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Mauvais FX, van Endert PM. Type 1 Diabetes: A Guide to Autoimmune Mechanisms for Clinicians. Diabetes Obes Metab 2025. [PMID: 40375390 DOI: 10.1111/dom.16460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/18/2025]
Abstract
Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells by autoreactive T lymphocytes, leading to insulin deficiency and lifelong insulin dependence. It develops in genetically predisposed individuals, triggered by environmental or immunological factors. Although the exact causes of T1D remain unknown, the autoimmune pathogenesis of the disease is clearly indicated by the genetic risk conferred by allelic human leukocyte antigens (HLA), the almost obligatory presence of islet cell autoantibodies (AAbs) and immune cell infiltration of pancreatic islets from patients. At the same time, epidemiological data point to a role of environmental factors, notably enteroviral infections, in the disease, although precise causative links between specific pathogens and T1D have been difficult to establish. Studies of human pancreas organs from patients made available through repositories and the advent of high-dimensional high-throughput technologies for genomic and proteomic studies have significantly elucidated our understanding of the disease in recent years and provided mechanistic insights that can be exploited for innovative targeted therapeutic approaches. This short overview will summarise current salient knowledge on immune cell and beta cell dysfunction in T1D pathogenesis. PLAIN LANGUAGE SUMMARY: Type 1 diabetes (T1D) is a chronic disease where the body's own immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to a lack of insulin, a hormone essential for regulating blood sugar, which means people with T1D need insulin for life. The disease can develop at any age but is most diagnosed in children and young adults. Despite advances in treatment, T1D still significantly reduces life expectancy, especially in countries with fewer healthcare resources. T1D develops in people with a genetic predisposition, often triggered by environmental factors such as viral infections or changes in the gut microbiome. The disease progresses silently through three stages: Stage 1: Autoantibodies to beta cell components appear, signalling the immune system is reacting against the pancreas, but there are no symptoms; Stage 2: Beta cell function starts to decline, but fasting blood sugar is still normal; Stage 3: Enough beta cells are destroyed that fasting blood sugar rises, and symptoms of diabetes appear. The risk of progressing from stage 1 to full-blown diabetes is about 35-50% within five years, and even higher from stage 2. Over 60 genes are linked to T1D risk, most of which affect how the immune system works. The strongest genetic risk comes from specific versions of histocompatibility genes, which help the immune system distinguish between the body's own cells and invaders. Some types of these genes make it easier for the immune system to mistakenly attack beta cells. However, 90% of people diagnosed with T1D have no family member with T1D, showing that genetics is only part of the story. Environmental factors also play a big role. For example, certain viral infections, especially with viruses infecting the intestine, are associated with a higher risk of developing T1D. The gut microbiome - the community of bacteria living in our intestines - also influences risk, with healthier, more diverse microbiomes appearing to offer some protection. In T1D, immune cells - especially so-called T lymphocytes - mistake beta cells in the pancreas for threats and destroy them. This process is called autoimmunity. The attack is often reflected by the presence of autoantibodies against proteins found in beta cells. Over time, as more beta cells are lost, the body can no longer produce enough insulin, leading to the symptoms of diabetes. Interestingly, not all people with T1D have the same pattern of disease. For example, children diagnosed before age 7 often have more aggressive disease, more autoantibodies, and stronger genetic risk factors than those diagnosed later. Much of our understanding of T1D has come from studying animal models, but new technologies now allow researchers to study human pancreas tissue and blood immune cells in greater detail. Scientists are also exploring how the gut microbiome, diet, and environmental exposures contribute to T1D risk and progression. Treatment currently focuses on replacing insulin, but researchers are working on therapies that target the immune system or aim to protect or replace beta cells. Strategies include immunotherapy, gene therapy, and even modifying the gut microbiome. The goal is to prevent or reverse the disease, not just manage its symptoms. In summary, T1D is a complex autoimmune disease influenced by both genes and the environment. It progresses silently before symptoms appear, and while insulin therapy is life-saving, new research is paving the way for treatments that could one day halt or even prevent the disease.
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Affiliation(s)
- François-Xavier Mauvais
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France
- Service de Physiologie - Explorations Fonctionnelles Pédiatriques, AP-HP, Hôpital Universitaire Robert Debré, Paris, France
| | - Peter M van Endert
- Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France
- Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker - Enfants Malades, Paris, France
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2
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Vasilev G, Kokudeva M, Siliogka E, Padilla N, Shumnalieva R, Della-Morte D, Ricordi C, Mihova A, Infante M, Velikova T. T helper 17 cells and interleukin-17 immunity in type 1 diabetes: From pathophysiology to targeted immunotherapies. World J Diabetes 2025; 16:99936. [PMID: 40236846 PMCID: PMC11947927 DOI: 10.4239/wjd.v16.i4.99936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/06/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells, which ultimately results in insulinopenia, hyperglycemia and lifelong need for exogenous insulin therapy. In the pathophysiological landscape of T1D, T helper 17 cells (Th17 cells) and their hallmark cytokine, interleukin (IL)-17, play pivotal roles from disease onset to disease progression. In this narrative mini-review, we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D, providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction. Furthermore, we summarized the main animal and clinical studies that investigated Th17- and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
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Affiliation(s)
- Georgi Vasilev
- Clinic of Neurology and Department of Emergency Medicine, UMHAT "Sv. Georgi", Plovdiv 4000, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Maria Kokudeva
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria
| | - Elina Siliogka
- Faculty of Medicine, National and Kapodistrian University of Athens, Athens 11527, Attikí, Greece
| | - Nathalia Padilla
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Russka Shumnalieva
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Rheumatology, Clinic of Rheumatology, University Hospital "St. Anna", Medical University-Sofia, Sofia 1612, Bulgaria
| | - David Della-Morte
- Department of Biomedicine and Prevention, Section of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome 00133, Italy
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | | | - Marco Infante
- Section of Diabetes & Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Rome 00131, Italy
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Sherman S, Slama R, Bar D, Schonmann Y, Cohen AD, Taieb YH, Mimouni D, Peretz A, Duskin-Bitan H. Type 1 Diabetes/Hidradenitis Suppurativa Comorbidity-A Population-Based Study. J Clin Med 2025; 14:2625. [PMID: 40283457 PMCID: PMC12028064 DOI: 10.3390/jcm14082625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 04/03/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Type 1 diabetes (T1D) and hidradenitis suppurativa (HS) share several metabolic and inflammatory dysfunctions. Prior studies of the potential link between the diseases either lacked validated T1D diagnoses or established only an indirect association. This study sought to determine the odds of HS developing in patients with a validated diagnosis of T1D and to characterize the clinical features of HS/T1D comorbidity. Methods: A population-based nested case-control study was conducted including patients with HS and controls matched 5:1 for age, sex, and primary care clinic. T1D was diagnosed using a specialized algorithm, achieving 90% accuracy. Diagnostic validity was confirmed by diabetes specialists who manually reviewed a random subset of the files. Unadjusted and adjusted odds ratios (OR/aOR) were calculated to determine the odds of incident HS in patients with T1D. Results: The study included 10,919 patients with HS and 53,314 controls. A history of T1D was associated with an elevated odds of new-onset HS (OR 1.80 95% CI (1.30-2.40), p < 0.001), even after adjusting for demographics and metabolic and autoimmune comorbidities (aORs > 1.7, p < 0.001). Patients with HS/T1D comorbidity had higher proportions of autoimmune conditions than patients with HS alone (p < 0.001) and a higher mean Charlson Comorbidity Index score than both patients with HS alone (3.5 vs. 0.9, p < 0.001) and T1D alone (3.5 vs. 2.2, p = 0.004). Conclusions: T1D is associated with higher odds of the subsequent development of HS. Awareness of HS/T1D comorbidity is recommended owing to the elevated burden of metabolic and autoimmune conditions.
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Affiliation(s)
- Shany Sherman
- Division of Dermatology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 4941492, Israel; (Y.H.T.); (D.M.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
| | - Ron Slama
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
| | - Danielle Bar
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
| | - Yochai Schonmann
- Department of Family Medicine, Faculty of Medicine & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel;
- Department of Quality Measurements and Research, Clalit Health Services, Tel Aviv 6209804, Israel;
| | - Arnon D. Cohen
- Department of Quality Measurements and Research, Clalit Health Services, Tel Aviv 6209804, Israel;
- Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410501, Israel
| | - Yossef H. Taieb
- Division of Dermatology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 4941492, Israel; (Y.H.T.); (D.M.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
| | - Daniel Mimouni
- Division of Dermatology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 4941492, Israel; (Y.H.T.); (D.M.)
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
| | - Alon Peretz
- Division of Community Medical Services, Clalit Health Services, Tel Aviv 6209804, Israel;
| | - Hadar Duskin-Bitan
- Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; (R.S.); (D.B.); (H.D.-B.)
- Institute of Endocrinology, Rabin Medical Center, Beilinson Hospital, Petach Tikva 4941492, Israel
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Mohamed Abdelgawwad El-Sehrawy AA, Mohammed MH, Salahldin OD, Uthirapathy S, Ballal S, Kalia R, Arya R, Joshi KK, Kadim AS, Kadhim AJ. Crosstalk between microRNA and inflammation; critical regulator of diabetes. Exp Cell Res 2025; 447:114507. [PMID: 40058448 DOI: 10.1016/j.yexcr.2025.114507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
A growing body of evidence indicates that microRNAs (miRNAs may be used as biomarkers for the diagnosis, prognosis, and treatment of diabetes, given their changed expression profile as the disease progresses. There is growing interest in using individual miRNAs or whole miRNA clusters linked to diabetes as therapeutic targets because of their abnormal expression and functioning. In diabetes, miRNAs are also involved in inflammatory and immunological responses. Additionally, the inflammatory response controls the generation, processing, and stability of pre- or mature miRNAs and miRNA biogenesis. With a comprehensive grasp of molecular biological activities and the signaling axis, this review emphasizes the critical functions of miRNAs in inflammatory and immunological processes in diabetes. We further emphasized the potential role of these miRNAs in controlling inflammation associated with diabetes. This assessment will direct the shift from many studies to practical applications for tailored diabetes treatment and assist in identifying new therapeutic targets and approaches.
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Affiliation(s)
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Rishiv Kalia
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Renu Arya
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India.
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India; Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India.
| | - Arshed Shakir Kadim
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, Babylon, 51001, Iraq.
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq.
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Xu Q, Yang Y, Huang Q, Xie L, Feng Y, Yang L. Extracellular(Serum) Levels of Matrix Metalloproteinases in Pediatric Type 1 Diabetes Mellitus and Association with Diabetic Ketoacidosis and Cerebral Edema. Diabetes Metab Syndr Obes 2025; 18:819-830. [PMID: 40129484 PMCID: PMC11932032 DOI: 10.2147/dmso.s507337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/12/2025] [Indexed: 03/26/2025] Open
Abstract
Background Type 1 diabetes mellitus (T1DM) in children is associated with acute complications such as diabetic ketoacidosis (DKA) and the severe risk of diabetic ketoacidosis-related cerebral edema (DKACE). Matrix metalloproteinases (MMPs) are implicated in inflammation and tissue remodeling, potentially contributing to these complications. This study explores the role of MMPs as biomarkers in pediatric T1DM patients with DKA and DKACE. Methods We conducted a systematic cross-sectional study at Jiangxi Children's Hospital, enrolling 56 pediatric patients with T1DM, categorized into three groups: T1DM without complications, DKA, and DKACE. Serum levels of MMP-2, MMP-3, and MMP-9 were measured through ELISA. Statistical analyses assessed correlations between MMPs, glucose metabolism, and inflammatory markers, evaluating potential biomarker utility in disease characterization. Results MMP-3 and MMP-9 levels were significantly elevated in the DKACE group compared to the T1DM and DKA groups, exhibiting strong correlations with decreased pH and bicarbonate levels (both p < 0.001). MMP-2 levels were reduced in DKACE, correlating positively with pH and bicarbonate levels. Post-clinical improvement analyses demonstrated no significant differences in MMP levels between DKA and DKACE groups, suggesting stabilization post-treatment regardless of initial acidosis severity. Conclusion The distinct patterns of MMP-3 and MMP-9 elevations in DKACE highlight their potential as biomarkers for identifying and monitoring severe DKA complications. The findings suggest these enzymes play a significant role in cerebral edema pathophysiology, making them viable targets for future therapeutic interventions.
