Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

Zirpel, Henner; Roep, Bart O.

doi:10.3389/fendo.2021.666795

Cited by 22 publications

(23 citation statements)

References 99 publications

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“…Upon stressful circumstances, beta cells-together with resident macrophages-secrete IL-1 and express the chemokine CXCL10, which attracts more T cells toward the islets (25)(26)(27)(28). Beta cells also produce TYK2 to undergo apoptosis, while further promoting inflammation by enhancing IFN-alpha signaling, upregulating HLA class 1 molecules and attracting CD8 T cells (29).…”

Section: Suppress or Reverse Autoimmunitymentioning

confidence: 99%

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

Hollander

Roep

2022

Front. Med.

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Type 1 diabetes (T1D) remains a devastating disease that requires much effort to control. Life-long daily insulin injections or an insulin pump are required to avoid severe complications. With many factors contributing to disease onset, T1D is a complex disease to cure. In this review, the risk factors, pathophysiology and defect pathways are discussed. Results from (pre)clinical studies are highlighted that explore restoration of insulin production and reduction of autoimmunity. It has become clear that treatment responsiveness depends on certain pathophysiological or genetic characteristics that differ between patients. For instance, age at disease manifestation associated with efficacy of immune intervention therapies, such as depleting islet-specific effector T cells or memory B cells and increasing immune regulation. The new challenge is to determine in whom to apply which intervention strategy. Within patients with high rates of insulitis in early T1D onset, therapy depleting T cells or targeting B lymphocytes may have a benefit, whereas slow progressing T1D in adults may be better served with more sophisticated, precise and specific disease modifying therapies. Genetic barcoding and immune profiling may help determining from which new T1D endotypes patients suffer. Furthermore, progressed T1D needs replenishment of insulin production besides autoimmunity reversal, as too many beta cells are already lost or defect. Recurrent islet autoimmunity and allograft rejection or necrosis seem to be the most challenging obstacles. Since beta cells are highly immunogenic under stress, treatment might be more effective with stress reducing agents such as glucagon-like peptide 1 (GLP-1) analogs. Moreover, genetic editing by CRISPR-Cas9 allows to create hypoimmunogenic beta cells with modified human leukocyte antigen (HLA) expression that secrete immune regulating molecules. Given the differences in T1D between patients, stratification of endotypes in clinical trials seems essential for precision medicines and clinical decision making.

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Section: Suppress or Reverse Autoimmunitymentioning

confidence: 99%

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

Hollander

Roep

2022

Front. Med.

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“…DCs and macrophages are present in pancreatic islets, and some have been shown to present β-cell antigens directly to diabetogenic T cells, at least in animal models [ 243 , 244 ]. Other APC populations are present in pancreatic lymph nodes, some resident that acquire antigens draining from islets, others draining directly from islets loaded with antigens.…”

Section: Applications Of His Models To Study Immune Tolerance and Autoimmune Processesmentioning

confidence: 99%

Modeling human T1D-associated autoimmune processes

Khosravi‐Maharlooei

Madley

Borsotti

et al. 2022

Molecular Metabolism

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Background Type 1 diabetes (T1D) is an autoimmune disease characterized by impaired immune tolerance to β-cell antigens and progressive destruction of insulin-producing β-cells. Animal models have provided valuable insights for understanding the etiology and pathogenesis of this disease, but they fall short of reflecting the extensive heterogeneity of the disease in humans, which is contributed by various combinations of risk gene alleles and unique environmental factors. Collectively, these factors have been used to define subgroups of patients, termed endotypes, with distinct predominating disease characteristics. Scope of review Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis. We describe the various models developed so far and the scientific questions that have been addressed using them. Finally, we discuss the limitations of these models, primarily ascribed to hosting a human immune system (HIS) in a xenogeneic recipient, and what remains to be done to improve their physiological relevance. Major conclusions To understand the role of genetic and environmental factors or evaluate immune-modifying therapies in humans, it is critical to develop and apply models in which human cells can be manipulated and their functions studied under conditions that recapitulate as closely as possible the physiological conditions of the human body. While microphysiological systems and living tissue slices provide some of these conditions, HIS mice enable more extensive analyses using in vivo systems.

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“…These differentially expressed circRNAs include circRNAs 000286 and 017277 whose downregulation reduces insulin biosynthesis and secretion and facilitates apoptosis of pancreatic β-cells ( 35 ), indicating that circRNAs may participate in proinflammatory cytokine-mediated β-cell dysfunction. Second, circRNAs may be associated with T1DM by influencing macrophages, which contribute to the loss of β-cells and subsequent development of hyperglycemia and are involved in the pathogenesis of T1DM ( 121 , 122 ). For example, hsa_circ_0060450, circPPM1F, and hsa_circ_0002202 are upregulated in peripheral blood mononuclear cells (PBMCs) from T1DM patients and sponge miR-199a-5p to inhibit the JAK-STAT signaling pathway induced by type I IFN (IFN-I) to further inhibit macrophage-mediated inflammation ( 36 ), regulate M1 macrophage activation via the circPPM1F−HuR−PPM1F−NF-κB axis ( 37 ), and mediate IFN-I-induced macrophage inflammation ( 38 ), respectively.…”

Section: Role Of Circrnas In T1dmmentioning

confidence: 99%

Circular RNAs in diabetes mellitus and its complications

et al. 2022

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Diabetes mellitus (DM) is an endocrine disorder characterized by a relative or absolute lack of insulin due to the dysfunction or destruction of β-cells. DM is one of the fastest growing challenges to global health in the 21st century and places a tremendous burden on affected individuals and their families and countries. Although insulin and antidiabetic drugs have been used to treat DM, a radical cure for the disease is unavailable. The pathogenesis of DM remains unclear. Emerging roles of circular RNAs (circRNAs) in DM have become a subject of global research. CircRNAs have been verified to participate in the onset and progression of DM, implying their potential roles as novel biomarkers and treatment tools. In the present review, we briefly introduce the characteristics of circRNAs. Next, we focus on specific roles of circRNAs in type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus and diabetes-associated complications.

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Islet-Resident Dendritic Cells and Macrophages in Type 1 Diabetes: In Search of Bigfoot’s Print

Cited by 22 publications

References 99 publications

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

From Disease and Patient Heterogeneity to Precision Medicine in Type 1 Diabetes

Modeling human T1D-associated autoimmune processes

Circular RNAs in diabetes mellitus and its complications

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