IMMUNOREACTIVE Α-Interferon IN INSULIN-SECRETING Β CELLS IN TYPE 1 DIABETES MELLITUS

Foulis, A. K.; Farquharson, M. A.; Meager, Anthony

doi:10.1016/s0140-6736(87)91128-7

Cited by 337 publications

(225 citation statements)

References 16 publications

Supporting

Mentioning

208

Contrasting

Unclassified

Order By: Relevance

“…This latter phenomenon is intimately associated with IFN-α production by beta cells [17] and is unique to type 1 diabetes [31]. Thus, vp1 staining of beta cells does not appear to be directly associated with secretion of IFN-α and it is unclear why IFN-α is produced by beta cells in those islets which hyperexpress class I MHC [26] but have no demonstrable viral capsid protein.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls. Methods Serial sections of paraffin-embedded pancreatic autopsy samples from 72 recent-onset type 1 diabetes patients and up to 161 controls were immunostained for insulin, glucagon, vp1, double-stranded RNA activated protein kinase R (PKR) and MHC class I. Results vp1-immunopositive cells were detected in multiple islets of 44 out of 72 young recent-onset type 1 diabetic patients, compared with a total of only three islets in three out of 50 neonatal and paediatric normal controls. vp1 staining was restricted to insulin-containing beta cells. Among the control pancreases, vp1 immunopositivity was also observed in some islets from ten out of 25 type 2 diabetic patients. A strong correlation was established between islet cell vp1 positivity and PKR production in insulin-containing islets of both type 1 and type 2 diabetic patients, consistent with a persistent viral infection of the islets. Conclusions/interpretation Immunoreactive vp1 is commonly found in the islets of recent-onset type 1 diabetes patients, but only rarely in normal paediatric controls. vp1 immunostaining was also observed in some islets of type 2 diabetes patients, suggesting that the phenomenon is not restricted to type 1 diabetes patients.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Similarly, CVBinfected islets produced IFN-α in vitro [16] and this has been associated with hyperexpression of class I MHC [17].…”

Section: Introductionmentioning

confidence: 98%

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

View full text Add to dashboard Cite

show abstract

“…The cytokine IFNα, a member of the type I IFN family, is expressed in human islets from patients with type 1 diabetes [7][8][9][10] and in the pancreas of NOD mice [11][12][13]. 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].…”

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

View full text Add to dashboard Cite

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.

show abstract

“…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.…”

mentioning

confidence: 98%

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

et al. 2016

View full text Add to dashboard Cite

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.

show abstract

IMMUNOREACTIVE Α-Interferon IN INSULIN-SECRETING Β CELLS IN TYPE 1 DIABETES MELLITUS

Cited by 337 publications

References 16 publications

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human 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

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

Contact Info

Product

Resources

About