The β-Cell in Type 1 Diabetes Pathogenesis: A Victim of Circumstances or an Instigator of Tragic Events?

Mallone, Roberto; Halliez, Clémentine; Rui, Jinxiu; Herold, Kevan C.

doi:10.2337/dbi21-0036

Cited by 16 publications

(13 citation statements)

References 72 publications

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“…Accordingly, proINS synthesis was also unaffected by IFN-α, while it was decreased by IFN-γ. β-cell de-differentiation might thus be a late event in T1D pathogenesis, induced by inflammatory cytokines that intervene later than IFN-α 37 , and may represent a defense mechanism to limit autoimmune vulnerability 38 . At earlier disease stages, the HLA-E upregulation induced by IFN-α 19 may provide another line of defense.…”

Section: Discussionmentioning

confidence: 99%

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Carré,

Zhou,

Perez-Hernandez

et al. 2023

Preprint

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Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation in in-vitro resting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and protein cissplicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-Brestricted vs. HLA-A-restricted CD8+ T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8+ T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Carré,

Zhou,

Perez-Hernandez

et al. 2023

Preprint

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“…Interestingly, T-cells cultured with autologous SC-islets from non-diabetic and T1D donors showed neither activation nor β-cell target cytotoxicity unless SC-islets were preliminarily exposed to endoplasmic reticulum stressors ( 147 ). This emphasizes the increasing appreciation of the active role that β-cells play in shaping their autoimmune vulnerability ( 148 – 151 ), which will be another paramount aspect to address using β-cell/T-cell crosstalk models.…”

Section: Applications Of In Vitro β-Cell Killing P...mentioning

confidence: 99%

In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities

et al. 2023

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Type 1 diabetes (T1D) is a disease of both autoimmunity and β-cells. The β-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8+ T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro β-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8+ T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the β-cell/immune crosstalk in an islet microenvironment; the features that make β-cells more sensitive to autoimmunity; therapeutic agents that may modulate β-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.

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“…Type 1 diabetes (T1D) is an autoimmune disease characterized by immune attack of the insulin-producing pancreatic beta-cells, leading to their destruction and the development of clinical hyperglycemia. An emerging concept in the T1D research field is that beta-cell dysfunction may play a causative role in disease pathogenesis through the alteration of the beta-cell-immune cell interface, thus contributing to the autoimmune attack of the beta-cells (11). We recently observed that autophagy is disrupted in the context of human T1D, and that disposal of damaged/dysfunctional beta-cell components is perturbed in autoantibody-positive human organ donors even prior to diabetes onset (12).…”

Section: Main Text Introductionmentioning

confidence: 99%

Real TimeIn vivoAnalysis of Pancreatic Beta-cell Autophagic Flux Reveals Impairment Before Onset of Autoimmune Diabetes

Melnyk,

Muralidharan,

Duffett

et al. 2023

Preprint

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The catabolic pathway of autophagy is critical for pancreatic beta-cell function and is defective in established type 1 diabetes (T1D). However, it is unclear when and how this critical cell process becomes defective during diabetes pathogenesis. To study the nature of autophagy dysfunction in the context of autoimmune diabetes, we utilized intravital microscopy to study autophagic flux in vivo in real time. We generated a custom AAV8-packaged mCherry-eGFP-LC3B biosensor driven by the insulin promoter for beta-cell-selective expression. For real time autophagic flux evaluation, fluorescent signal from eGFP and mCherry fluorophores was correlated in space and time to follow the process of autophagosome-lysosome fusion. We observed autophagic flux defects in the beta-cells of non-obese diabetic (NOD) mouse model of T1D prior to hyperglycemia onset that were less apparent in mice without a functional immune system. We also evaluated autophagic flux in human donor islets that were transplanted under the kidney capsule of immune incompetent mice. Collectively, we provide the first evaluation of autophagic flux in vivo in 4D and demonstrate that autophagy defects precede hyperglycemia in NOD mice suggesting a potential causative role for these defects in beta-cell demise during T1D pathogenesis.

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The β-Cell in Type 1 Diabetes Pathogenesis: A Victim of Circumstances or an Instigator of Tragic Events?

Cited by 16 publications

References 72 publications

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells

In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities

Real TimeIn vivoAnalysis of Pancreatic Beta-cell Autophagic Flux Reveals Impairment Before Onset of Autoimmune Diabetes

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