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Guyer P, Seminova K, Lugar M, Manganaro A, Velarde de la Cruz EE, Hartley R, Smithmyer ME, Speake C, Bonifacio E, Kent SC, James EA. T cell and autoantibody recognition of nucleus-associated islet autoantigens in individuals with type 1 diabetes. Diabetologia 2025:10.1007/s00125-025-06458-8. [PMID: 40490584 DOI: 10.1007/s00125-025-06458-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 03/17/2025] [Indexed: 06/11/2025]
Abstract
AIMS/HYPOTHESIS There is a progressive loss of self-tolerance in type 1 diabetes, manifested by the appearance of various autoantibodies. Array-based screening identified antibodies that recognise nucleus-associated proteins in individuals with type 1 diabetes, but the role of these antigens in the disease is poorly understood. Antibodies against MutL homologue 1 (MLH1) and nucleoporin 50 (NUP50) are enriched in DR4-positive and DR3-positive individuals, respectively. Therefore, we sought to investigate CD4+ T cell recognition of these antigens and to assess whether cellular and humoral recognition of these autoantigens are linked. METHODS We used a systematic discovery process to identify CD4+ T cell epitopes within MLH1 and NUP50. We synthesised peptides derived from these antigens and then measured their ability to bind to recombinant DRB1*04:01 or DRB1*03:01 protein, our two HLA class II types of interest. We assessed peptide immunogenicity by expanding peripheral blood T cells in vitro and visualising peptide-specific T cells using HLA class II tetramers. We then performed direct tetramer staining of samples from individuals with type 1 diabetes and HLA-matched control individuals to enumerate MLH1- or NUP50-reactive CD4+ T cells and characterise their cell surface phenotype. Responses were also characterised using islet-derived T cells from pancreatic organ donors with type 1 diabetes using cytokine release as a readout. Antibody responses against both antigens were measured in matched serum samples using a previously published ELISA assay. RESULTS Our discovery process revealed three novel DRB1*03:01-restricted NUP50 epitopes and four novel DRB1*04:01-restricted MLH1 epitopes that are present within the peripheral blood of individuals with type 1 diabetes and among pancreatic islet infiltrates. T cells specific for these epitopes were significantly more frequent in individuals with diabetes than in HLA haplotype-matched control individuals (p=0.0012 and 0.030 for NUP50 and MLH1, respectively). Variable levels of antibody responses were observed: elevated levels of MLH1 and NUP50 antibodies were present in individuals with type 1 diabetes, especially those with the HLA-DR types with previously reported associations, but high titres did not always directly correlate with elevated T cell frequency. CONCLUSIONS/INTERPRETATION The observation that T cell and antibody responses can target nucleus-associated self-antigens confirms and extends previously published studies. Disease-associated recognition of a class of proteins that are not exclusively expressed in pancreatic islets implies a systemic autoimmune component to the disease process. Linked antibody recognition does not appear to be a general phenomenon, suggesting a subtle relationship between humoral and cellular responses to these self-antigens.
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Affiliation(s)
- Perrin Guyer
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | | | - Marija Lugar
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Anthony Manganaro
- Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Erandi E Velarde de la Cruz
- Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Rachel Hartley
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | | | - Cate Speake
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Ezio Bonifacio
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Sally C Kent
- Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Eddie A James
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
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Lachota M, Zagożdżon R. Synthetic receptor-based cell therapies for autoimmune diseases: an update. Cytotherapy 2025:S1465-3249(25)00064-7. [PMID: 40117434 DOI: 10.1016/j.jcyt.2025.02.007] [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: 11/22/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 03/23/2025]
Abstract
Increasing frequency of autoimmune diseases is one of the major problems in modern societies. Despite the introduction of new therapeutic agents for autoimmunity over the past several decades, more progress is needed. Synthetic receptor-based cell therapies are being adopted as an option for treating autoimmune diseases from the field of oncology. Currently evaluated strategies can be summarized into two approaches. The first one is the elimination of autoreactive cells by targeting them, for example, with CAR-T or CAAR-T cells. The second is based on rebalancing the proinflammatory milieu with engineered immunosuppressive cells, for example, CAR-Treg. Both approaches can be supplemented with the use of synthetic systems such as Split-CAR, SynNotch, MESA, GEMS, and SNIPR, or prospective off-the-shelf approaches, for example, in situ use of the in vitro transcribed mRNA, ultimately allowing for enhanced efficacy and safety. The primary goal of our review is to provide some perspective on both strategies in basic, translational, and clinical studies with all their advantages and disadvantages to allow for informed future design of adoptive cell therapies for autoimmune diseases.
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Affiliation(s)
- Mieszko Lachota
- Laboratory of Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland; Department of Ophthalmology, Children's Memorial Health Institute, Warsaw, Poland
| | - Radosław Zagożdżon
- Laboratory of Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland.
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Alhamar G, Vinci C, Franzese V, Tramontana F, Le Goux N, Ludvigsson J, Nissim A, Strollo R. The role of oxidative post-translational modifications in type 1 diabetes pathogenesis. Front Immunol 2025; 16:1537405. [PMID: 40028329 PMCID: PMC11868110 DOI: 10.3389/fimmu.2025.1537405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 01/22/2025] [Indexed: 03/05/2025] Open
Abstract
The pathogenesis of type 1 diabetes (T1D) involves a complex interplay of genetic predisposition, immune processes, and environmental factors, leading to the selective destruction of pancreatic beta-cells by the immune system. Emerging evidence suggests that intrinsic beta-cell factors, including oxidative stress and post-translational modifications (PTM) of beta-cell antigens, may also contribute to their immunogenicity, shedding new light on the multifaceted pathogenesis of T1D. Over the past 30 years, neoepitopes generated by PTMs have been hypothesized to play a role in T1D pathogenesis, but their involvement has only been systematically investigated in recent years. In this review, we explored the interplay between oxidative PTMs, neoepitopes, and T1D, highlighting oxidative stress as a pivotal factor in immune system dysfunction, beta-cell vulnerability, and disease onset.
