Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes

Rutman, Alissa K.; Negi, Sarita; Gasparrini, Marco; Hasilo, Craig; Paraskevas, Steven

doi:10.1210/en.2018-00649

Cited by 39 publications

(28 citation statements)

References 95 publications

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“…Exosomes from healthy beta cells efficiently trigger antigen-presenting cell (APC) activation and T-cell proliferation in vitro and accelerate islet infiltration by immune cells in non-obese diabetic resistant mice in vivo ( 13 ). In human T1D patients, healthy beta EV mediate B- and T-cell activation ( 16 ). It has further been hypothesized that aberrant sorting in stressed beta cells could fuel release of misfolded immunogenic proteins and danger-associated molecular patterns (DAMP) inside EV.…”

Section: Introductionmentioning

confidence: 99%

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

et al. 2020

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Inflammation stimulates release of a heterogeneous population of beta EV with differential expression of immunogenic substances involved in immune cell recruitment and activation. HIGHLIGHTS-Stress engenders an up to four-fold increase in the volume of the vesiculome and enhanced auto-antigen release-Cytokines are selectively sorted into EV subspecies-TLR-binding microRNAs are enriched in sEV-EV from stressed beta cells promote dendritic and macrophage cell activation.

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Section: Introductionmentioning

confidence: 99%

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

et al. 2020

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“…Furthermore, miRNAs can be packed in EVs released from maternal cells, and can modulate specific cellular processes in the recipient cells (Kosaka et al, 2013). A few studies investigated EVs protein cargo (Cianciaruso et al, 2017;Hasilo et al, 2017;Rutman et al, 2018) and total plasma miRNA in T1D (Garcia-Contreras et al, 2017) so far, however, the immunomodulatory role of EVs miRNA has not been well established. To our knowledge, this is the first EVs study demonstrating beta-cell-released EVs presence in blood plasma using TEM (Figure 1), and the potential role of EVs miRNA in the etiology of T1D.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Derived Human-miRNAs Modulate the Immune System in Type 1 Diabetes

Tesovnik

Kovač

Pohar

et al. 2020

Front. Cell Dev. Biol.

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Extracellular vesicles with their molecular cargo can modulate target cell response and may affect the pathogenesis of diseases. The extracellular vesicles containing micro-RNAs (miRNAs), which are often studied as disease biomarkers, but rarely as mediators of the disease development. The role of extracellular vesicles derived miRNAs in type 1 diabetes is currently not well established. We observed a fraction of blood plasma extracellular vesicles positive for membrane proteins potentially associated with insulinproducing beta-cells and identified differentially expressed extracellular vesicles derived miRNAs in individuals with type 1 diabetes. These differentially expressed extracellular vesicles derived human miRNAs in participants with type 1 diabetes and participants with Langerhans islets beta-cells destruction showed the ability to activate TLR7/8 signaling cascade and increase activation as well as cytotoxicity of the effector blood immune cells with cytokine and chemokine release. Our results illustrate extracellular vesicles derived human miRNAs as modulators of the immune system in type 1 diabetes autoimmunity, providing potentially new insight into the pathogenesis of the disease, and novel molecular targets for intervention and type 1 diabetes prevention.

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“…Interestingly, in-depth analysis of their content has revealed the presence of insulin, C-peptide proteins, glutamic acid decarboxylase 65 (GAD65), low levels of glucagon and endothelial nitric oxide synthase, suggesting that they mostly originate from insulin-producing ß-cells. 17 Further, many miRNAs have been found to be enriched in EVs derived from ß-cells. 18 Regarding T1D pathogenesis, the current hypothesis is that pro-inflammatory cytokines secreted by immune cells within the pancreas contribute to creating an inflammatory microenvironment that, in turn, promotes the ß-cells attack by the immune system.…”

Section: Evs In T1d Pathogenesismentioning

confidence: 99%

“…In the last decade, many studies have sought to characterize the nature of EVs cargo. Interestingly, in‐depth analysis of their content has revealed the presence of insulin, C‐peptide proteins, glutamic acid decarboxylase 65 (GAD65), low levels of glucagon and endothelial nitric oxide synthase, suggesting that they mostly originate from insulin‐producing ß‐cells 17 . Further, many miRNAs have been found to be enriched in EVs derived from ß‐cells 18 .…”

Section: Type 1 Diabetesmentioning

confidence: 99%

Chicken-or-egg question: Which came first, extracellular vesicles or autoimmune diseases?

Maione

Cappellano

Bellan

et al. 2020

Journal of Leukocyte Biology

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Extracellular vesicles (EVs) have attracted great interest as contributors to autoimmune disease (AD) pathogenesis, owing to their immunomodulatory potential; they may also play a role in triggering tolerance disruption, by delivering auto-antigens. EVs are released by almost all cell types, and afford paracrine or distal cell communication, functioning as biological carriers of active molecules including lipids, proteins, and nucleic acids. Depending on stimuli from the external microenvironment or on their cargo, EVs can promote or suppress immune responses. ADs are triggered by inappropriate immune-system activation against the self, but their precise etiology is still poorly understood. Accumulating evidence indicates that lifestyle and diet have a strong impact on their clinical onset and development. However, to date the mechanisms underlying AD pathogenesis are not fully clarified, and reliable markers, which would provide early prediction and disease progression monitoring, are lacking. In this connection, EVs have recently been indicated as a promising source of AD biomarkers. Although EV isolation is currently based on differential centrifugation or density-gradient ultracentrifugation, the resulting co-isolation of contaminants (i.e., protein aggregates), and the pooling of all EVs in one sample, limit this approach to abundantly-expressed EVs. Flow cytometry is one of the most promising methods for detecting EVs as biomarkers, and may have diagnostic applications. Furthermore, very recent findings describe a new method for identifying and sorting EVs by flow cytometry from freshly collected body fluids, based on specific EV surface markers.

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Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes

Cited by 39 publications

References 95 publications

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

Molecular and Functional Diversity of Distinct Subpopulations of the Stressed Insulin-Secreting Cell's Vesiculome

Extracellular Vesicles Derived Human-miRNAs Modulate the Immune System in Type 1 Diabetes

Chicken-or-egg question: Which came first, extracellular vesicles or autoimmune diseases?

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