Similar to the human immunopathology, infiltrates are not seen in all pancreatic islets and include different kinds of immune cells (21). This model is the first animal model to activate IKK2/NF-kB in b-cells and to prove directly its capability to trigger diabetes development on its own.…”

Section: Discussionmentioning

confidence: 99%

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

et al. 2014

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Type 1 diabetes is a multifactorial inflammatory disease in genetically susceptible individuals characterized by progressive autoimmune destruction of pancreatic b-cells initiated by yet unknown factors. Although animal models of type 1 diabetes have substantially increased our understanding of disease pathogenesis, heterogeneity seen in human patients cannot be reflected by a single model and calls for additional models covering different aspects of human pathophysiology. Inhibitor of kB kinase (IKK)/nuclear factor-kB (NF-kB) signaling is a master regulator of inflammation; however, its role in diabetes pathogenesis is controversially discussed by studies using different inhibition approaches. To investigate the potential diabetogenic effects of NF-kB in b-cells, we generated a gain-of-function model allowing conditional IKK2/NF-kB activation in b-cells. A transgenic mouse model that expresses a constitutively active mutant of human IKK2 dependent on Pdx-1 promoter activity (IKK2-CA Pdx-1 ) spontaneously develops full-blown immunemediated diabetes with insulitis, hyperglycemia, and hypoinsulinemia. Disease development involves a gene expression program mimicking virus-induced diabetes and allergic inflammatory responses as well as increased major histocompatibility complex class I/II expression by b-cells that could collectively promote diabetes development. Potential novel diabetes candidate genes were also identified. Interestingly, animals successfully recovered from diabetes upon transgene inactivation. Our data give the first direct evidence that b-cell-specific IKK2/NF-kB activation is a potential trigger of immune-mediated diabetes. Moreover, IKK2-CA Pdx-1 mice provide a novel tool for studying critical checkpoints in diabetes pathogenesis and mechanisms governing b-cell degeneration/ regeneration. Diabetes 2014;63:960-975 | DOI: 10.233763:960-975 | DOI: 10. /db13-1037 Type 1 diabetes is an autoimmune disease in genetically predisposed individuals and presumably triggered and/or accelerated by environmental factors (1). Analyses of animal models of type 1 diabetes have greatly improved our knowledge about disease pathophysiology and genetic contribution. However, there is still an unmet need to understand islet cell pathology and ongoing inflammatory processes within the islets of Langerhans.

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Section: Discussionmentioning

confidence: 99%

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

et al. 2014

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“…Although immunohistochemical studies have suggested the expression of type I IFN (10,11) and some ISGs (12,13) in T1D islets, other studies have failed to detect type I IFN in pancreata from subjects with diabetes (14). End point PCR, with no or limited quantitative value, has suggested IFN-a expression to be more prevalent in T1D than in control pancreata (15,16), but this has not been confirmed by quantitative methods.…”

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confidence: 98%

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

et al. 2016

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A primary insult to the pancreatic islets of Langerhans, leading to the activation of innate immunity, has been suggested as an important step in the inflammatory process in type 1 diabetes (T1D). The aim of this study was to examine whether interferon (IFN)-stimulated genes (ISGs) are overexpressed in human T1D islets affected with insulitis. By using laser capture microdissection and a quantitative PCR array, 23 of 84 examined ISGs were found to be overexpressed by at least fivefold in insulitic islets from living patients with recent-onset T1D, participating in the Diabetes Virus Detection (DiViD) study, compared with islets from organ donors without diabetes. Most of the overexpressed ISGs, including GBP1, TLR3, OAS1, EIF2AK2, HLA-E, IFI6, and STAT1, showed higher expression in the islet core compared with the peri-islet area containing the surrounding immune cells. In contrast, the T-cell attractant chemokine CXCL10 showed an almost 10-fold higher expression in the peri-islet area than in the islet, possibly partly explaining the localization of T cells mainly to this region. In conclusion, insulitic islets from recent-onset T1D subjects show overexpression of ISGs, with an expression pattern similar to that seen in islets infected with virus or exposed to IFN-γ/interleukin-1β or IFN-α.

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“…Children genetically at risk for type 1 diabetes present a type I IFNinducible transcriptional signature that precedes the development of autoantibodies [14,15], and IFNα plays a major role as mediator of HLA class overexpression in human islet cells, a key event in early type 1 diabetes [16,17]. Laser-captured islets obtained from living donors with recent onset type 1 diabetes showed a significant increase in nearly 50% of the IFN-stimulated genes (ISGs) evaluated [18].…”

Section: Introductionmentioning

confidence: 99%

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

et al. 2017

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Aims/hypothesis Three hallmarks of the pancreatic islets in early human type 1 diabetes are overexpression of HLA class I, endoplasmic reticulum (ER) stress and beta cell apoptosis. The mediators of these phenomena remain to be defined. The type I interferon IFNα is expressed in human islets from type 1 diabetes patients and mediates HLA class I overexpression. We presently evaluated the mechanisms involved in IFNα-induced HLA class I expression in human beta cells and determined whether this cytokine contributes to ER stress and apoptosis. Methods IFNα-induced inflammation, ER stress and apoptosis were evaluated by RT-PCR, western blot, immunofluorescence and nuclear dyes, and proteins involved in type I interferon signalling were inhibited by small interfering RNAs. All experiments were performed in human islets or human EndoC-βH1 cells.Results IFNα upregulates HLA class I, inflammation and ER stress markers in human beta cells via activation of the candidate gene TYK2, and the transcription factors signal transducer and activator of transcription 2 and IFN regulatory factor 9. Furthermore, it acts synergistically with IL-1β to induce beta cell apoptosis. Conclusions/interpretation The innate immune effects induced by IFNα may induce and amplify the adaptive immune response against human beta cells, indicating that IFNα has a central role in the early phases of diabetes.

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Immunopathology of the human pancreas in type-I diabetes

Cited by 80 publications

References 90 publications

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

Expression of Interferon-Stimulated Genes in Insulitic Pancreatic Islets of Patients Recently Diagnosed With Type 1 Diabetes

Interferon-α mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes

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