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Affiliation(s)
- Ghadeer Alhamar
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Chiara Vinci
- Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Valentina Franzese
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Rome, Italy
- Department of Medicine, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy
- Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Flavia Tramontana
- Department of Medicine, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Nelig Le Goux
- Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Johnny Ludvigsson
- Crown Princess Victoria Children’s Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Ahuva Nissim
- Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Rocky Strollo
- Department for the Promotion of Human Science and Quality of Life, San Raffaele Open University, Rome, Italy
- Department of Medicine, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy
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4
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Weiner HL. Immune mechanisms and shared immune targets in neurodegenerative diseases. Nat Rev Neurol 2025; 21:67-85. [PMID: 39681722 DOI: 10.1038/s41582-024-01046-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2024] [Indexed: 12/18/2024]
Abstract
The immune system plays a major part in neurodegenerative diseases. In some, such as multiple sclerosis, it is the primary driver of the disease. In others, such as Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, it has an amplifying role. Immunotherapeutic approaches that target the adaptive and innate immune systems are being explored for the treatment of almost all neurological diseases, and the targets and approaches are often common across diseases. Microglia are the primary immune cells in the brain that contribute to disease pathogenesis, and are consequently a common immune target for therapy. Other therapeutic approaches target components of the peripheral immune system, such as regulatory T cells and monocytes, which in turn act within the CNS. This Review considers in detail how microglia, monocytes and T cells contribute to the pathogenesis of multiple sclerosis, Alzheimer disease, amyotrophic lateral sclerosis and Parkinson disease, and their potential as shared therapeutic targets across these diseases. The microbiome is also highlighted as an emerging therapeutic target that indirectly modulates the immune system. Therapeutic approaches being developed to target immune function in neurodegenerative diseases are discussed, highlighting how immune-based approaches developed to treat one disease could be applicable to multiple other neurological diseases.
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Affiliation(s)
- Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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James SA, Joshua IA. Charting Peptide Shared Sequences Between 'Diabetes-Viruses' and Human Pancreatic Proteins, Their Structural and Autoimmune Implications. Bioinform Biol Insights 2024; 18:11779322241289936. [PMID: 39502449 PMCID: PMC11536397 DOI: 10.1177/11779322241289936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 08/21/2024] [Indexed: 11/08/2024] Open
Abstract
Diabetes mellitus (DM) is a metabolic syndrome characterized by hyperglycaemia, polydipsia, polyuria, and weight loss, among others. The pathophysiology for the disorders is complex and results in pancreatic abnormal function. Viruses have also been implicated in the metabolic syndrome. This study charted peptides to investigate and predict the autoimmune potential of shared sequences between 8 viral species proteins (which we termed 'diabetes-viruses') and the human pancreatic proteins. The structure and immunological relevance of shared sequences between viruses reported in DM onset and human pancreatic proteins were analysed. At nonapeptide mapping between human pancreatic protein and 'diabetic-viruses', reveal 1064 shared sequences distributed among 454 humans and 4288 viral protein sequences. The viral results showed herpesviruses, enterovirus (EV), human endogenous retrovirus, influenza A viruses, rotavirus, and rubivirus sequences are hosted by the human pancreatic protein. The most common shared nonapeptide was AAAAAAAAA, present in 30 human nonredundant sequences. Among the viral species, the shared sequence NSLEVLFQG occurred in 18 nonredundant EVs protein, while occurring merely in 1 human protein, whereas LGLDIEIAT occurred in 8 influenza A viruses overlapping to 1 human protein and KDELSEARE occurred in 2 rotaviruses. The prediction of the location of the shared sequences in the protein structures, showed most of the shared sequences are exposed and located either on the surface or cleft relative to the entire protein structure. Besides, the peptides in the viral protein shareome were predicted computationally for binding to MHC molecules. Here analyses showed that the entire 1064 shared sequences predicted 203 to be either HLA-A or B supertype-restricted epitopes. Fifty-one of the putative epitopes matched reported HLA ligands/T-cell epitopes majorly coming from EV B supertype representative allele restrictions. These data, shared sequences, and epitope charts provide important insight into the role of viruses on the onset of DM and its implications.
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Affiliation(s)
- Stephen A James
- Department of Biochemistry, Kaduna State University, Kaduna, Nigeria
- School of Data Sciences, Centre of Bioinformatics, Perdana University, Kuala Lumpur, Malaysia
| | - Istifanus A Joshua
- Department of Community Medicine, College of Medicine, Kaduna State University, Kaduna, Nigeria
- Department of Community Medicine, College of Health Sciences, Federal University Wukari, Wukari, Nigeria
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Kato M, Abdollahi M, Omori K, Malek V, Lanting L, Kandeel F, Rawson J, Tsark W, Zhang L, Wang M, Tunduguru R, Natarajan R. Lowering an ER stress-regulated long noncoding RNA protects mice from diabetes and isolated pancreatic islets from cell death. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102252. [PMID: 39071954 PMCID: PMC11278341 DOI: 10.1016/j.omtn.2024.102252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/13/2024] [Indexed: 07/30/2024]
Abstract
We investigated the role of the endoplasmic reticulum (ER) stress-regulated long noncoding RNA (lncRNA) lncMGC in pancreatic islets and the pathology of type 1 diabetes (T1D), as well as the potential of lncMGC-based therapeutics. In vivo, blood glucose levels (BGLs) and HbA1c were significantly lower in lncMGC-knockout (KO)-streptozotocin (STZ)-treated diabetic mice compared to wild-type STZ. Antisense oligonucleotides (GapmeR) targeting lncMGC significantly attenuated insulitis and BGLs in T1D NOD mice compared to GapmeR-negative control (NC). GapmeR-injected T1D Akita mice showed significantly lower BGLs compared to Akita-NC mice. hlncMGC-GapmeR lowered BGLs in partially humanized lncMGC (hlncMGC)-STZ mice compared to NC-injected mice. CHOP (ER stress regulating transcription factor) and lncMGC were upregulated in islets from diabetic mice but not in lncMGC-KO and GapmeR-injected diabetic mice, suggesting ER stress involvement. In vitro, hlncMGC-GapmeR increased the viability of isolated islets from human donors and hlncMGC mice and protected them from cytokine-induced apoptosis. Anti-ER stress and anti-apoptotic genes were upregulated, but pro-apoptotic genes were down-regulated in lncMGC KO mice islets and GapmeR-treated human islets. Taken together, these results show that a GapmeR-targeting lncMGC is effective in ameliorating diabetes in mice and also preserves human and mouse islet viability, implicating clinical translation potential.