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Affiliation(s)
- Qingbo Xu
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
| | - Yu Yang
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
| | - Qiang Huang
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
- Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Liling Xie
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
| | - Yaqin Feng
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
| | - Li Yang
- Department of Endocrinology, Jiangxi Provincial Children’s Hospital, Nanchang, Jiangxi, 330038, People’s Republic of China
- The Affiliated Children’s Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330038, People’s Republic of China
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Milicic T, Jotic A, Lalic K, Lukic L, Macesic M, Stanarcic Gajovic J, Stoiljkovic M, Milovancevic M, Rafailovic D, Bozovic A, Lalic NM. Insulin Secretion and Insulin Sensitivity Change in Different Stages of Adult-Onset Type 1 Diabetes: A Cross-Sectional Study. J Clin Med 2025; 14:1109. [PMID: 40004639 PMCID: PMC11856604 DOI: 10.3390/jcm14041109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/01/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Previous studies reported impairments in insulin secretion during different stages of type 1 diabetes (T1D), while data regarding insulin sensitivity and immunological changes are still controversial. We analyzed the following: (a) insulin secretion, (b) insulin sensitivity, and (c) pro-inflammatory interleukin-17 (IL-17) levels in peripheral blood in 17 healthy first-degree relatives in stage 1 (FDRs1) (GAD+, IA2+), 34 FDRs in stage 0 (FDRs0) (GAD-, IA2A-), 24 recent-onset T1D (R-T1D) patients in the insulin-requiring state (IRS), 10 in clinical remission (CR), and 18 healthy unrelated controls (HC). Methods: Insulin secretion was evaluated by an IVGTT and a glucagon stimulation test, expressed as a first-phase insulin response (FPIR) and a basal/stimulated C-peptide. Insulin sensitivity was tested by the euglycemic hyperinsulinemic clamp, expressed as an M value. Results: FDRs1 had a lower FPIR than FDRs0 (p < 0.05) and HC (p < 0.001) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01). Moreover, FDRs1 had lower basal/stimulated C-peptide than FDRs0 (p < 0.01/p < 0.05) and HC (p < 0.001/p = 0.001) but higher levels than RT1D-IRS (p < 0.001/p < 0.001). However, the M value was similar among FDRs1, FDRs0, and HC (p = 1.0) but higher than RT1D-IRS (p < 0.001) and RT1D-CR (p < 0.01), while RT1D-IRS and RT1D-CR had lower M than HC (p < 0.001; p < 0.001; respectively). FDRs1 had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.05). RT1D-IRS had higher IL-17 than FDRs0 (p < 0.001) and HC (p < 0.001), which was similar to RT1D-CR vs. FDRs0 (p < 0.001) and HC (p < 0.05). Conclusions: Early changes in pre-T1D might involve an initial decline of insulin secretion associated with a pro-inflammatory attack, which does not influence insulin sensitivity, whereas later, insulin sensitivity deterioration seems to be associated with the prominent reduction in insulin secretion.
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Affiliation(s)
- Tanja Milicic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Aleksandra Jotic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Katarina Lalic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Ljiljana Lukic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Marija Macesic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Jelena Stanarcic Gajovic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Milica Stoiljkovic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
| | - Mina Milovancevic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
| | - Djurdja Rafailovic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
| | - Aleksandra Bozovic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
| | - Nebojsa M. Lalic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Doktora Subotica 13, 11000 Belgrade, Serbia; (A.J.); (K.L.); (L.L.); (M.M.); (J.S.G.); (M.S.); (M.M.); (D.R.); (A.B.); (N.M.L.)
- Faculty of Medicine, University of Belgrade, Doktora Subotica 8, 11000 Belgrade, Serbia
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Jeun R. Immunotherapies for prevention and treatment of type 1 diabetes. Immunotherapy 2025; 17:201-210. [PMID: 40033931 PMCID: PMC11951698 DOI: 10.1080/1750743x.2025.2473311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/25/2025] [Indexed: 03/05/2025] Open
Abstract
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β-cells of the pancreatic islets necessitating lifelong insulin therapy. Despite significant advancements in diabetes technology with increasingly sophisticated methods of insulin delivery and glucose monitoring, people with T1D remain at risk of severe complications like hypoglycemia and diabetic ketoacidosis. There has long been an interest in altering the immune response in T1D to prevent or cure T1D across its various stages with limited efficacy. This review highlights immunomodulatory approaches over the years including the anti-CD3 monoclonal antibody teplizumab which is now approved to delay onset of T1DM and other interventions under current investigation.
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Affiliation(s)
- Rebecca Jeun
- Division of Endocrinology, Diabetes & Metabolism, University of Louisville, Louisville, KY, USA
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8
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Li H, Zou L, Long Z, Zhan J. Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets. Front Immunol 2025; 15:1537909. [PMID: 39877357 PMCID: PMC11772204 DOI: 10.3389/fimmu.2024.1537909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Background Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined. Methods Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets. Results In patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways. Conclusion This study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.
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Affiliation(s)
- Huahua Li
- Department of Geriatric, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Lingling Zou
- Department of Geriatric, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Zhaowei Long
- Department of Geriatric, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Junkun Zhan
- Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Aging and Age-related Disease Research, Central South University, Changsha, China
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9
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Liu YC, Liao YT, Lin KH. The relationship between schizophrenia or schizoaffective disorder and type 1 diabetes mellitus: a scoping review of observational studies. NEUROPSYCHIATRIE : KLINIK, DIAGNOSTIK, THERAPIE UND REHABILITATION : ORGAN DER GESELLSCHAFT OSTERREICHISCHER NERVENARZTE UND PSYCHIATER 2024; 38:163-173. [PMID: 38833151 DOI: 10.1007/s40211-024-00499-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 05/11/2024] [Indexed: 06/06/2024]
Abstract
OBJECTIVE Both schizophrenia and type 1 diabetes mellitus (T1D) are known as immune-related disorders. We systematically reviewed observational studies to explore the relationship between schizophrenia or schizoaffective disorder and T1D. METHODS A preliminary search of articles was completed using the following databases: Airiti Library, CINAHL Complete (via EBSCOhost), OVID MEDLINE, Embase, and PubMed. Two researchers independently assessed each study's quality based on Joanna Briggs Institute (JBI). A narrative review summarized the potential relationship between the two diseases. RESULTS Eleven studies were included in the final analysis. Six observational studies investigated the risk of schizophrenia and schizoaffective disorder in patients with T1D. Two studies showed negative correlations, one showed no correlation, and three showed positive correlations. On the other hand, five studies reported the prevalence of T1D in patients with schizophrenia. Two of them showed positive associations, and three others showed no association. Although the majority of the included studies suggested a positive association between the two medical conditions, these studies were still too heterogeneous to draw consistent results. CONCLUSION We found conflicting results regarding the bidirectional relationship between schizophrenia or schizoaffective disorder and T1D. These may stem from differences in study design, sampling methods, or definition of diagnoses, which are essential aspects to consider in future research.
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Affiliation(s)
- Yi-Chun Liu
- Department of Psychiatry, Changhua Christian Children's Hospital, 500, Changhua, Taiwan
- Department of Psychiatry, Changhua Christian Hospital, 500, Changhua, Taiwan
- Department of Healthcare Administration, Asia University, 413, Taichung, Taiwan
- Department of Eldercare, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Yin-To Liao
- Department of Psychiatry, China Medical University and China Medical University Hospital, 413, Taichung, Taiwan
| | - Kuan-Han Lin
- Department of Healthcare Administration, Asia University, 413, Taichung, Taiwan.
- Asia University, No.500, Lioufeng Road, 41354, Taichung City, Wufeng District, Taiwan.
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10
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Nematisouldaragh D, Nguyen H, Rabinovich-Nikitin I. Agonists, inverse agonists, and antagonists as therapeutic approaches to manipulate retinoic acid-related orphan receptors. Can J Physiol Pharmacol 2024; 102:620-633. [PMID: 38728749 DOI: 10.1139/cjpp-2024-0099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2024]
Abstract
Retinoic acid-related orphan receptors (RORs) serve as transcription factors that play a pivotal role in a myriad of physiological processes within the body. Their involvement extends to critical biological processes that confer protective effects in the heart, immune system, and nervous system, as well as contributing to the mitigation of several aggressive cancer types. These protective functions are attributed to ROR's regulation of key proteins and the management of various cellular processes, including autophagy, mitophagy, inflammation, oxidative stress, and glucose metabolism, highlighting the emerging need for pharmacological approaches to modulate ROR expression. Thus, the modulation of RORs is a rapidly growing area of research aimed not only at comprehending these receptors, but also at manipulating them to attain the desired physiological response. Despite the presence of natural ROR ligands, the development of synthetic agonists with high selectivity for these receptors holds substantial therapeutic potential. The exploration and advancement of such compounds can effectively target diseases associated with ROR dysregulation, thereby providing avenues for therapeutic interventions. Herein, we provide a comprehensive examination of the multifaceted role of ROR in diverse physiological and pathophysiological conditions, accompanied by an in-depth exploration of a spectrum of ROR agonists, inverse agonists, and antagonists.
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Affiliation(s)
- Darya Nematisouldaragh
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Huong Nguyen
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
| | - Inna Rabinovich-Nikitin
- Department of Physiology and Pathophysiology, Rady College of Medicine, Max Rady Faculty of Health Sciences, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, Canada
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11
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Lee H, Kim MJ, Lee IK, Hong CW, Jeon JH. Impact of hyperglycemia on immune cell function: a comprehensive review. Diabetol Int 2024; 15:745-760. [PMID: 39469566 PMCID: PMC11512986 DOI: 10.1007/s13340-024-00741-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/10/2024] [Indexed: 10/30/2024]
Abstract
Hyperglycemia, a hallmark of diabetes and various metabolic disorders, has profound implications for immune cell function. The relationship between elevated blood glucose levels and immune cell function is a topic of significant medical interest. In this review, we aim to comprehensively review effects of hyperglycemia on various immune cell types and its clinical implications, particularly T cells, macrophages, natural killer cells, and neutrophils. It aims to consolidate current knowledge on the subject, with a focus on both type 1 and type 2 diabetes, as well as other pathological states where hyperglycemia is a concern. A comprehensive examination of recent studies and clinical data was conducted to assess effects of hyperglycemia on immune cell function. Evidence indicates that hyperglycemia can significantly alter immune cell function, with different diabetic conditions showing varied responses. Roles of key metabolic hormones in regulating T cell function highlight potential therapeutic targets for restoring immune balance. In addition, reprogramming of innate immune cells such as macrophages and natural killer cells under hyperglycemic conditions suggests a complex metabolic-immunological interface. This review will contribute to a better understanding of the link between diabetes, other metabolic disorders, and immune function. By examining recent research and clinical findings, this review will enhance our comprehension of the mechanisms at play and guide future medical strategies for managing and treating conditions associated with hyperglycemia.
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Affiliation(s)
- Hoyul Lee
- Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea
| | - Min-Ji Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-Ro, Buk-Gu, Daegu, 41404 Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Chang-Won Hong
- Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hoguk-Ro, Buk-Gu, Daegu, 41404 Republic of Korea
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12
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Tatovic D, Marwaha A, Taylor P, Hanna SJ, Carter K, Cheung WY, Luzio S, Dunseath G, Hutchings HA, Holland G, Hiles S, Fegan G, Williams E, Yang JHM, Domingo-Vila C, Pollock E, Wadud M, Ward-Hartstonge K, Marques-Jones S, Bowen-Morris J, Stenson R, Levings MK, Gregory JW, Tree TIM, Dayan C. Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial. Nat Med 2024; 30:2657-2666. [PMID: 39079992 PMCID: PMC11405276 DOI: 10.1038/s41591-024-03115-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/05/2024] [Indexed: 09/18/2024]
Abstract
Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12-18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte-macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).
