Localization of enteroviral RNA within the pancreas in donors with T1D and T1D-associated autoantibodies

Geravandi, Shirin; Richardson, Sarah J.; Pugliese, Alberto; Maedler, Kathrin

doi:10.1016/j.xcrm.2021.100371

Cited by 21 publications

(29 citation statements)

References 43 publications

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“…Considering that AREG can restrain the antiviral activity of CD8 +T cells in hepatitis B (38) we can suppose that its reduction could eventually be protective against virus infection, the potential candidate in T1D pathogenesis (36,39,40). The decreased expression of PDE12 in our T1D patients is in accordance with this.…”

Section: Discussionsupporting

confidence: 80%

“…Through EFGR binding AREG promotes the immunosuppressive activity of Foxp3 regulatory T cells (Tregs) responsible for maintaining immune homeostasis and peripheral tolerance to self-antigens ( 37 ). Considering that AREG can restrain the antiviral activity of CD8+T cells in hepatitis B ( 38 ) we can suppose that its reduction could eventually be protective against virus infection, the potential candidate in T1D pathogenesis ( 36 , 39 , 40 ). The decreased expression of PDE12 in our T1D patients is in accordance with this.…”

Section: Discussionmentioning

confidence: 99%

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Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes

et al. 2022

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BackgroundChanges in innate and adaptive immunity occurring in/around pancreatic islets had been observed in peripheral blood mononuclear cells (PBMC) of Caucasian T1D patients by some, but not all researchers. The aim of our study was to investigate whether gene expression patterns of PBMC of the highly admixed Brazilian population could add knowledge about T1D pathogenic mechanisms.MethodsWe assessed global gene expression in PBMC from two groups matched for age, sex and BMI: 20 patients with recent-onset T1D (≤ 6 months from diagnosis, in a time when the autoimmune process is still highly active), testing positive for one or more islet autoantibodies and 20 islet autoantibody-negative healthy controls.ResultsWe identified 474 differentially expressed genes between groups. The most expressed genes in T1D group favored host defense, inflammatory and anti-bacterial/antiviral effects (LFT, DEFA4, DEFA1, CTSG, KCNMA1) and cell cycle progression. Several of the downregulated genes in T1D target cellular repair, control of inflammation and immune tolerance. They were related to T helper 2 pathway, induction of FOXP3 expression (AREG) and immune tolerance (SMAD6). SMAD6 expression correlated negatively with islet ZnT8 antibody. The expression of PDE12, that offers resistance to viral pathogens was decreased and negatively related to ZnT8A and GADA levels. The increased expression of long non coding RNAs MALAT1 and NEAT1, related to inflammatory mediators, autoimmune diseases and innate immune response against viral infections reinforced these dataConclusionsOur analysis suggested the activation of cell development, anti-infectious and inflammatory pathways, indicating immune activation, whereas immune-regulatory pathways were downregulated in PBMC from recent-onset T1D patients with a differential genetic profile.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes

et al. 2022

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“…The hyperexpression of HLA class I molecules in islets and the aberrant expression of HLA class II molecules by beta cells were initially reported in the mid-1980s, yet were not fully accepted until very recently, when, taking advantage of novel technologies, multiple biobanks, and islet cells isolated from donors with T1D, these findings were confirmed and further expanded. The additional features that were reported in recent years include critical alterations of extracellular matrix components, evidence of exocrine abnormalities and inflammation (Campbell-Thompson et al 2015), rare donors with evidence of amyloid deposition (Westermark et al 2017, Denroche & Verchere 2018, Beery et al 2019, and multidisciplinary evidence for viral infections (Dunne et al 2019, Apaolaza et al 2021, Geravandi et al 2021. Thus, our understanding of pancreas pathology and associated molecular changes has evolved over time, and our knowledge is now more comprehensive.…”

Section: Key Features Of Pancreas Pathology In T1dmentioning

confidence: 99%

“…There is extensive support for a viral contribution to the disease pathogenesis, particularly by enteroviruses , Dunne et al 2019. At the level of the pancreas, enterovirus proteins, enterovirus RNA, and an active anti-viral host response have been demonstrated in the pancreata of T1D donors from each of the three biobanks , Geravandi et al 2021. Viral capsid protein is detected in a small number of beta cells, typically only in ICIs, often in association with hyperexpression of HLA class I molecules and insulitis (Richardson et al 2009(Richardson et al , 2013.…”

Section: Viral Infectionsmentioning

confidence: 99%

100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story

Richardson

Pugliese

2022

Journal of Endocrinology

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We review the current knowledge of pancreas pathology in type 1 diabetes. During the last two decades dedicated efforts towards the recovery of pancreas from deceased patients with type 1 diabetes have promoted significant advances in the characterization of the pathological changes associated with this condition. The implementation autoantibody screening among organ donors has also allowed examining pancreas pathology in the absence of clinical disease, but in the presence of serological markers of autoimmunity. The assessment of key features of pancreas pathology across various disease stages allows driving parallels with clinical disease stages. The main pathological abnormalities observed in the pancreas with type 1 diabetes are beta cell loss, insulitis, and more recently hyperexpression of HLA class I and class II molecules have been reproduced and validated. Additionally, there are changes affecting extracellular matrix components, evidence of viral infections, inflammation, and ER stress, which could contribute to beta cell dysfunction and the stimulation of apoptosis and autoimmunity. The increasing appreciation that beta cell loss can be less severe at diagnosis than previously estimated, the coexistence of beta cell dysfunction, and the persistence of key features of pancreas pathology for years after diagnosis impact the perception of the dynamics of this chronic process. The emerging information is helping identifying novel therapeutic targets and have implications for the design of clinical trials.

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“…Among identified environmental factors, viral infections have been undoubtedly shown to play a prominent role (2,3). As a matter of fact, multiple evidences of Enterovirus infection of pancreatic islets in T1D donors have now been confirmed by several studies, also adopting rigorous methodological cross-validation approaches in various patient cohorts (4)(5)(6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

et al. 2022

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The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.

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Localization of enteroviral RNA within the pancreas in donors with T1D and T1D-associated autoantibodies

Cited by 21 publications

References 43 publications

Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes

Prevalence of Inflammatory Pathways Over Immuno-Tolerance in Peripheral Blood Mononuclear Cells of Recent-Onset Type 1 Diabetes

100 YEARS OF INSULIN: Pancreas pathology in type 1 diabetes: an evolving story

Increased Expression of Viral Sensor MDA5 in Pancreatic Islets and in Hormone-Negative Endocrine Cells in Recent Onset Type 1 Diabetic Donors

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