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Affiliation(s)
- Mitsuo Kato
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Maryam Abdollahi
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Keiko Omori
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Vajir Malek
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Linda Lanting
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Walter Tsark
- Transgenic Mouse Facility, Center for Comparative Medicine, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Lingxiao Zhang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Mei Wang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Ragadeepthi Tunduguru
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA
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Stucchi A, Maspes F, Montee-Rodrigues E, Fousteri G. Engineered Treg cells: The heir to the throne of immunotherapy. J Autoimmun 2024; 144:102986. [PMID: 36639301 DOI: 10.1016/j.jaut.2022.102986] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/15/2022] [Indexed: 01/13/2023]
Abstract
Recently, increased interest in the use of Tregs as adoptive cell therapy for the treatment of autoimmune diseases and transplant rejection had led to several advances in the field. However, Treg cell therapies, while constantly advancing, indiscriminately suppress the immune system without the permanent stabilization of certain diseases. Genetically modified Tregs hold great promise towards solving these problems, but, challenges in identifying the most potent Treg subtype, accompanied by the ambiguity involved in identifying the optimal Treg source, along with its expansion and engineering in a clinical-grade setting remain paramount. This review highlights the recent advances in methodologies for the development of genetically engineered Treg cell-based treatments for autoimmune, inflammatory diseases, and organ rejection. Additionally, it provides a systematized guide to all the recent progress in the field and informs the readers of the feasibility and safety of engineered adoptive Treg cell therapy, with the aim to provide a framework for researchers involved in the development of engineered Tregs.
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Affiliation(s)
- Adriana Stucchi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Federica Maspes
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Ely Montee-Rodrigues
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Cambridge Epigenetix, Cambridge, Cambridgeshire, United Kingdom
| | - Georgia Fousteri
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
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Costanzo A, Clarke D, Holt M, Sharma S, Nagy K, Tan X, Kain L, Abe B, Luce S, Boitard C, Wyseure T, Mosnier LO, Su AI, Grimes C, Finn MG, Savage PB, Gottschalk M, Pettus J, Teyton L. Repositioning the Early Pathology of Type 1 Diabetes to the Extraislet Vasculature. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1094-1104. [PMID: 38426888 PMCID: PMC10944819 DOI: 10.4049/jimmunol.2300769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024]
Abstract
Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.
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Affiliation(s)
- Anne Costanzo
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Don Clarke
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Marie Holt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Siddhartha Sharma
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Kenna Nagy
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Xuqian Tan
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Lisa Kain
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Brian Abe
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | | | | | - Tine Wyseure
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Laurent O. Mosnier
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA
| | - Andrew I. Su
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA
| | - Catherine Grimes
- Department of Chemistry and Biochemistry, University of Delaware, Newark, DE
| | - M. G. Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA
| | - Paul B. Savage
- Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT
| | - Michael Gottschalk
- Rady Children’s Hospital, University of California San Diego, San Diego, CA
| | - Jeremy Pettus
- UC San Diego School of Medicine, University of California San Diego, San Diego, CA
| | - Luc Teyton
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [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: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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Lansberry TR, Stabler CL. Immunoprotection of cellular transplants for autoimmune type 1 diabetes through local drug delivery. Adv Drug Deliv Rev 2024; 206:115179. [PMID: 38286164 PMCID: PMC11140763 DOI: 10.1016/j.addr.2024.115179] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/19/2023] [Accepted: 01/19/2024] [Indexed: 01/31/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in the destruction of insulin-secreting β cells of the islets of Langerhans. Allogeneic islet transplantation could be a successful treatment for T1DM; however, it is limited by the need for effective, permanent immunosuppression to prevent graft rejection. Upon transplantation, islets are rejected through non-specific, alloantigen specific, and recurring autoimmune pathways. Immunosuppressive agents used for islet transplantation are generally successful in inhibiting alloantigen rejection, but they are suboptimal in hindering non-specific and autoimmune pathways. In this review, we summarize the challenges with cellular immunological rejection and therapeutics used for islet transplantation. We highlight agents that target these three immune rejection pathways and how to package them for controlled, local delivery via biomaterials. Exploring macro-, micro-, and nano-scale immunomodulatory biomaterial platforms, we summarize their advantages, challenges, and future directions. We hypothesize that understanding their key features will help identify effective platforms to prevent islet graft rejection. Outcomes can further be translated to other cellular therapies beyond T1DM.
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Affiliation(s)
- T R Lansberry
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - C L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; Department of Immunology and Pathology, College of Medicine, University of Florida, Gainesville, FL, USA; University of Florida Diabetes Institute, Gainesville, FL, USA.