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Affiliation(s)
- Danijela Tatovic
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
| | | | - Peter Taylor
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Stephanie J Hanna
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Kym Carter
- Diabetes Research Unit Cymru, Institute for Life Sciences, Swansea University, Swansea, UK
| | - W Y Cheung
- Diabetes Research Unit Cymru, Institute for Life Sciences, Swansea University, Swansea, UK
| | - Steve Luzio
- Diabetes Research Unit Cymru, Institute for Life Sciences, Swansea University, Swansea, UK
| | - Gareth Dunseath
- Diabetes Research Unit Cymru, Institute for Life Sciences, Swansea University, Swansea, UK
| | | | - Gail Holland
- Swansea Trials Unit, Swansea University Medical School, Swansea, UK
| | - Steve Hiles
- Swansea Trials Unit, Swansea University Medical School, Swansea, UK
| | - Greg Fegan
- Swansea Trials Unit, Swansea University Medical School, Swansea, UK
| | - Evangelia Williams
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Jennie H M Yang
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Clara Domingo-Vila
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Emily Pollock
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Muntaha Wadud
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Kirsten Ward-Hartstonge
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Jane Bowen-Morris
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Rachel Stenson
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Megan K Levings
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - John W Gregory
- Division of Population Medicine, Cardiff University School of Medicine, Cardiff, UK
| | - Timothy I M Tree
- Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, Guy's Hospital, London, UK
| | - Colin Dayan
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
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13
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Chakraborty R, Mukherjee AK, Bala A. Breakthroughs in road mapping IL-35 mediated immunotherapy for type-1 and autoimmune diabetes mellitus. Cytokine 2024; 181:156692. [PMID: 38986251 DOI: 10.1016/j.cyto.2024.156692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/22/2024] [Accepted: 07/05/2024] [Indexed: 07/12/2024]
Abstract
IL-35 is a recently discovered protein made up of IL-12α and IL-27β chains. It is encoded by IL12A and EBI3 genes. Interest in researching IL-35 has significantly increased in recent years, as evidenced by numerous scientific publications. Diabetes is on the rise globally, causing more illness and death in developing countries. The International Diabetes Federation (IDF) reports that diabetes is increasingly affecting children and teenagers, with varying rates across different regions. Therefore, scientists seek new diabetes treatments despite the growth of drug research. Recent research aims to emphasize IL-35 as a critical regulator of diabetes, especially type 1 and autoimmune diabetes. This review provides an overview of recent research on IL-35 and its link to diabetes and its associated complications. Studies suggest that IL-35 can offer protection against type-1 diabetes and autoimmune diabetes by regulating macrophage polarization, T-cell-related cytokines, and regulatory B cells (Bregs). This review will hopefully assist biomedical scientists in exploring the potential role of IL-35-mediated immunotherapy in treating diabetes. However, further research is necessary to determine the exact mechanism and plan clinical trials.
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Affiliation(s)
- Ratul Chakraborty
- Pharmacology and Drug Discovery Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati 781035, Assam, India; Academy of Scientific and Innovative Research (AcSIR), AcSIR (an Indian Institute of National Importance), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002, India
| | - Ashis K Mukherjee
- Microbial Biotechnology and Protein Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati 781035, Assam, India
| | - Asis Bala
- Pharmacology and Drug Discovery Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati 781035, Assam, India; Academy of Scientific and Innovative Research (AcSIR), AcSIR (an Indian Institute of National Importance), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201002, India.
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14
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Luo Y, Zhu J, Hu Z, Luo W, Du X, Hu H, Peng S. Progress in the Pathogenesis of Diabetic Encephalopathy: The Key Role of Neuroinflammation. Diabetes Metab Res Rev 2024; 40:e3841. [PMID: 39295168 DOI: 10.1002/dmrr.3841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/29/2024] [Accepted: 06/27/2024] [Indexed: 09/21/2024]
Abstract
Diabetic encephalopathy (DE) is a severe complication that occurs in the central nervous system (CNS) and leads to cognitive impairment. DE involves various pathophysiological processes, and its pathogenesis is still unclear. This review summarised current research on the pathogenesis of diabetic encephalopathy, which involves neuroinflammation, oxidative stress, iron homoeostasis, blood-brain barrier disruption, altered gut microbiota, insulin resistance, etc. Among these pathological mechanisms, neuroinflammation has been focused on. This paper summarises some of the molecular mechanisms involved in neuroinflammation, including the Mammalian Target of Rapamycin (mTOR), Lipocalin-2 (LCN-2), Pyroptosis, Advanced Glycosylation End Products (AGEs), and some common pro-inflammatory factors. In addition, we discuss recent advances in the study of potential therapeutic targets for the treatment of DE against neuroinflammation. The current research on the pathogenesis of DE is progressing slowly, and more research is needed in the future. Further study of neuroinflammation as a mechanism is conducive to the discovery of more effective treatments for DE in the future.
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Affiliation(s)
- Yifan Luo
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Clinical Medicine, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Jinxi Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Clinical Medicine, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Ziyan Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Department of Clinical Medicine, The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Wei Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaohong Du
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Haijun Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shengliang Peng
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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15
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Zaongo SD, Zongo AW, Chen Y. Mechanisms underlying the development of type 1 diabetes in ART-treated people living with HIV: an enigmatic puzzle. Front Immunol 2024; 15:1470308. [PMID: 39257582 PMCID: PMC11383789 DOI: 10.3389/fimmu.2024.1470308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 08/12/2024] [Indexed: 09/12/2024] Open
Abstract
The immunopathogenesis of HIV infection remains poorly understood. Despite the widespread use of effective modern antiretroviral therapy (ART), people living with HIV (PLWH) are known to develop several comorbidities, including type 1 diabetes (T1DM). However, the etiology and critical mechanisms accounting for the onset of T1DM in the preceding context remain unknown. This article proposes to address this topic in order to provide further understanding and future research directions.
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Affiliation(s)
- Silvere D Zaongo
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
| | - Abel W Zongo
- College of Food Science and Technology, Zhejiang University of Technology, Hangzhou, China
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
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16
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Herold KC, Delong T, Perdigoto AL, Biru N, Brusko TM, Walker LSK. The immunology of type 1 diabetes. Nat Rev Immunol 2024; 24:435-451. [PMID: 38308004 PMCID: PMC7616056 DOI: 10.1038/s41577-023-00985-4] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2023] [Indexed: 02/04/2024]
Abstract
Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.
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Affiliation(s)
- Kevan C Herold
- Department of Immunobiology, Yale University, New Haven, CT, USA.
- Department of Internal Medicine, Yale University, New Haven, CT, USA.
| | - Thomas Delong
- Anschutz Medical Campus, University of Colorado, Denver, CO, USA
| | - Ana Luisa Perdigoto
- Department of Internal Medicine, Yale University, New Haven, CT, USA
- Internal Medicine, VA Connecticut Healthcare System, West Haven, CT, USA
| | - Noah Biru
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Lucy S K Walker
- Institute of Immunity & Transplantation, University College London, London, UK.
- Division of Infection & Immunity, University College London, London, UK.
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Kaur N, Singh J, Minz RW, Anand S, Saikia B, Bhadada SK, Dayal D, Kumar M, Dhanda SK. Shared and distinct genetics of pure type 1 diabetes and type 1 diabetes with celiac disease, homology in their auto-antigens and immune dysregulation states: a study from North India. Acta Diabetol 2024; 61:791-805. [PMID: 38483572 DOI: 10.1007/s00592-024-02258-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 02/11/2024] [Indexed: 05/18/2024]
Abstract
AIM This study was undertaken to explicate the shared and distinctive genetic susceptibility and immune dysfunction in patients with T1D alone and T1D with CD (T1D + CD). METHODS A total of 100 T1D, 50 T1D + CD and 150 healthy controls were recruited. HLA-DRB1/DQB1 alleles were determined by PCR-sequence-specific primer method, SNP genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP-array and genotyping for INS-23 Hph1 A/T was done by RFLP. Autoantibodies and cytokine estimation was done by ELISA. Immune-regulation was analysed by flow-cytometry. Clustering of autoantigen epitopes was done by epitope cluster analytical tool. RESULTS Both T1D alone and T1D + CD had a shared association of DRB1*03:01, DRB1*04, DRB3*01:07/15 and DQB1*02. DRB3*01:07/15 confers the highest risk for T1D with relative risk of 11.32 (5.74-22.31). Non-HLA gene polymorphisms PTPN22 and INS could discriminate between T1D and T1D + CD. T1D + CD have significantly higher titers of autoantibodies, expression of costimulatory molecules on CD4 and CD8 cells, and cytokine IL-17A and TGF-β1 levels compared to T1D patients. Epitopes from immunodominant regions of autoantigens of T1D and CD clustered together with 40% homology. CONCLUSION Same HLA genes provide susceptibility for both T1D and CD. Non-HLA genes CTLA4, PTPN22 and INS provide further susceptibility while different polymorphisms in PTPN22 and INS can discriminate between T1D and T1D + CD. Epitope homology between autoantigens of two diseases further encourages the two diseases to occur together. The T1D + CD being more common in females along with co-existence of thyroid autoimmunity, and have more immune dysregulated state than T1D alone.
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Affiliation(s)
- Navchetan Kaur
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Jagdeep Singh
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ranjana W Minz
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Shashi Anand
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Biman Saikia
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Sanjay K Bhadada
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Devi Dayal
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Manoj Kumar
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Sandeep K Dhanda
- Division of Vaccine Discovery, La Jolla Institute of Allergy and Immunology, San Diego, CA, USA
- Now at Department of Oncology, Saint Jude Children's Research Hospital, Memphis, TN, USA
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18
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Starskaia I, Valta M, Pietilä S, Suomi T, Pahkuri S, Kalim UU, Rasool O, Rydgren E, Hyöty H, Knip M, Veijola R, Ilonen J, Toppari J, Lempainen J, Elo LL, Lahesmaa R. Distinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies. Nat Commun 2024; 15:3810. [PMID: 38714671 PMCID: PMC11076468 DOI: 10.1038/s41467-024-47918-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 04/12/2024] [Indexed: 05/10/2024] Open
Abstract
Previous studies have revealed heterogeneity in the progression to clinical type 1 diabetes in children who develop islet-specific antibodies either to insulin (IAA) or glutamic acid decarboxylase (GADA) as the first autoantibodies. Here, we test the hypothesis that children who later develop clinical disease have different early immune responses, depending on the type of the first autoantibody to appear (GADA-first or IAA-first). We use mass cytometry for deep immune profiling of peripheral blood mononuclear cell samples longitudinally collected from children who later progressed to clinical disease (IAA-first, GADA-first, ≥2 autoantibodies first groups) and matched for age, sex, and HLA controls who did not, as part of the Type 1 Diabetes Prediction and Prevention study. We identify differences in immune cell composition of children who later develop disease depending on the type of autoantibodies that appear first. Notably, we observe an increase in CD161 expression in natural killer cells of children with ≥2 autoantibodies and validate this in an independent cohort. The results highlight the importance of endotype-specific analyses and are likely to contribute to our understanding of pathogenic mechanisms underlying type 1 diabetes development.
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Grants
- 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B, 3-SRA-2020-955-S-B JDRF
- BMH4-CT98-3314 European Commission (EC)
- Academy of Finland (292538, 292335, 294337, 319280, 31444, 319280, 329277, 331790, 310561, 314443, 329278, 335434, 335611 and 341342), Novo Nordisk Foundation, Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017 [Decision No 250114]; Special Research Funds for University Hospitals in Finland; Diabetes Research Foundation, Finland; European Foundation for the Study of Diabetes; Päivikki and Sakari Sohlberg Foundation; Pediatric Research Foundation. Business Finland, the Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, the Finnish Cancer Foundation, InFLAMES Flagship Programme of the Academy of Finland, Diabetes Wellness Suomi, the Finnish cultural foundation. the European Research Council ERC (677943), the Finnish Medical Foundation, the Finnish Pediatric Research Foundation and the Hospital Districht of South-West Finland.
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Affiliation(s)
- Inna Starskaia
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
| | - Milla Valta
- Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Sami Pietilä
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Tomi Suomi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Sirpa Pahkuri
- Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Ubaid Ullah Kalim
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Omid Rasool
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Emilie Rydgren
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, and Fimlab Laboratories, Tampere, Finland
| | - Mikael Knip
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Riitta Veijola
- Department of Pediatrics, Research Unit of Clinical Medicine, Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Jorma Toppari
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
- Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland
| | - Johanna Lempainen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.
- Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
- Clinical Microbiology, Turku University Hospital, Turku, Finland.
| | - Laura L Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
- Institute of Biomedicine, University of Turku, Turku, Finland.
| | - Riitta Lahesmaa
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
- Institute of Biomedicine, University of Turku, Turku, Finland.
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Obeagu EI, Obeagu GU. Type 1 diabetes mellitus: Roles of neutrophils in the pathogenesis. Medicine (Baltimore) 2023; 102:e36245. [PMID: 38115297 PMCID: PMC10727583 DOI: 10.1097/md.0000000000036245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 12/21/2023] Open
Abstract
Circulating neutrophil counts are reduced both in healthy autoantibody-positive individuals and in patients with type 1 diabetes, which may be related on cell-specific autoimmunity. This paper was written to give an update on roles of neutrophils in the pathogenesis of type 1 diabetes mellitus. Different research search engines like PubMed Central, Scopus, Web of Science, Researchgate, Google Scholar etc were utilised for writing this paper. A drop in blood neutrophil counts in type 1 diabetes may be caused by decreased neutrophil generation and maturation, tissue maintenance, consumption, or peripheral damage. Neutrophil count variations between studies may be explained by results from various stages of diabetes or by ethnic groups. Neutrophils can induce type 1 diabetes by colonizing pancreatic islets and interacting with other immune cells, according to exciting findings that shed new light on their role in the pathogenesis of the disease. Knowing more about the function of neutrophils in the pathogenesis of type 1 diabetes will help in early diagnosis, treatment, and even prevention of the disease.
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Liu YC, Liao YT, Chen VCH, Chen YL. Association Between Maternal Mood Disorders and Schizophrenia and the Risk of Type 1 Diabetes in Offspring: A Nationwide Cohort Study. Neuropsychiatr Dis Treat 2023; 19:2511-2518. [PMID: 38029045 PMCID: PMC10674753 DOI: 10.2147/ndt.s437430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 11/16/2023] [Indexed: 12/01/2023] Open
Abstract
Objective Our study aimed to determine whether mothers with bipolar disorder, major depressive disorder, schizophrenia, or schizoaffective disorder affected the risk of type 1 diabetes (T1D) in their offspring. Methods We conducted a nationwide cohort study by using data from Taiwan's National Health Insurance Research Database and the Maternal and Child Health Database from 2004 to 2018. A total of 2,556,640 mother-child pairs were identified. Cox proportional hazards models were used to compare the risk of T1D between children born to mothers with mood disorders and schizophrenia and those without. Results No significant difference in risk of T1D was observed between the offspring of mothers with major psychiatric disorders and those without (adjusted hazard ratio (aHR) of 0.86 with a 95% confidence interval (CI) of 0.58-1.24). In subgroup analysis, we found an aHR of 1.81 with a 95% CI of 0.83-3.82 in the maternal bipolar disorder on the risk of T1D in offspring and an aHR of 0.87 (95% CI: 0.59-1.25) in maternal major depressive disorder. In the schizophrenia/schizoaffective disorder group, aHR cannot be obtained due to lesser than three events in the analysis. Conclusion The risk of T1D in offspring of mothers with mood disorders and schizophrenia was not significant. However, children born to mothers with bipolar disorder may have a tendency to develop T1D. The relationship between maternal psychiatric disorders and the risk of T1D in offspring warrants further investigation in studies with longer follow-up periods.
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Affiliation(s)
- Yi-Chun Liu
- Department of Psychiatry, Changhua Christian Children’s Hospital, Changhua, 500, Taiwan
- Department of Psychiatry, Changhua Christian Hospital, Changhua, 500, Taiwan
- Department of Healthcare Administration, Asia University, Taichung, 413, Taiwan
- Department of Eldercare, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Yin-To Liao
- Department of Psychiatry, China Medical University Hospital, Taichung, 404, Taiwan
- China Medical University, Taichung, 406, Taiwan
| | - Vincent Chin-Hung Chen
- School of Medicine, Chang Gung University, Taoyuan, 333, Taiwan
- Department of Psychiatry, Chiayi Chang Gung Memorial Hospital, Chiayi, 613, Taiwan
| | - Yi-Lung Chen
- Department of Healthcare Administration, Asia University, Taichung, 413, Taiwan
- Department of Psychology, Asia University, Taichung, 413, Taiwan
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21
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Riaz F, Wei P, Pan F. PPARs at the crossroads of T cell differentiation and type 1 diabetes. Front Immunol 2023; 14:1292238. [PMID: 37928539 PMCID: PMC10623333 DOI: 10.3389/fimmu.2023.1292238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023] Open
Abstract
T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Ping Wei
- Department of Otolaryngology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
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22
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Shaukat A, Zaidi A, Anwar H, Kizilbash N. Mechanism of the antidiabetic action of Nigella sativa and Thymoquinone: a review. Front Nutr 2023; 10:1126272. [PMID: 37818339 PMCID: PMC10561288 DOI: 10.3389/fnut.2023.1126272] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 07/27/2023] [Indexed: 10/12/2023] Open
Abstract
Introduction Long used in traditional medicine, Nigella sativa (NS; Ranunculaceae) has shown significant efficacy as an adjuvant therapy for diabetes mellitus (DM) management by improving glucose tolerance, decreasing hepatic gluconeogenesis, normalizing blood sugar and lipid imbalance, and stimulating insulin secretion from pancreatic cells. In this review, the pharmacological and pharmacokinetic properties of NS as a herbal diabetes medication are examined in depth, demonstrating how it counteracts oxidative stress and the onset and progression of DM. Methods This literature review drew on databases such as Google Scholar and PubMed and various gray literature sources using search terms like the etiology of diabetes, conventional versus herbal therapy, subclinical pharmacology, pharmacokinetics, physiology, behavior, and clinical outcomes. Results The efficiency and safety of NS in diabetes, notably its thymoquinone (TQ) rich volatile oil, have drawn great attention from researchers in recent years; the specific therapeutic dose has eluded determination so far. TQ has anti-diabetic, anti-inflammatory, antioxidant, and immunomodulatory properties but has not proved druggable. DM's intimate link with oxidative stress, makes NS therapy relevant since it is a potent antioxidant that energizes the cell's endogenous arsenal of antioxidant enzymes. NS attenuates insulin resistance, enhances insulin signaling, suppresses cyclooxygenase-2, upregulates insulin-like growth factor-1, and prevents endothelial dysfunction in DM. Conclusion The interaction of NS with mainstream drugs, gut microbiota, and probiotics opens new possibilities for innovative therapies. Despite its strong potential to treat DM, NS and TQ must be examined in more inclusive clinical studies targeting underrepresented patient populations.
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Affiliation(s)
- Arslan Shaukat
- Department of Physiology, Government College University - GCU, Faisalabad, Punjab, Pakistan
| | - Arsalan Zaidi
- National Probiotic Laboratory, National Institute for Biotechnology and Genetic Engineering College - NIBGE-C, Faisalabad, Punjab, Pakistan
- Pakistan Institute of Engineering and Applied Sciences - PIEAS, Nilore, Islamabad, Pakistan
| | - Haseeb Anwar
- Department of Physiology, Government College University - GCU, Faisalabad, Punjab, Pakistan
| | - Nadeem Kizilbash
- Department Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
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23
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Harrison LC, Bandala‐Sanchez E, Oakey H, Colman PG, Watson K, Kim KW, Wu R, Hamilton‐Williams EE, Stone NL, Haynes A, Thomson RL, Vuillermin PJ, Soldatos G, Rawlinson WD, McGorm KJ, Morahan G, Barry SC, Sinnott RO, Wentworth JM, Couper JJ, Penno MAS. A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes. J Diabetes Investig 2023; 14:1092-1100. [PMID: 37312283 PMCID: PMC10445231 DOI: 10.1111/jdi.14031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/28/2023] [Accepted: 05/07/2023] [Indexed: 06/15/2023] Open
Abstract
AIMS/INTRODUCTION Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.
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Affiliation(s)
- Leonard C Harrison
- Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
| | - Esther Bandala‐Sanchez
- Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
| | - Helena Oakey
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Peter G Colman
- Department of Diabetes and EndocrinologyRoyal Melbourne HospitalMelbourneVictoriaAustralia
| | - Kelly Watson
- Department of Diabetes and EndocrinologyRoyal Melbourne HospitalMelbourneVictoriaAustralia
| | - Ki Wook Kim
- Virology Research Laboratory, Serology and Virology DivisionNSW Health, Prince of Wales HospitalSydneyNew South WalesAustralia
- Schools of Biomedical Sciences and Biotechnology and Biomolecular Sciences, Faculty of MedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Roy Wu
- Virology Research Laboratory, Serology and Virology DivisionNSW Health, Prince of Wales HospitalSydneyNew South WalesAustralia
- Schools of Biomedical Sciences and Biotechnology and Biomolecular Sciences, Faculty of MedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | | | - Natalie L Stone
- Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
| | - Aveni Haynes
- Telethon Kids Institute for Child Health Research, Centre for Child Health Researchthe University of Western AustraliaPerthWestern AustraliaAustralia
| | - Rebecca L Thomson
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Peter J Vuillermin
- Faculty of School of MedicineDeakin UniversityGeelongVictoriaAustralia
- Child Health Research UnitBarwon HealthGeelongVictoriaAustralia
| | - Georgia Soldatos
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive MedicineMonash UniversityMelbourneVictoriaAustralia
- Diabetes and Vascular Medicine UnitMonash HealthMelbourneVictoriaAustralia
| | - William D Rawlinson
- Virology Research Laboratory, Serology and Virology DivisionNSW Health, Prince of Wales HospitalSydneyNew South WalesAustralia
- Schools of Biomedical Sciences and Biotechnology and Biomolecular Sciences, Faculty of MedicineUniversity of New South WalesSydneyNew South WalesAustralia
| | - Kelly J McGorm
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Grant Morahan
- Centre for Diabetes Research, Harry Perkins Institute of Medical ResearchThe University of Western AustraliaPerthWestern AustraliaAustralia
| | - Simon C Barry
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Richard O Sinnott
- Melbourne eResearch Group, School of Computing and Information ServicesUniversity of MelbourneMelbourneVictoriaAustralia
| | - John M Wentworth
- Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- Department of Diabetes and EndocrinologyRoyal Melbourne HospitalMelbourneVictoriaAustralia
| | - Jennifer J Couper
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
- Women's and Children's HospitalNorth AdelaideSouth AustraliaAustralia
| | - Megan AS Penno
- Robinson Research Institute and Adelaide Medical SchoolUniversity of AdelaideAdelaideSouth AustraliaAustralia
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Chen Z, Qiao S, Yang L, Sun M, Li B, Lu A, Li F. Mechanistic Insights into the Roles of the IL-17/IL-17R Families in Pancreatic Cancer. Int J Mol Sci 2023; 24:13539. [PMID: 37686343 PMCID: PMC10487659 DOI: 10.3390/ijms241713539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/17/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
The members of the cytokine interleukin 17 (IL-17) family, along with their receptors (IL-17R), are vital players in a range of inflammatory diseases and cancer. Although generally regarded as proinflammatory, the effects they exhibit on cancer progression are a double-edged sword, with both antitumor and protumor activities being discovered. There is growing evidence that the IL-17 signaling pathways have significant impacts on the tumor microenvironment (TME), immune response, and inflammation in various types of cancer, including pancreatic cancer. However, the detailed mechanistic functions of the IL-17/IL-17R families in pancreatic cancer were rarely systematically elucidated. This review considers the role of the IL-17/IL-17R families in inflammation and tumor immunity and elaborates on the mechanistic functions and correlations of these members with pathogenesis, progression, and chemoresistance in pancreatic cancer. By summarizing the advanced findings on the role of IL-17/IL17R family members and IL-17 signaling pathways at the molecular level, cellular level, and disease level in pancreatic cancer, this review provides an in-depth discussion on the potential of IL-17/IL-17R as prognostic markers and therapeutic targets in pancreatic cancer.