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11
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Dabiri H, Sadeghizadeh M, Ziaei V, Moghadasi Z, Maham A, Hajizadeh-Saffar E, Habibi-Anbouhi M. Development of an ostrich-derived single-chain variable fragment (scFv) against PTPRN extracellular domain. Sci Rep 2024; 14:3689. [PMID: 38355744 PMCID: PMC10866909 DOI: 10.1038/s41598-024-53386-5] [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: 10/15/2023] [Accepted: 01/31/2024] [Indexed: 02/16/2024] Open
Abstract
In type 1 diabetes, the immune system destroys pancreatic beta cells in an autoimmune condition. To overcome this disease, a specific monoclonal antibody that binds to pancreatic beta cells could be used for targeted immunotherapy. Protein tyrosine phosphatase receptor N (PTPRN) is one of the important surface antigen candidates. Due to its high sequence homology among mammals, so far, no single-chain monoclonal antibody has been produced against this receptor. In this study, we developed a novel single-chain variable fragment (scFv) against the PTPRN extracellular domain. To this aim, ostrich species was used as a host is far phylogenetically birds from mammals to construct a phage display library for the first time. An ostrich-derived scfv phage display library was prepared and biopanning steps were done to enrich and screen for isolating the best anti-PTPRN binders. An scFv with appropriate affinity and specificity to the PTPRN extracellular domain was selected and characterized by ELISA, western blotting, and flow cytometry. The anti-PTPRN scFv developed in this study could be introduced as an effective tool that can pave the way for the creation of antibody-based targeting systems in cooperation with the detection and therapy of type I diabetes.
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Affiliation(s)
- Hamed Dabiri
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Sadeghizadeh
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Vahab Ziaei
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Zahra Moghadasi
- National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran
| | - Ali Maham
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Hajizadeh-Saffar
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Advanced Therapy Medicinal Product Technology Development Center (ATMP-TDC), Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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12
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Lemos JRN, Hirani K, von Herrath M. Immunological and virological triggers of type 1 diabetes: insights and implications. Front Immunol 2024; 14:1326711. [PMID: 38239343 PMCID: PMC10794398 DOI: 10.3389/fimmu.2023.1326711] [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: 10/23/2023] [Accepted: 12/07/2023] [Indexed: 01/22/2024] Open
Abstract
Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.
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Affiliation(s)
- Joana R. N. Lemos
- Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, United States
| | - Khemraj Hirani
- Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Endocrine, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Matthias von Herrath
- Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Endocrine, Diabetes, and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
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13
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James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC. The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 2023; 78:101809. [PMID: 37734713 PMCID: PMC10622886 DOI: 10.1016/j.molmet.2023.101809] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. SCOPE OF REVIEW Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. MAJOR CONCLUSIONS The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
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Affiliation(s)
- Eddie A James
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Alok V Joglekar
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amelia K Linnemann
- Center for Diabetes and Metabolic Diseases, and Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Sally C Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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14
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Martin TM, Burke SJ, Wasserfall CH, Collier JJ. Islet beta-cells and intercellular adhesion molecule-1 (ICAM-1): Integrating immune responses that influence autoimmunity and graft rejection. Autoimmun Rev 2023; 22:103414. [PMID: 37619906 PMCID: PMC10543623 DOI: 10.1016/j.autrev.2023.103414] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 08/16/2023] [Accepted: 08/20/2023] [Indexed: 08/26/2023]
Abstract
Type 1 diabetes (T1D) develops due to autoimmune targeting of the pancreatic islet β-cells. Clinical symptoms arise from reduced insulin in circulation. The molecular events and interactions between discrete immune cell populations, infiltration of such leukocytes into pancreatic and islet tissue, and selective targeting of the islet β-cells during autoimmunity and graft rejection are not entirely understood. One protein central to antigen presentation, priming of immune cells, trafficking of leukocytes, and vital for leukocyte effector function is the intercellular adhesion molecule-1 (ICAM-1). The gene encoding ICAM-1 is transcriptionally regulated and rapidly responsive (i.e., within hours) to pro-inflammatory cytokines. ICAM-1 is a transmembrane protein that can be glycosylated; its presence on the cell surface provides co-stimulatory functions for immune cell activation and stabilization of cell-cell contacts. ICAM-1 interacts with the β2-integrins, CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1), which are present on discrete immune cell populations. A whole-body ICAM-1 deletion protects NOD mice from diabetes onset, strongly implicating this protein in autoimmune responses. Since several different cell types express ICAM-1, its biology is fundamentally essential for various physiological and pathological outcomes. Herein, we review the role of ICAM-1 during both autoimmunity and islet graft rejection to understand the mechanism(s) leading to islet β-cell death and dysfunction that results in insufficient circulating quantities of insulin to control glucose homeostasis.
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Affiliation(s)
- Thomas M Martin
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, United States of America
| | - Susan J Burke
- Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America
| | - Clive H Wasserfall
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, United States of America
| | - J Jason Collier
- Laboratory of Islet Biology and Inflammation, Pennington Biomedical Research Center, Baton Rouge, LA 70808, United States of America; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, United States of America.
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15
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Kinney SM, Ortaleza K, Won SY, Licht BJM, Sefton MV. Immunomodulation by subcutaneously injected methacrylic acid-based hydrogels and tolerogenic dendritic cells in a mouse model of autoimmune diabetes. Biomaterials 2023; 301:122265. [PMID: 37586232 DOI: 10.1016/j.biomaterials.2023.122265] [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: 05/26/2023] [Revised: 07/25/2023] [Accepted: 07/30/2023] [Indexed: 08/18/2023]
Abstract
Type 1 diabetes is an autoimmune disease associated with the destruction of insulin-producing β cells. Immunotherapies are being developed to mitigate autoimmune diabetes. One promising option is the delivery of tolerogenic dendritic cells (DCs) primed with specific β-cell-associated autoantigens. These DCs can combat autoreactive cells and promote expansion of β-cell-specific regulatory immune cells, including Tregs. Tolerogenic DCs are typically injected systemically (or near target lymph nodes) in suspension, precluding control over the microenvironment surrounding tolerogenic DC interactions with the host. In this study we show that degradable, synthetic methacrylic acid (MAA)-based hydrogels are an inherently immunomodulating delivery vehicle that enhances tolerogenic DC therapy in the context of autoimmune diabetes. MAA hydrogels were found to affect the local recruitment and activation state of macrophages, DCs, T cells and other cells. Delivering tolerogenic DCs in the MAA hydrogel improved the local host response (e.g., fewer cytotoxic T cells) and enhanced peripheral Treg expansion. Non obese diabetic (NOD) mice treated with tolerogenic DCs subcutaneously injected in MAA hydrogels showed a delay in onset of autoimmune diabetes compared to control vehicles. Our findings further demonstrate the usefulness of MAA-based hydrogels as platforms for regenerative medicine in the context of type 1 diabetes.