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Affiliation(s)
- Zheng Chen
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Shuangying Qiao
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Liu Yang
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Meiheng Sun
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Boyue Li
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Aiping Lu
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Fangfei Li
- Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China; (Z.C.); (S.Q.); (L.Y.); (M.S.); (B.L.)
- Institute of Precision Medicine and Innovative Drug Discovery (PMID), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
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25
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Martín-Vázquez E, Cobo-Vuilleumier N, López-Noriega L, Lorenzo PI, Gauthier BR. The PTGS2/COX2-PGE 2 signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus. Int J Biol Sci 2023; 19:4157-4165. [PMID: 37705740 PMCID: PMC10496497 DOI: 10.7150/ijbs.86492] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/24/2023] [Indexed: 09/15/2023] Open
Abstract
Prostaglandins are lipid mediators involved in physiological processes, such as constriction or dilation of blood vessels, but also pathophysiological processes, which include inflammation, pain and fever. They are produced by almost all cell types in the organism by activation of Prostaglandin endoperoxide synthases/Cyclooxygenases. The inducible Prostaglandin Endoperoxide Synthase 2/Cyclooxygenase 2 (PTGS2/COX2) plays an important role in pathologies associated with inflammatory signaling. The main product derived from PTGS2/COX2 expression and activation is Prostaglandin E2 (PGE2), which promotes a wide variety of tissue-specific effects, pending environmental inputs. One of the major sources of PGE2 are infiltrating inflammatory cells - the production of this molecule increases drastically in damaged tissues. Immune infiltration is a hallmark of type 1 diabetes mellitus, a multifactorial disease that leads to autoimmune-mediated pancreatic beta cell destruction. Controversial effects for the PTGS2/COX2-PGE2 signaling cascade in pancreatic islet cells subjected to diabetogenic conditions have been reported, allocating PGE2 as both, cause and consequence of inflammation. Herein, we review the main effects of this molecular pathway in a tissue-specific manner, with a special emphasis on beta cell mass protection/destruction and its potential role in the prevention or development of T1DM. We also discuss strategies to target this pathway for future therapies.
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Affiliation(s)
- Eugenia Martín-Vázquez
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Livia López-Noriega
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Petra I. Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
| | - Benoit R. Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain
- Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain
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26
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Arif S, Domingo-Vila C, Pollock E, Christakou E, Williams E, Tree TIM. Monitoring islet specific immune responses in type 1 diabetes clinical immunotherapy trials. Front Immunol 2023; 14:1183909. [PMID: 37283770 PMCID: PMC10240960 DOI: 10.3389/fimmu.2023.1183909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/02/2023] [Indexed: 06/08/2023] Open
Abstract
The number of immunotherapeutic clinical trials in type 1 diabetes currently being conducted is expanding, and thus there is a need for robust immune-monitoring assays which are capable of detecting and characterizing islet specific immune responses in peripheral blood. Islet- specific T cells can serve as biomarkers and as such can guide drug selection, dosing regimens and immunological efficacy. Furthermore, these biomarkers can be utilized in patient stratification which can then benchmark suitability for participation in future clinical trials. This review focusses on the commonly used immune-monitoring techniques including multimer and antigen induced marker assays and the potential to combine these with single cell transcriptional profiling which may provide a greater understanding of the mechanisms underlying immuno-intervention. Although challenges remain around some key areas such as the need for harmonizing assays, technological advances mean that multiparametric information derived from a single sample can be used in coordinated efforts to harmonize biomarker discovery and validation. Moreover, the technologies discussed here have the potential to provide a unique insight on the effect of therapies on key players in the pathogenesis of T1D that cannot be obtained using antigen agnostic approaches.
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Alsharairi NA. Exploring the Diet-Gut Microbiota-Epigenetics Crosstalk Relevant to Neonatal Diabetes. Genes (Basel) 2023; 14:genes14051017. [PMID: 37239377 DOI: 10.3390/genes14051017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Neonatal diabetes (NDM) is a rare monogenic disorder that presents as hyperglycemia during the first six months of life. The link between early-life gut microbiota dysbiosis and susceptibility to NDM remains uncertain. Experimental studies have demonstrated that gestational diabetes mellitus (GDM) could develop into meconium/gut microbiota dysbiosis in newborns, and thus, it is thought to be a mediator in the pathogenesis of NDM. Epigenetic modifications have been considered as potential mechanisms by which the gut microbiota and susceptibility genes interact with the neonatal immune system. Several epigenome-wide association studies have revealed that GDM is associated with neonatal cord blood and/or placental DNA methylation alterations. However, the mechanisms linking diet in GDM with gut microbiota alterations, which may in turn induce the expression of genes linked to NDM, are yet to be unraveled. Therefore, the focus of this review is to highlight the impacts of diet, gut microbiota, and epigenetic crosstalk on altered gene expression in NDM.
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Affiliation(s)
- Naser A Alsharairi
- Heart, Mind & Body Research Group, Griffith University, Gold Coast, QLD P.O. Box 4222, Australia
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Zala A, Thomas R. Antigen-specific immunotherapy to restore antigen-specific tolerance in Type 1 diabetes and Graves' disease. Clin Exp Immunol 2023; 211:164-175. [PMID: 36545825 PMCID: PMC10019129 DOI: 10.1093/cei/uxac115] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 10/23/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Type 1 diabetes and Graves' disease are chronic autoimmune conditions, characterized by a dysregulated immune response. In Type 1 diabetes, there is beta cell destruction and subsequent insulin deficiency whereas in Graves' disease, there is unregulated excessive thyroid hormone production. Both diseases result in significant psychosocial, physiological, and emotional burden. There are associated risks of diabetic ketoacidosis and hypoglycaemia in Type 1 diabetes and risks of thyrotoxicosis and orbitopathy in Graves' disease. Advances in the understanding of the immunopathogenesis and response to immunotherapy in Type 1 diabetes and Graves' disease have facilitated the introduction of targeted therapies to induce self-tolerance, and subsequently, the potential to induce long-term remission if effective. We explore current research surrounding the use of antigen-specific immunotherapies, with a focus on human studies, in Type 1 diabetes and Graves' disease including protein-based, peptide-based, dendritic-cell-based, and nanoparticle-based immunotherapies, including discussion of factors to be considered when translating immunotherapies to clinical practice.
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Affiliation(s)
- Aakansha Zala
- Frazer Institute, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - Ranjeny Thomas
- Correspondence: Ranjeny Thomas, Frazer Institute, The University of Queensland.
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Roep BO. The need and benefit of immune monitoring to define patient and disease heterogeneity, mechanisms of therapeutic action and efficacy of intervention therapy for precision medicine in type 1 diabetes. Front Immunol 2023; 14:1112858. [PMID: 36733487 PMCID: PMC9887285 DOI: 10.3389/fimmu.2023.1112858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
The current standard of care for type 1 diabetes patients is limited to treatment of the symptoms of the disease, insulin insufficiency and its complications, not its cause. Given the autoimmune nature of type 1 diabetes, immunology is critical to understand the mechanism of disease progression, patient and disease heterogeneity and therapeutic action. Immune monitoring offers the key to all this essential knowledge and is therefore indispensable, despite the challenges and costs associated. In this perspective, I attempt to make this case by providing evidence from the past to create a perspective for future trials and patient selection.
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The role of cytokines and T-bet, GATA3, ROR-γt, and FOXP3 transcription factors of T cell subsets in the natural clinical progression of Type 1 Diabetes. Immunol Res 2023; 71:451-462. [PMID: 36595206 DOI: 10.1007/s12026-022-09355-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/26/2022] [Indexed: 01/04/2023]
Abstract
Th cells play an important role in pathogenesis of type 1 diabetes (T1D). Peripheral blood mononuclear cells were isolated from peripheral blood samples from newly diagnosed (ND), 1-year (1YD), and 5-year T1D (5YD) patients (n:8 of each group), 8 healthy controls (HC), and cultured for 24 h under unstimulated (US) and stimulated conditions. Cell ratios of Th1, Th2, Th17, Treg, and intracellular levels of IFN-γ, TNF-α, IL-10, TGF-β, IL-5, IL-13, IL-17, and IL-21 cytokines were evaluated using the flow cytometry. mRNA expressions of transcription factors T-bet, GATA3, ROR-γt, and FOXP3 of these cells were determined by real-time PCR. Reduced CD4+CD25high cell ratios were detected in ND. CD4+CD25high cells were found to be reduced in ND and 1YD compared to HC under IL-2-stimulated conditions. Intracellular IFN-γ and TNF-α levels were low in all patients under US and IL-12-stimulated conditions. IL-17A and IL-21 were found to be high in patients with IL-6-stimulated conditions. Expressions of IL-10 and TGF-β have been observed to be reduced in patients. Th1/Th2, Th17/Treg, and Th1/Treg ratios were higher in patient groups. FOXP3 and GATA3 mRNA expressions were found to be low in patients, while RORγt and T-bet mRNA levels were higher than HC. Th1, Th17, and Treg cells and their cytokines have been shown to be associated with type 1 diabetes.
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Speake C, Habib T, Lambert K, Hundhausen C, Lord S, Dufort MJ, Skinner SO, Hu A, Kinsman M, Jones BE, Maerz MD, Tatum M, Hocking AM, Nepom GT, Greenbaum CJ, Buckner JH. IL-6-targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function. JCI Insight 2022; 7:e159436. [PMID: 36282595 PMCID: PMC9746808 DOI: 10.1172/jci.insight.159436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 10/12/2022] [Indexed: 12/15/2022] Open
Abstract
Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti-IL-6 (siltuximab) or anti-IL-6 receptor (IL-6R; tocilizumab) therapies and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced ICOS expression on T follicular helper cell populations and T cell receptor-driven (TCR-driven) STAT3 phosphorylation. Siltuximab reversed resistance to Treg-mediated suppression and increased TCR-driven phosphorylated STAT3 and production of IL-10, IL-21, and IL-27 by T effectors. Together, these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell-intrinsic changes that may influence therapeutic outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | - Alex Hu
- Center for Systems Immunology, and
| | | | | | | | | | | | - Gerald T. Nepom
- Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
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Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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Kou X, Liu J, Wang D, Yu M, Li C, Lu L, Chen C, Liu D, Yu W, Yu T, Liu Y, Mao X, Naji A, Cai T, Sun L, Shi S. Exocrine pancreas regeneration modifies original pancreas to alleviate diabetes in mouse models. Sci Transl Med 2022; 14:eabg9170. [PMID: 35921475 DOI: 10.1126/scitranslmed.abg9170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Diabetes is a major public health issue because of its widely epidemic nature and lack of cure. Here, we show that pancreas-derived mesenchymal stem cells (PMSCs) are capable of regenerating exocrine pancreas when implanted into the kidney capsule of mice with streptozotocin (STZ)-induced diabetes. Mechanistically, we found that the regenerated exocrine pancreas elevated interleukin-6 (IL-6) in PMSC implants, which transiently activated tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) to inhibit IL-17, thereby rescuing damaged exocrine pancreas and islet β cells. In addition, we used knockout mouse models to show that global lack of IL-6, TNF-α, or IFN-γ resulted in increased severity of STZ-induced diabetes and resistance to PMSC implantation therapy, confirming the roles of these factors in safeguarding pancreatic β cells. Furthermore, removal of the kidney capsule PMSC implants at 28 days after implantation did not affect the PMSC-initiated therapeutic effect on diabetic mice. This study reveals a previously unknown role of exocrine pancreas regeneration in safeguarding β cells and demonstrates a "soil-rescues-seed" strategy for type 1 diabetes therapy.
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Affiliation(s)
- Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
| | - Jin Liu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Laboratory for Aging Research, State Key Laboratory of Biotherapy and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dandan Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Ming Yu
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Can Li
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Lu Lu
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA
| | - Dawei Liu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China
| | - Wenjing Yu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA
| | - Tingting Yu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Department of Orthodontics, Peking University School & Hospital of Stomatology, #22 Zhongguancun South Avenue, Beijing 100081, China
| | - Yao Liu
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Department of Pediatric Dentistry, School of Stomatology, China Medical University, Shenyang 110002, China
| | - Xueli Mao
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Ali Naji
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Tao Cai
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.,Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Songtao Shi
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China.,Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, PA 19104, USA.,Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China
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Shen X, Wei H, Li J, Wei W, Zhang B, Lu C, Yan C, Li S, Bao L, Zhang J, Zhang C, Li Y. Ectopic Colonization and Immune Landscapes of Periodontitis Microbiota in Germ-Free Mice With Streptozotocin-Induced Type 1 Diabetes Mellitus. Front Microbiol 2022; 13:889415. [PMID: 35756043 PMCID: PMC9226645 DOI: 10.3389/fmicb.2022.889415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/10/2022] [Indexed: 02/05/2023] Open
Abstract
A two-way relationship between diabetes and periodontitis has been discussed recently. Periodontitis microbiota might affect the immune homeostasis of diabetes, but the molecular mechanism of their interactions is still not clear. The aims of this study were to clarify the possible immune regulatory effects of periodontitis microbiota on diabetes and the correlation between immunomodulation and ectopic colonization. A model of germ-free mice with streptozotocin-induced type 1 diabetes mellitus (T1D), which was orally inoculated with mixed saliva samples for 2 weeks, was used in this study. Those mice were randomly divided into two groups, namely, SP (where the T1D mice were orally inoculated with mixed saliva samples from periodontitis patients) and SH (where the T1D mice were orally inoculated with mixed saliva samples from healthy subjects). Ectopic colonization of saliva microbiota was assessed using culture-dependent method and Sanger sequencing, and the composition of gut microbiota was analyzed using 16S rRNA gene sequencing. Changes in 15 types of immune cells and six cytokines either from the small intestine or spleen were detected by multicolor flow cytometry. The correlation between gut microbiota and immune cells was evaluated by redundancy analysis. Although periodontitis microbiota minorly colonized the lungs, spleens, and blood system, they predominantly colonized the gut, which was mainly invaded by Klebsiella. SH and SP differed in beta diversity of the gut bacterial community. Compared to SH, microbial alteration in small intestine occurred with an increase of Lacticaseibacillus, Bacillus, Agathobacter, Bacteroides, and a decrease of Raoultella in SP. More types of immune cells were disordered in the spleen than in the small intestine by periodontitis microbiota, mainly with a dramatical increase in the proportion of macrophages, plasmacytoid dendritic cells (pDCs), monocytes, group 3 innate lymphoid cells, CD4-CD8- T cells and Th17 cells, as well as a decline of αβT cells in SP. Cytokines of IFNγ, IL17, and IL22 produced by CD4 + T cells as well as IL22 produced by ILCs of small intestine rose in numbers, and the intestinal and splenic pDCs were positively regulated by gut bacterial community in SP. In conclusion, periodontitis microbiota invasion leads to ectopic colonization of the extra-oral sites and immune cells infiltration, which might cause local or systemic inflammation. Those cells are considered to act as a “bridge” between T1D and periodontitis.
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Affiliation(s)
- Xin Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Hong Wei
- Central Laboratory, Clinical Medicine Scientific and Technical Innovation Park, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Jian Li
- Institute of Immunology, PLA, Army Medical University, Chongqing, China
| | - Wei Wei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Bo Zhang
- Department of Stomatology, Minda Hospital of Hubei Minzu University, Enshi, China
| | - Changqing Lu
- Department of Anatomy, West China School of Basic Medical and Forensic Medicine, Sichuan University, Chengdu, China
| | - Caixia Yan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Shuzhen Li
- CAS Key Laboratory of Environmental Biotechnology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Lirong Bao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jinmei Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Cheng Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yan Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Niinistö S, Miettinen ME, Cuthbertson D, Honkanen J, Hakola L, Autio R, Erlund I, Arohonka P, Vuorela A, Härkönen T, Hyöty H, Krischer JP, Vaarala O, Knip M, Virtanen SM, TRIGR Investigators. Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity-The TRIGR Nested Case-Control Study. Front Immunol 2022; 13:858875. [PMID: 35693790 PMCID: PMC9175567 DOI: 10.3389/fimmu.2022.858875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/27/2022] [Indexed: 12/03/2022] Open
Abstract
Aims Altered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity. Methods Serum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers. Results Correlations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations. Conclusions In cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. Trial registry number NCT00179777.
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Affiliation(s)
- Sari Niinistö
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Maija E. Miettinen
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - David Cuthbertson
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Jarno Honkanen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Leena Hakola
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
- Tampere University Hospital, Research, Development and Innovation Center, Tampere, Finland
| | - Reija Autio
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Iris Erlund
- Department of Government Services, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Petra Arohonka
- Department of Government Services, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Arja Vuorela
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Taina Härkönen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Jeffrey P. Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Outi Vaarala
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
| | - Suvi M. Virtanen
- Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland
- Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
- Tampere University Hospital, Research, Development and Innovation Center, Tampere, Finland
- Center for Child Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
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Moeinafshar A, Razi S, Rezaei N. Interleukin 17, the double-edged sword in atherosclerosis. Immunobiology 2022; 227:152220. [PMID: 35452921 DOI: 10.1016/j.imbio.2022.152220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 11/05/2022]
Abstract
Cardiovascular diseases, including atherosclerosis, are the number one cause of death worldwide. These diseases have taken the place of pneumonia and other infectious diseases in the epidemiological charts. Thus, their importance should not be underestimated. Atherosclerosis is an inflammatory disease. Therefore, immunological signaling molecules and immune cells carry out a central role in its etiology. One of these signaling molecules is interleukin (IL)-17. This relatively newly discovered signaling molecule might have a dual role as acting both pro-atherogenic and anti-atherogenic depending on the situation. The majority of articles have discussed IL-17 and its action in atherosclerosis, and it may be a new target for the treatment of patients with this disease. In this review, the immunological basis of atherosclerosis with an emphasis on the role of IL-17 and a brief explanation of the role of IL-17 on atherosclerogenic disorders will be discussed.
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Affiliation(s)
- Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Gomez-Muñoz L, Perna-Barrull D, Caroz-Armayones JM, Murillo M, Rodriguez-Fernandez S, Valls A, Vazquez F, Perez J, Corripio R, Castaño L, Bel J, Vives-Pi M. Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes. Front Immunol 2022; 13:825426. [PMID: 35280980 PMCID: PMC8904370 DOI: 10.3389/fimmu.2022.825426] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/31/2022] [Indexed: 01/10/2023] Open
Abstract
The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and β-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naïve T lymphocytes, regulatory T cells (TREG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-β1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of TREG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.
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Affiliation(s)
- Laia Gomez-Muñoz
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - David Perna-Barrull
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Josep M. Caroz-Armayones
- Department of Political and Social Sciences, Health Inequalities Research Group (GREDS-EMCONET), Pompeu Fabra University, Barcelona, Spain
- Johns Hopkins University–Pompeu Fabra University Public Policy Center, Barcelona, Spain
| | - Marta Murillo
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Silvia Rodriguez-Fernandez
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Aina Valls
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Federico Vazquez
- Endocrinology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Jacobo Perez
- Pediatric Endocrinology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Autonomous University of Barcelona, Sabadell, Spain
| | - Raquel Corripio
- Pediatric Endocrinology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Autonomous University of Barcelona, Sabadell, Spain
| | - Luis Castaño
- Cruces University Hospital, Biocruces Bizkaia Research Institute, UPV/EHU, CIBERDEM, CIBERER, Endo-ERN, Bilbao, Spain
| | - Joan Bel
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Marta Vives-Pi
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
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Taurine Grafted Micro-Implants Improved Functions without Direct Dependency between Interleukin-6 and the Bile Acid Lithocholic Acid in Plasma. Biomedicines 2022; 10:biomedicines10010111. [PMID: 35052790 PMCID: PMC8772949 DOI: 10.3390/biomedicines10010111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/14/2021] [Accepted: 12/21/2021] [Indexed: 01/27/2023] Open
Abstract
A recent study showed an association between diabetes development and the bile acid lithocholic acid (LCA), while another study demonstrated positive biological effects of the conjugated bile acid, taurocholic acid (TCA), on pancreatic cells. Thus, this study aimed to encapsulate TCA with primary islets (graft) and study the biological effects of the graft, post-transplantation, in diabetic mice, including effects on LCA concentrations. Sixteen mature adult mice were made diabetic and randomly divided into two equal groups, control and test (transplanted encapsulated islets without or with TCA). Graft pharmaceutical features pre-transplantation, and biological effects including on LCA concentrations post-transplantation, were measured. TCA-microcapsules had an oval shape and similar size compared with the control. The treatment group survived longer, showed improved glucose and interleukin-6 concentrations, and lower LCA concentrations in plasma, large intestine, faeces, liver and spleen, compared with control. Results suggest that TCA incorporation with islets encapsulated graft exerted beneficial effects, but there was no direct and significant dependency between concentrations of interleukin-6 and LCA.
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Alblihed M. Primary understanding of type 1 diabetes as an autoimmune disease. SAUDI JOURNAL FOR HEALTH SCIENCES 2022. [DOI: 10.4103/sjhs.sjhs_50_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
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Greenbaum CJ, Serti E, Lambert K, Weiner LJ, Kanaparthi S, Lord S, Gitelman SE, Wilson DM, Gaglia JL, Griffin KJ, Russell WE, Raskin P, Moran A, Willi SM, Tsalikian E, DiMeglio LA, Herold KC, Moore WV, Goland R, Harris M, Craig ME, Schatz DA, Baidal DA, Rodriguez H, Utzschneider KM, Nel HJ, Soppe CL, Boyle KD, Cerosaletti K, Keyes-Elstein L, Long SA, Thomas R, McNamara JG, Buckner JH, Sanda S. IL-6 receptor blockade does not slow β cell loss in new-onset type 1 diabetes. JCI Insight 2021; 6:150074. [PMID: 34747368 PMCID: PMC8663550 DOI: 10.1172/jci.insight.150074] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/22/2021] [Indexed: 12/30/2022] Open
Abstract
BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.