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Affiliation(s)
- Sean M Kinney
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Canada; Institute of Biomedical Engineering, University of Toronto, Canada
| | - Krystal Ortaleza
- Institute of Biomedical Engineering, University of Toronto, Canada
| | - So-Yoon Won
- Institute of Biomedical Engineering, University of Toronto, Canada
| | | | - Michael V Sefton
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Canada; Institute of Biomedical Engineering, University of Toronto, Canada.
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16
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Giannoukakis N. Tolerogenic dendritic cells in type 1 diabetes: no longer a concept. Front Immunol 2023; 14:1212641. [PMID: 37388741 PMCID: PMC10303908 DOI: 10.3389/fimmu.2023.1212641] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/31/2023] [Indexed: 07/01/2023] Open
Abstract
Tolerogenic dendritic cells (tDC) arrest the progression of autoimmune-driven dysglycemia into clinical, insulin-requiring type 1 diabetes (T1D) and preserve a critical mass of β cells able to restore some degree of normoglycemia in new-onset clinical disease. The safety of tDC, generated ex vivo from peripheral blood leukocytes, has been demonstrated in phase I clinical studies. Accumulating evidence shows that tDC act via multiple layers of immune regulation arresting the action of pancreatic β cell-targeting effector lymphocytes. tDC share a number of phenotypes and mechanisms of action, independent of the method by which they are generated ex vivo. In the context of safety, this yields confidence that the time has come to test the best characterized tDC in phase II clinical trials in T1D, especially given that tDC are already being tested for other autoimmune conditions. The time is also now to refine purity markers and to "universalize" the methods by which tDC are generated. This review summarizes the current state of tDC therapy for T1D, presents points of intersection of the mechanisms of action that the different embodiments use to induce tolerance, and offers insights into outstanding matters to address as phase II studies are imminent. Finally, we present a proposal for co-administration and serially-alternating administration of tDC and T-regulatory cells (Tregs) as a synergistic and complementary approach to prevent and treat T1D.
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Affiliation(s)
- Nick Giannoukakis
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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17
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English J, Patrick S, Stewart LD. The potential role of molecular mimicry by the anaerobic microbiome in the aetiology of autoimmune disease. Anaerobe 2023; 80:102721. [PMID: 36940867 DOI: 10.1016/j.anaerobe.2023.102721] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/28/2023] [Accepted: 03/13/2023] [Indexed: 03/23/2023]
Abstract
Autoimmune diseases are thought to develop as a consequence of various environmental and genetic factors, each of which contributes to dysfunctional immune responses and/or a breakdown in immunological tolerance towards native structures. Molecular mimicry by microbial components is among the environmental factors thought to promote a breakdown in immune tolerance, particularly through the presence of cross-reactive epitopes shared with the human host. While resident members of the microbiome are essential promoters of human health through immunomodulation, defence against pathogenic colonisation and conversion of dietary fibre into nutritional resources for host tissues, there may be an underappreciated role of these microbes in the aetiology and/or progression of autoimmune disease. An increasing number of molecular mimics are being identified amongst the anaerobic microbiota which structurally resemble endogenous components and, in some cases, for example the human ubiquitin mimic of Bacteroides fragilis and DNA methyltransferase of Roseburia intestinalis, have been associated with promoting antibody profiles characteristic of autoimmune diseases. The persistent exposure of molecular mimics from the microbiota to the human immune system is likely to be involved in autoantibody production that contributes to the pathologies associated with immune-mediated inflammatory disorders. Here-in, examples of molecular mimics that have been identified among resident members of the human microbiome and their ability to induce autoimmune disease through cross-reactive autoantibody production are discussed. Improved awareness of the molecular mimics that exist among human colonisers will help elucidate the mechanisms involved in the breakdown of immune tolerance that ultimately lead to chronic inflammation and downstream disease.
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Affiliation(s)
- Jamie English
- Institute for Global Food Security, School of Biological Sciences, Queen's University, Belfast. 19 Chlorine Gardens, Belfast, BT9 5DL, UK
| | - Sheila Patrick
- Institute for Global Food Security, School of Biological Sciences, Queen's University, Belfast. 19 Chlorine Gardens, Belfast, BT9 5DL, UK; The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Linda D Stewart
- Institute for Global Food Security, School of Biological Sciences, Queen's University, Belfast. 19 Chlorine Gardens, Belfast, BT9 5DL, UK.