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Affiliation(s)
- Carla J Greenbaum
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | | | - Katharina Lambert
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | | | | | - Sandra Lord
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | | | | | - Jason L Gaglia
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Philip Raskin
- University of Texas, Southwestern, Dallas, Texas, USA
| | | | - Steven M Willi
- Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Linda A DiMeglio
- Riley Children's Hospital, Indiana University, Indianapolis, Indiana, USA
| | | | - Wayne V Moore
- University of Missouri, Kansas City, Kansas City, Missouri, USA
| | | | - Mark Harris
- Children's Health Queensland Hospital, South Brisbane, Australia.,University of Queensland, Queensland, Brisbane, Australia
| | - Maria E Craig
- University of Sydney, Sydney New South Wales, Australia
| | | | | | | | | | - Hendrik J Nel
- University of Queensland, Queensland, Brisbane, Australia
| | | | | | - Karen Cerosaletti
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | | | - S Alice Long
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | - Ranjeny Thomas
- University of Queensland, Queensland, Brisbane, Australia
| | - James G McNamara
- National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Jane H Buckner
- Center for Interventional Immunology and Diabetes Program, Benaroya Research Institute, Seattle, Washington, USA
| | - Srinath Sanda
- Immune Tolerance Network, Seattle, Washington, USA.,University of California, San Francisco, San Francisco, California, USA
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Zhou X, Yang M, Lv Y, Li H, Wu S, Min J, Shen G, He Y, Lei P. Adoptive transfer of GRP78-treated dendritic cells alleviates insulitis in NOD mice. J Leukoc Biol 2021; 110:1023-1031. [PMID: 34643294 DOI: 10.1002/jlb.3ma0921-219rrrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 09/18/2021] [Accepted: 09/23/2021] [Indexed: 11/09/2022] Open
Abstract
The 78-kDa glucose-regulated protein (GRP78) has extracellular, anti-inflammatory properties that can aid resolving inflammation. It has been established previously that GRP78 induced myeloid CD11c+ cell differentiation into distinct tolerogenic cells. This tolerance induction makes GRP78 a potential therapeutic agent for transplanted allogeneic grafts and autoimmune diseases, such as type 1 diabetes. In this research, it is revealed that rmGRP78-treated NOD mice bone marrow-derived CD11c+ cells (GRP78-DCs) highly expressed B7-H4 but down-regulated CD86 and CD40, and retained a tolerogenic signature even after stimulation by LPS. In the assessment of in vivo therapeutic efficacy after the adoptive transfer of GRP78-DCs into NOD mice, fluorescent imaging analyses revealed that the transfer specifically homed in inflamed pancreases, promoting β-cell survival and alleviating insulitis in NOD mice. The adoptive transfer of GRP78-DCs also helped reduce Th1, Th17, and CTL, suppressing inflammatory cytokine production in vivo. The findings suggest that adoptive GRP78-DC transfer is critical to resolving inflammation in NOD mice and may have relevance in a clinical setting.
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Affiliation(s)
- Xiaoqi Zhou
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Nuclear Medicine and PET Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Muyang Yang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,College of Biomedicine and Health and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Yibing Lv
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heli Li
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sha Wu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangdong Provincial Key Laboratory of Proteomics, Guangzhou, China
| | - Jie Min
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guanxin Shen
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong He
- Department of Nuclear Medicine and PET Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ping Lei
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ludvigsson J, Routray I, Vigård T, Hanås R, Rathsman B, Carlsson A, Särnblad S, Albin AK, Arvidsson CG, Samuelsson U, Casas R. Combined Etanercept, GAD-alum and vitamin D treatment: an open pilot trial to preserve beta cell function in recent onset type 1 diabetes. Diabetes Metab Res Rev 2021; 37:e3440. [PMID: 33486892 DOI: 10.1002/dmrr.3440] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/31/2020] [Accepted: 01/11/2021] [Indexed: 12/21/2022]
Abstract
AIM We aimed to study the feasibility and tolerability of a combination therapy consisting of glutamic acid decarboxylase (GAD-alum), Etanercept and vitamin D in children and adolescents with newly diagnosed with type 1 diabetes (T1D), and evaluate preservation of beta cell function. MATERIAL AND METHODS Etanercept Diamyd Combination Regimen is an open-labelled multi-centre study pilot trial which enrolled 20 GAD antibodies positive T1D patients (7 girls and 13 boys), aged (mean ±SD): 12.4 ± 2.3 (8.3-16.1) years, with a diabetes duration of 81.4 ± 22.1 days. Baseline fasting C-peptide was 0.24 ± 0.1 (0.10-0.35) nmol/l. The patients received Day 1-450 Vitamin D (Calciferol) 2000 U/d per os, Etanercept sc Day 1-90 0.8 mg/kg once a week and GAD-alum sc injections (20 μg, Diamyd™) Day 30 and 60. They were followed for 30 months. RESULTS No treatment related serious adverse events were observed. After 6 months 90-min stimulated C-peptide had improved in 8/20 patients and C-peptide area under the curve (AUC) after Mixed Meal Tolerance Test in 5 patients, but declined thereafter, while HbA1c and insulin requirement remained close to baseline. Administration of Etanercept did not reduce tumour necrosis factor (TNF) spontaneous secretion from peripheral blood mononuclear cells, but rather GAD65-induced TNF-α increased. Spontaneous interleukin-17a secretion increased after the administration of Etanercept, and GAD65-induced cytokines and chemokines were also enhanced following 1 month of Etanercept administration. CONCLUSIONS Combination therapy with parallel treatment with GAD-alum, Etanercept and vitamin D in children and adolescents with type 1 diabetes was feasible and tolerable but had no beneficial effects on the autoimmune process or beta cell function.
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Affiliation(s)
- Johnny Ludvigsson
- Department of Biomedical and Clinical Sciences, Crown Princess Victoria Children´s Hospital and Division of Pediatrics, Linköping University, Linköping, Sweden
| | - Indusmita Routray
- Department of Biomedical and Clinical Sciences, Division of Pediatrics, Linköping University, Linköping, Sweden
| | - Tore Vigård
- Department of Clinical Sciences, Pediatric Endocrinology, Lund University, Malmö, Sweden
- Department of Pediatrics, Skåne University Hospital, Malmö, Sweden
| | - Ragnar Hanås
- Department of Pediatrics, NU Hospital Group, Uddevalla, Sweden
- Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Björn Rathsman
- Sachska Pediatric Hospital, Södersjukhuset, Stockholm, Sweden
| | - Annelie Carlsson
- Department of Clinical Sciences, Pediatric Autoimmunity, Lund University, Lund, Sweden
- Skåne University Hospital, Lund, Sweden
| | - Stefan Särnblad
- Department of Pediatrics, University Hospital, Örebro, Sweden
| | - Anna-Karin Albin
- Department of Pediatrics, Helsingborg Central Hospital, Helsingborg, Sweden
| | | | - Ulf Samuelsson
- Department of Biomedical and Clinical Sciences, Crown Princess Victoria Children´s Hospital and Division of Pediatrics, Linköping University, Linköping, Sweden
| | - Rosaura Casas
- Department of Biomedical and Clinical Sciences, Division of Pediatrics, Linköping University, Linköping, Sweden
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Pk SK, S SV, Kumaran T, N JD, G LD. Association of IL-17A Polymorphism with Chronic Periodontitis in Type 1 Diabetic Patients. JOURNAL OF DENTISTRY (SHIRAZ, IRAN) 2021; 22:180-186. [PMID: 34514065 PMCID: PMC8417545 DOI: 10.30476/dentjods.2020.86990.1222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/02/2020] [Accepted: 10/14/2020] [Indexed: 11/19/2022]
Abstract
STATEMENT OF THE PROBLEM The association of genetic polymorphisms with periodontitis has been studied extensively. The interleukin -17 (IL-17) is a group of cytokines, which comprises six different molecules (IL-17A, B, C, D, E & F). Among these, IL-17A & F are the most commonly understood cytokine, which plays a critical role in inflammatory diseases and periodontal inflammation. PURPOSE To evaluate whether IL-17A gene polymorphism is associated with increased risk of chronic periodontitis in type 1 diabetes patients. MATERIALS AND METHOD This quantitative case- control study was carried out in 60 subjects in 4 groups. The study groups included group A: 15 type 1 diabetes patients (T1DM) with chronic periodontitis (CP), group B: 15 T1DM patients without CP, group C: 15 Non-diabetic patients with CP, group D: 15 Non-diabetic patients without CP. Blood samples were drawn from the subjects and analyzed for IL-17A polymorphism by using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS There was no statistical significant difference seen in the genotype distribution among CP patients with or without T1DM and healthy controls. Odds ratio and p value indicated that increased risks for CP were associated with IL-17A allele (G) in patients with T1DM. This allele was correlated with worse clinical parameters of CP in T1DM patients. CONCLUSION The present study revealed that IL-17A (rs2275913) polymorphism was not associated with increased risk for CP in T1DM patients.
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Affiliation(s)
- Sasi Kumar Pk
- Dept. of Periodontics, JKKN Dental College, Erode, Tamilnadu-638183, India, Ph.D scholar, Saveetha Institute of Medical and Technical Science, Chennai, Tamilnadu
| | - Sheeja Varghese S
- Dean, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, Tamilnadu, India
| | - Thanga Kumaran
- Dept. of Periodontics, JKKN Dental College, Tamilnadu, India
| | - Jaga Desaan N
- Dept. of Prosthodontics, JKKN Dental College and Hospital, Tamilnadu, India
| | - Lambo Daran G
- Dept. of Prosthodontics, JKKN Dental College and Hospital, Tamilnadu, India
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Rajendran S, Quesada-Masachs E, Zilberman S, Graef M, Kiosses WB, Chu T, Benkahla MA, Lee JHM, von Herrath M. IL-17 is expressed on beta and alpha cells of donors with type 1 and type 2 diabetes. J Autoimmun 2021; 123:102708. [PMID: 34358764 DOI: 10.1016/j.jaut.2021.102708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/11/2021] [Accepted: 07/13/2021] [Indexed: 12/30/2022]
Abstract
PURPOSE IL-17 is an important effector cytokine driving immune-mediated destruction in autoimmune diseases such as psoriasis. Blockade of the IL-17 pathway after the initiation of insulitis was effective in delaying or preventing the onset of type 1 diabetes (T1D) in rodent models. Expression of IL-17 transcripts in islets from a donor with recent-onset T1D has been reported, however, studies regarding IL-17 protein expression are lacking. We aimed to study whether IL-17 is being expressed in the islets of diabetic donors. METHODS We stained human pancreatic tissues from non-diabetic (n = 5), auto-antibody positive (aab+) (n = 5), T1D (n = 6) and T2D (n = 5) donors for IL-17, Insulin, and Glucagon, and for CD45 in selected cases. High resolution images were acquired with Zeiss laser scanning confocal microscope LSM780 and analyzed with Zen blue 2.3 software. Cases stained for CD45 were also acquired with widefield slide scanner and analyzed with QuPath software. RESULTS We observed a clear cytoplasmic staining for IL-17 in insulin-containing islets of donors with T1D and T2D, accounting for an average of 7.8 ± 8.4% and 14.9 ± 16.8% of total islet area, respectively. Both beta and alpha cells were sources of IL-17, but CD45+ cells were not a major source of IL-17 in those donors. Expression of IL-17 was reduced in islets of non-diabetic donors, aab+ donors and in insulin-deficient islets of donors with T1D. CONCLUSION Our finding that IL-17 is expressed in islets of donors with T1D or T2D is quite intriguing and warrants further mechanistic studies in human islets to understand the role of IL-17 in the context of metabolic and immune stress in beta cells.
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Affiliation(s)
| | | | | | | | | | - Tiffany Chu
- La Jolla Institute for Immunology, La Jolla, CA, USA
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Arif S, Pujol-Autonell I, Kamra Y, Williams E, Yusuf N, Domingo-Vila C, Shahrabi Y, Pollock E, Khatri L, Peakman M, Tree T, Lorenc A. Mapping T Cell Responses to Native and Neo-Islet Antigen Epitopes in at Risk and Type 1 Diabetes Subjects. Front Immunol 2021; 12:675746. [PMID: 34262563 PMCID: PMC8274489 DOI: 10.3389/fimmu.2021.675746] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022] Open
Abstract
Aims Recent studies highlight the potentially important role of neoepitopes in breaking immune tolerance in type 1 diabetes. T cell reactivity to these neoepitopes has been reported, but how this response compares quantitatively and phenotypically with previous reports on native epitopes is not known. Thus, an understanding of the relationship between native and neoepitopes and their role as tolerance breakers or disease drivers in type 1 diabetes is required. We set out to compare T cell reactivity and phenotype against a panel of neo- and native islet autoantigenic epitopes to examine how this relates to stages of type 1 diabetes development. Methods Fifty-four subjects comprising patients with T1D, and autoantibody-positive unaffected family members were tested against a panel of neo- and native epitopes by ELISPOT (IFN-γ, IL-10, and IL-17). A further subset of two patients was analyzed by Single Cell Immune Profiling (RNAseq and TCR α/β) after stimulation with pools of native and neoepitope peptides. Results T cell responses to native and neoepitopes were present in patients with type 1 diabetes and at-risk subjects, and overall, there were no significant differences in the frequency, magnitude, or phenotype between the two sets of peptide stimuli. Single cell RNAseq on responder T cells revealed a similar profile in T1D patients stimulated with either neo- or native epitopes. A pro-inflammatory gene expression profile (TNF-α, IFN-γ) was dominant in both native and neoepitope stimulated T cells. TCRs with identical clonotypes were found in T cell responding to both native and neoepitopes. Conclusion/Interpretation These data suggest that in peripheral blood, T cell responses to both native and neoepitopes are similar in terms of frequency and phenotype in patients with type 1 diabetes and high-risk unaffected family members. Furthermore, using a combination of transcriptomic and clonotypic analyses, albeit using a limited panel of peptides, we show that neoepitopes are comparable to native epitopes currently in use for immune-monitoring studies.
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Affiliation(s)
- Sefina Arif
- Department of Immunobiology, King’s College London, Guy’s Hospital, London, United Kingdom
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Harris KM, Clements MA, Kwilasz AJ, Watkins LR. T cell transgressions: Tales of T cell form and function in diverse disease states. Int Rev Immunol 2021; 41:475-516. [PMID: 34152881 PMCID: PMC8752099 DOI: 10.1080/08830185.2021.1921764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/17/2021] [Accepted: 04/20/2021] [Indexed: 01/03/2023]
Abstract
Insights into T cell form, function, and dysfunction are rapidly evolving. T cells have remarkably varied effector functions including protecting the host from infection, activating cells of the innate immune system, releasing cytokines and chemokines, and heavily contributing to immunological memory. Under healthy conditions, T cells orchestrate a finely tuned attack on invading pathogens while minimizing damage to the host. The dark side of T cells is that they also exhibit autoreactivity and inflict harm to host cells, creating autoimmunity. The mechanisms of T cell autoreactivity are complex and dynamic. Emerging research is elucidating the mechanisms leading T cells to become autoreactive and how such responses cause or contribute to diverse disease states, both peripherally and within the central nervous system. This review provides foundational information on T cell development, differentiation, and functions. Key T cell subtypes, cytokines that create their effector roles, and sex differences are highlighted. Pathological T cell contributions to diverse peripheral and central disease states, arising from errors in reactivity, are highlighted, with a focus on multiple sclerosis, rheumatoid arthritis, osteoarthritis, neuropathic pain, and type 1 diabetes.
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Affiliation(s)
- Kevin M. Harris
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Madison A. Clements
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Andrew J. Kwilasz
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
| | - Linda R. Watkins
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado, Boulder, CO U.S.A
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Mitrašinović-Brulić M, Dervišević A, Začiragić A, Fočak M, Valjevac A, Hadžović-Džuvo A, Suljević D. Vitamin D3 attenuates oxidative stress and regulates glucose level and leukocyte count in a semi-chronic streptozotocin-induced diabetes model. J Diabetes Metab Disord 2021; 20:771-779. [PMID: 34178862 DOI: 10.1007/s40200-021-00814-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/02/2021] [Indexed: 12/13/2022]
Abstract
Purpose Vitamin D3 (vit-D3) is a potent immunomodulator with anti-inflammatory and antioxidative properties. We used streptozotocin (STZ)-induced rat model of diabetes (DM) to evaluate the effects of vit-D3. We measured serum biochemical parameters, interleukin-17 (IL-17), osteocalcin (OC), malondialdehyde (MDA), and immune cell count on the 21st day of experiment. Method A total of 24 Wistar rats were randomly divided into three groups. Each group had eight rats. During the 1st day of the experiment, the control group was injected intraperitoneally with citrate buffer, while STZ group and STZ + vit-D3 group were injected by a single i.p. dose (35 mg/kg) of STZ dissolved in citrate buffer (pH 4,5; 0,1 M). Vitamin D3 was applied via oral gavage once daily to the STZ + vit-D3 group for a total period of 14 days, starting from the 7th day of the experiment. Results STZ rats showed a significant reduction in OC and an increase in MDA and IL-17 serum concentrations compared to the control rats. We also observed a significant STZ-associated decrease in the number of lymphocytes and a significant increase in monocyte and eosinophil number. Oral treatment with vit-D3 to STZ-induced diabetic rats significantly increased OC and decreased MDA serum levels. Furthermore, vit-D3 treatment resulted in a good regulation of hematopoiesis such as increase in the number of segmented granulocytes and lymphocytes and a reduction in the number of monocytes and eosinophils. Conclusion Vit-D3 treatment has important therapeutic effects; among many others it can attenuate oxidative stress and ameliorate the hyperglycemic state in the STZ-induced rat diabetic model, which is promising for further clinical trials.
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Affiliation(s)
- Maja Mitrašinović-Brulić
- Faculty of Science, Department of Biology, University of Sarajevo, Zmaja od Bosne 33-35 , 71 000 Sarajevo, Bosnia and Herzegovina
| | - Amela Dervišević
- Medical Faculty, Department of Human Physiology, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Asija Začiragić
- Medical Faculty, Department of Human Physiology, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Muhamed Fočak
- Faculty of Science, Department of Biology, University of Sarajevo, Zmaja od Bosne 33-35 , 71 000 Sarajevo, Bosnia and Herzegovina
| | - Amina Valjevac
- Medical Faculty, Department of Human Physiology, University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Almira Hadžović-Džuvo
- Outpatient Clinic With a Daily Hospital 'Dr Al Tawil', Research Unit, Sarajevo, Bosnia and Herzegovina
| | - Damir Suljević
- Faculty of Science, Department of Biology, University of Sarajevo, Zmaja od Bosne 33-35 , 71 000 Sarajevo, Bosnia and Herzegovina
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Costa FRC, Leite JA, Rassi DM, da Silva JF, Elias-Oliveira J, Guimarães JB, Foss-Freitas MC, Câmara NOS, Pontillo A, Tostes RC, Silva JS, Carlos D. NLRP1 acts as a negative regulator of Th17 cell programming in mice and humans with autoimmune diabetes. Cell Rep 2021; 35:109176. [PMID: 34038731 DOI: 10.1016/j.celrep.2021.109176] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 11/30/2020] [Accepted: 05/04/2021] [Indexed: 01/07/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic β cells. We show here that the protein NOD-like receptor family pyrin domain containing 1 (NLRP1) has a key role in the pathogenesis of mouse and human T1D. More specifically, downregulation of NLRP1 expression occurs during T helper 17 (Th17) differentiation, alongside greater expression of several molecules related to Th17 cell differentiation in a signal transducers and activators of transcription 3 (STAT3)-dependent pathway. These changes lead to a consequent increase in interleukin 17 (IL-17) production within the pancreas and higher incidence of diabetes in streptozotocin (STZ)-injected mice. Finally, in patients with T1D and a SNP (rs12150220) in NLRP1, there is a robust decrease in IL-17 levels in serum and in memory Th17 cells from peripheral blood mononuclear cells. Our results demonstrate that NLRP1 acts as a negative regulator of the Th17 cell polarization program, making it an interesting target for intervention during the early stages of T1D.
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Affiliation(s)
- Frederico R C Costa
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Jefferson A Leite
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Diane M Rassi
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Josiane F da Silva
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Jefferson Elias-Oliveira
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Jhefferson B Guimarães
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Maria C Foss-Freitas
- Department of Clinical Medicine, Internal Medicine Division, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, and Caswell Diabetes Institute University of Michigan, Ann Arbor, MI, USA
| | - Niels O S Câmara
- Department of Immunology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Department of Immunology, Institute of Biomedical Sciences (ICB), University of São Paulo, São Paulo, SP, Brazil
| | - Alessandra Pontillo
- Department of Immunology, Institute of Biomedical Sciences (ICB), University of São Paulo, São Paulo, SP, Brazil
| | - Rita C Tostes
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - João S Silva
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Fiocruz- Bi-Institutional Translational Medicine Platform, Ribeirão Preto, SP, Brazil
| | - Daniela Carlos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
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Tiwari R, Singh RD, Binwal M, Srivastav AK, Singh N, Khan H, Gangopadhyay S, Argaria N, Saxena PN, Roy SK, Kumar M, Sharma V, Srivastava V. Perinatal exposure to silver nanoparticles reprograms immunometabolism and promotes pancreatic beta-cell death and kidney damage in mice. Nanotoxicology 2021; 15:636-660. [PMID: 33876704 DOI: 10.1080/17435390.2021.1909767] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Silver nanoparticles (AgNPs) are extensively utilized in food, cosmetics, and healthcare products. Though the effects of AgNPs exposure on adults are well documented, the long-term effects of gestational/perinatal exposure upon the health of offspring have not been addressed. Herein, we show that only perinatal exposure to AgNPs through the mother could lead to chronic inflammation in offspring which persists till adulthood. Further, AgNPs exposure altered offspring's immune responses against environmental stresses. AgNPs exposed offspring showed an altered response in splenocyte proliferation assay when challenged to lipopolysaccharide, concanavalin-A, AgNPs, or silver ions. Perinatal AgNPs exposure affected metabolic parameters (resistin, glucagon-like peptide-1, leptin, insulin) and upregulated JNK/P38/ERK signaling in the pancreas. We observed pancreatic damage, reduced insulin level, and increased blood glucose levels. Further, we observed renal damage, particularly to tubular and glomerular regions as indicated by histopathology and electron microscopy. Our study thus shows that only perinatal exposure to AgNPs could induce persistent inflammation, alter immune responses against foreign antigens and metabolism which may contribute to pancreatic and renal damage later in life.
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Affiliation(s)
- Ratnakar Tiwari
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Department of Biochemistry, School of Dental Sciences, Babu Banarasi Das University, Lucknow, India
| | - Radha Dutt Singh
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India
| | - Monika Binwal
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Anurag Kumar Srivastav
- Animal House Facility, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Neha Singh
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India
| | - Hafizurrahman Khan
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India
| | - Siddhartha Gangopadhyay
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India
| | - Nidhi Argaria
- Advanced Imaging Facility, Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Prem Narain Saxena
- Advanced Imaging Facility, Nanomaterial Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Somendu Kumar Roy
- Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India.,Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Mahadeo Kumar
- Animal House Facility, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Vineeta Sharma
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India
| | - Vikas Srivastava
- Developmental Toxicology Laboratory, Systems Toxicology & Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, Lucknow, India.,Academy of Scientific Innovation and Research (AcSIR), Ghaziabad, India
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50
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Cheon SY, Lee JE. Extracellular Vesicles and Immune System in Ageing and Immune Diseases. Exp Neurobiol 2021; 30:32-47. [PMID: 33632983 PMCID: PMC7926047 DOI: 10.5607/en20059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/06/2021] [Accepted: 01/17/2021] [Indexed: 02/06/2023] Open
Abstract
Immune system is essential for host homeostasis. Immune cells communicate with each other by binding to receptors or by releasing vesicles including chemokines and cytokines. Under healthy circumstances, immune cell-derived factors are critical for cellular growth, division and function, whereas under conditions such as ageing and inflammatory states, they can aggravate pathologies and cause disease. Cell-derived membranous extracellular vesicles mediate cell-to-cell communication and are implicated in various physiological and pathological processes involving ageing and age-related diseases. Extracellular vesicles are responsible for spreading detrimental factors to the surroundings and the propagation phase of inflammatory diseases. The regulation of extracellular vesicles is a putative target for treatment of inflammatory diseases. Moreover, their features are ideal for developing biomarkers and drug delivery systems modulated by bioengineering in inflammatory diseases. The present review summarizes the current understanding of extracellular vesicles in ageing and inflammatory diseases.
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Affiliation(s)
- So Yeong Cheon
- Department of Biotechnology, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Korea
| | - Jong Eun Lee
- Department of Anatomy, Yonsei University College of Medicine, Seoul 03722, Korea
- BK21 PLUS Project for Medical Science, and Brain Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
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