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18
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Garg R, Agarwal A, Katekar R, Dadge S, Yadav S, Gayen JR. Chromogranin A-derived peptides pancreastatin and catestatin: emerging therapeutic target for diabetes. Amino Acids 2023:10.1007/s00726-023-03252-x. [PMID: 36914766 DOI: 10.1007/s00726-023-03252-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 02/16/2023] [Indexed: 03/16/2023]
Abstract
Chromogranin A (ChgA) is an acidic pro-protein found in neuroendocrine organs, pheochromocytoma chromaffin granules, and tumor cells. Proteolytic processing of ChgA gives rise to an array of biologically active peptides such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin, which have diverse roles in regulating cardiovascular functions and metabolism, as well as inflammation. Intricate tissue-specific role of ChgA-derived peptide activity in preclinical rodent models of metabolic syndrome reveals complex effects on carbohydrate and lipid metabolism. Indeed, ChgA-derived peptides, PST and CST, play a pivotal role in metabolic syndrome such as obesity, insulin resistance, and diabetes mellitus. Additionally, supplementation of specific peptide in ChgA-KO mice have an opposing effect on physiological functions, such as PST supplementation reduces insulin sensitivity and enhances inflammatory response. In contrast, CST supplementation enhances insulin sensitivity and reduces inflammatory response. In this review, we focus on the tissue-specific role of PST and CST as therapeutic targets in regulating carbohydrate and lipid metabolism, along with the associated risk factors.
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Affiliation(s)
- Richa Garg
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Arun Agarwal
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Roshan Katekar
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shailesh Dadge
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shubhi Yadav
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
| | - Jiaur R Gayen
- Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.
- Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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19
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Rodrigues Oliveira SM, Rebocho A, Ahmadpour E, Nissapatorn V, de Lourdes Pereira M. Type 1 Diabetes Mellitus: A Review on Advances and Challenges in Creating Insulin Producing Devices. MICROMACHINES 2023; 14:151. [PMID: 36677212 PMCID: PMC9867263 DOI: 10.3390/mi14010151] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 12/25/2022] [Accepted: 12/30/2022] [Indexed: 06/17/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is the most common autoimmune chronic disease in young patients. It is caused by the destruction of pancreatic endocrine β-cells that produce insulin in specific areas of the pancreas, known as islets of Langerhans. As a result, the body becomes insulin deficient and hyperglycemic. Complications associated with diabetes are life-threatening and the current standard of care for T1DM consists still of insulin injections. Lifesaving, exogenous insulin replacement is a chronic and costly burden of care for diabetic patients. Alternative therapeutic options have been the focus in these fields. Advances in molecular biology technologies and in microfabrication have enabled promising new therapeutic options. For example, islet transplantation has emerged as an effective treatment to restore the normal regulation of blood glucose in patients with T1DM. However, this technique has been hampered by obstacles, such as limited islet availability, extensive islet apoptosis, and poor islet vascular engraftment. Many of these unsolved issues need to be addressed before a potential cure for T1DM can be a possibility. New technologies like organ-on-a-chip platforms (OoC), multiplexed assessment tools and emergent stem cell approaches promise to enhance therapeutic outcomes. This review will introduce the disorder of type 1 diabetes mellitus, an overview of advances and challenges in the areas of microfluidic devices, monitoring tools, and prominent use of stem cells, and how they can be linked together to create a viable model for the T1DM treatment. Microfluidic devices like OoC platforms can establish a crucial platform for pathophysiological and pharmacological studies as they recreate the pancreatic environment. Stem cell use opens the possibility to hypothetically generate a limitless number of functional pancreatic cells. Additionally, the integration of stem cells into OoC models may allow personalized or patient-specific therapies.
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Affiliation(s)
- Sonia M. Rodrigues Oliveira
- HMRI-Hunter Medical Research Institute, New Lambton, NSW 2305, Australia
- CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
| | - António Rebocho
- Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ehsan Ahmadpour
- Drug Applied Research Center, Department of Parasitology and Mycology, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Department of Parasitology and Mycology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
| | - Veeranoot Nissapatorn
- Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand
- School of Allied Health Sciences, Southeast Asia Water Team (SEAWater Team), World Union for Herbal Drug Discovery (WUHeDD), Research Excellence Center for Innovation and Health Products, Walailak University, Nakhon Si Thammarat 80160, Thailand
| | - Maria de Lourdes Pereira
- CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
- Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
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20
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Pilśniak A, Otto-Buczkowska E. Type 1 diabetes - What's new in prevention and therapeutic strategies? Pediatr Endocrinol Diabetes Metab 2023; 29:196-201. [PMID: 38031834 PMCID: PMC10679919 DOI: 10.5114/pedm.2023.132028] [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: 06/29/2022] [Accepted: 04/10/2023] [Indexed: 12/01/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder, and insulin deficiency is the result of b-cell dysfunction. Treatment of type 1 diabetes requires constant parenteral insulin administration, which can be very burdensome for the patient. Meticulous use of insulin therapy does not protect the patient against complications. Hence, the search for other methods of treatment as well as ways of preventing the onset of diabetes has been ongoing for a long time. The main obstacle in the implementation of the prevention task is the need to identify people at risk of developing diabetes before the start of autoimmunity. It seems that primary prevention is still unrealistic at the moment, because we do not know all the factors leading to the activation of autoimmunity processes. Research on the use of late secondary prevention in people who develop glucose tolerance disorders or in the early period after the onset of type 1 diabetes are at the most advanced stage. Gene therapy is another attempt at an alternative treatment and prevention of type 1 diabetes and still requires further research. Recent years have brought a lot of information about the nature of type 1 diabetes and the mechanisms leading to its development. However, it has not yet been established what factors decide about the initiation of autoimmunity and what determines the dynamics of these processes.
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Affiliation(s)
- Aleksandra Pilśniak
- Department of Internal Medicine, Autoimmune and Metabolic Diseases, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland
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21
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Guyer P, Arribas-Layton D, Manganaro A, Speake C, Lord S, Eizirik DL, Kent SC, Mallone R, James EA. Recognition of mRNA Splice Variant and Secretory Granule Epitopes by CD4+ T Cells in Type 1 Diabetes. Diabetes 2023; 72:85-96. [PMID: 36201618 PMCID: PMC9797322 DOI: 10.2337/db22-0191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 10/02/2022] [Indexed: 01/19/2023]
Abstract
A recent discovery effort resulted in identification of novel splice variant and secretory granule antigens within the HLA class I peptidome of human islets and documentation of their recognition by CD8+ T cells from peripheral blood and human islets. In the current study, we applied a systematic discovery process to identify novel CD4+ T cell epitopes derived from these candidate antigens. We predicted 145 potential epitopes spanning unique splice junctions and within conventional secretory granule antigens and measured their in vitro binding to DRB1*04:01. We generated HLA class II tetramers for the 35 peptides with detectable binding and used these to assess immunogenicity and isolate T cell clones. Tetramers corresponding to peptides with verified immunogenicity were then used to label T cells specific for these putative epitopes in peripheral blood. T cells that recognize distinct epitopes derived from a cyclin I splice variant, neuroendocrine convertase 2, and urocortin-3 were detected at frequencies that were similar to those of an immunodominant proinsulin epitope. Cells specific for these novel epitopes predominantly exhibited a Th1-like surface phenotype. Among the three epitopes, responses to the cyclin I peptide exhibited a distinct memory profile. Responses to neuroendocrine convertase 2 were detected among pancreatic infiltrating T cells. These results further establish the contribution of unconventional antigens to the loss of tolerance in autoimmune diabetes.
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Affiliation(s)
- Perrin Guyer
- Center for Translational Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA
| | - David Arribas-Layton
- Center for Translational Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA
| | - Anthony Manganaro
- Division of Diabetes, Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Cate Speake
- Diabetes Clinical Research Program and Center for Interventional Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA
| | - Sandra Lord
- Diabetes Clinical Research Program and Center for Interventional Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA
| | - Decio L. Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Sally C. Kent
- Division of Diabetes, Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Roberto Mallone
- INSERM, CNRS, Institut Cochin, Université de Paris, Paris, France
- Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Hôpitaux Universitaires Paris Centre, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Eddie A. James
- Center for Translational Immunology, Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA
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22
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Reys LL, Silva SS, Soares da Costa D, Reis RL, Silva TH. Fucoidan-based hydrogels particles as versatile carriers for diabetes treatment strategies. JOURNAL OF BIOMATERIALS SCIENCE. POLYMER EDITION 2022; 33:1939-1954. [PMID: 35699411 DOI: 10.1080/09205063.2022.2088533] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
There is a current lack of fully efficient therapies for diabetes mellitus, a chronic disease where the metabolism of blood glucose is severely hindered by a deficit in insulin or cell resistance to this hormone. Therefore, it is crucial to develop new therapeutic strategies to treat this disease, including devices for the controlled delivery of insulin or encapsulation of insulin-producing cells. In this work, fucoidan (Fu) - a marine sulfated polysaccharide exhibiting relevant properties on reducing blood glucose and antioxidant and anti-inflammatory effects - was used for the development of versatile carriers envisaging diabetes advanced therapies. Fu was functionalized by methacrylation (MFu) using 8% and 12% (v/v) of methacrylic anhydride and further photocrosslinked using visible light in the presence of triethanolamine and eosin-y to produce hydrogel particles. Degree of methacrylation varied between 2.78 and 6.50, as determined by 1HNMR, and the produced particles have an average diameter ranging from 0.63 to 1.3 mm (dry state). Insulin (5%) was added to MFu solution to produce drug-loaded particles and the release profile was assessed in phosphate buffer solution (PBS) and simulated intestinal fluid (SIF) for 24 h. Insulin was released in a sustained manner during the initial 8 h, reaching then a plateau, higher in PBS than in SIF, indicating that lower pH favors drug liberation. Moreover, the ability of MFu particles to serve as templates for the culture of human pancreatic cells was assessed using 1.1B4 cell line during up to 7 days. During the culture period studied, pancreatic beta cells were proliferating, with a global viability over 80% and tend to form pseudo-islets, thus suggesting that the proposed biomaterial could be a good candidate as versatile carrier for diabetes treatment as they sustain the release of insulin and support pancreatic beta cells viability.
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Affiliation(s)
- Lara L Reys
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Simone S Silva
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Diana Soares da Costa
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Rui L Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Tiago H Silva
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics of University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.,ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
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23
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Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes. Front Immunol 2022; 13:886736. [PMID: 35603161 PMCID: PMC9114814 DOI: 10.3389/fimmu.2022.886736] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/08/2022] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that develops in the interplay between genetic and environmental factors. A majority of individuals who develop T1D have a HLA make up, that accounts for 50% of the genetic risk of disease. Besides these HLA haplotypes and the insulin region that importantly contribute to the heritable component, genome-wide association studies have identified many polymorphisms in over 60 non-HLA gene regions that also contribute to T1D susceptibility. Combining the risk genes in a score (T1D-GRS), significantly improved the prediction of disease progression in autoantibody positive individuals. Many of these minor-risk SNPs are associated with immune genes but how they influence the gene and protein expression and whether they cause functional changes on a cellular level remains a subject of investigation. A positive correlation between the genetic risk and the intensity of the peripheral autoimmune response was demonstrated both for HLA and non-HLA genetic risk variants. We also observed epigenetic and genetic modulation of several of these T1D susceptibility genes in dendritic cells (DCs) treated with vitamin D3 and dexamethasone to acquire tolerogenic properties as compared to immune activating DCs (mDC) illustrating the interaction between genes and environment that collectively determines risk for T1D. A notion that targeting such genes for therapeutic modulation could be compatible with correction of the impaired immune response, inspired us to review the current knowledge on the immune-related minor risk genes, their expression and function in immune cells, and how they may contribute to activation of autoreactive T cells, Treg function or β-cell apoptosis, thus contributing to development of the autoimmune disease.
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Affiliation(s)
- Chelsea Gootjes
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Jaap Jan Zwaginga
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Bart O Roep
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Tatjana Nikolic
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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24
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Understanding the Mechanism of Diabetes Mellitus in a LRBA-Deficient Patient. BIOLOGY 2022; 11:biology11040612. [PMID: 35453810 PMCID: PMC9025338 DOI: 10.3390/biology11040612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/03/2022] [Accepted: 04/07/2022] [Indexed: 12/04/2022]
Abstract
The scope of this study is to show that DM in a LRBA-deficient patient with a stop codon mutation (c.3999 G > A) was not mediated through autoimmunity. We have evaluated the ability of the proband’s T cells to be activated by assessing their CTLA-4 expression. A nonsignificant difference was seen in the CTLA-4 expression on CD3+ T cells compared to the healthy control at basal level and after stimulation with PMA/ionomycin. Blood transcriptomic analysis have shown a remarkable increase in abundance of transcripts related to CD71+ erythroid cells. There were no differences in the expression of modules related to autoimmunity diseases between the proband and pooled healthy controls. In addition, our novel findings show that siRNA knockdown of LRBA in mouse pancreatic β-cells leads reduced cellular proinsulin, insulin and consequently insulin secretion, without change in cell viability in cultured MIN6 cells.
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25
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Srivastava N, Hu H, Vomund AN, Peterson OJ, Baker RL, Haskins K, Teyton L, Wan X, Unanue ER. Chromogranin A Deficiency Confers Protection From Autoimmune Diabetes via Multiple Mechanisms. Diabetes 2021; 70:2860-2870. [PMID: 34497137 PMCID: PMC8660984 DOI: 10.2337/db21-0513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/31/2021] [Indexed: 11/13/2022]
Abstract
Recognition of β-cell antigens by autoreactive T cells is a critical step in the initiation of autoimmune type1 diabetes. A complete protection from diabetes development in NOD mice harboring a point mutation in the insulin B-chain 9-23 epitope points to a dominant role of insulin in diabetogenesis. Generation of NOD mice lacking the chromogranin A protein (NOD.ChgA-/-) completely nullified the autoreactivity of the BDC2.5 T cell and conferred protection from diabetes onset. These results raised the issue concerning the dominant antigen that drives the autoimmune process. Here we revisited the NOD.ChgA-/- mice and found that their lack of diabetes development may not be solely explained by the absence of chromogranin A reactivity. NOD.ChgA-/- mice displayed reduced presentation of insulin peptides in the islets and periphery, which corresponded to impaired T-cell priming. Diabetes development in these mice was restored by antibody treatment targeting regulatory T cells or inhibiting transforming growth factor-β and programmed death-1 pathways. Therefore, the global deficiency of chromogranin A impairs recognition of the major diabetogenic antigen insulin, leading to broadly impaired autoimmune responses controlled by multiple regulatory mechanisms.
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Affiliation(s)
- Neetu Srivastava
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Hao Hu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Anthony N Vomund
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Orion J Peterson
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Rocky L Baker
- Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO
| | - Kathryn Haskins
- Department of Immunology and Microbiology, University of Colorado Anschutz School of Medicine, Aurora, CO
| | - Luc Teyton
- Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA
| | - Xiaoxiao Wan
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Emil R Unanue
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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26
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Liu QR, Zhu M, Zhang P, Mazucanti CH, Huang NS, Lang DL, Chen Q, Auluck P, Marenco S, O'Connell JF, Ferrucci L, Chia CW, Egan JM. Novel Human Insulin Isoforms and Cα-Peptide Product in Islets of Langerhans and Choroid Plexus. Diabetes 2021; 70:2947-2956. [PMID: 34649926 PMCID: PMC8660980 DOI: 10.2337/db21-0198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 09/07/2021] [Indexed: 11/26/2022]
Abstract
Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.
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Affiliation(s)
- Qing-Rong Liu
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Min Zhu
- Longitudinal Study Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Pingbo Zhang
- Longitudinal Study Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Caio H Mazucanti
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Nicholas S Huang
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Doyle L Lang
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Qinghua Chen
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Pavan Auluck
- Human Brain Collection Core, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
| | - Stefano Marenco
- Human Brain Collection Core, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
| | - Jennifer F O'Connell
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Luigi Ferrucci
- Longitudinal Study Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Chee W Chia
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Josephine M Egan
- Diabetes Section, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD
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27
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Hegazy WAH, Rajab AAH, Abu Lila AS, Abbas HA. Anti-diabetics and antimicrobials: Harmony of mutual interplay. World J Diabetes 2021; 12:1832-1855. [PMID: 34888011 PMCID: PMC8613656 DOI: 10.4239/wjd.v12.i11.1832] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/26/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is one of the four major non-communicable diseases, and appointed by the world health organization as the seventh leading cause of death worldwide. The scientists have turned over every rock in the corners of medical sciences in order to come up with better understanding and hence more effective treatments of diabetes. The continuous research on the subject has elucidated the role of immune disorders and inflammation as definitive factors in the trajectory of diabetes, assuring that blood glucose adjustments would result in a relief in the systemic stress leading to minimizing inflammation. On a parallel basis, microbial infections usually take advantage of immunity disorders and propagate creating a pro-inflammatory environment, all of which can be reversed by antimicrobial treatment. Standing at the crossroads between diabetes, immunity and infection, we aim in this review at projecting the interplay between immunity and diabetes, shedding the light on the overlapping playgrounds for the activity of some antimicrobial and anti-diabetic agents. Furthermore, we focused on the anti-diabetic drugs that can confer antimicrobial or anti-virulence activities.
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Affiliation(s)
- Wael A H Hegazy
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
| | - Azza A H Rajab
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
| | - Amr S Abu Lila
- Department of Pharmaceutics, Zagazig University, Faculty of Pharmacy, Zagzig 44519, Egypt
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
| | - Hisham A Abbas
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
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28
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Anderson AM, Landry LG, Alkanani AA, Pyle L, Powers AC, Atkinson MA, Mathews CE, Roep BO, Michels AW, Nakayama M. Human islet T cells are highly reactive to preproinsulin in type 1 diabetes. Proc Natl Acad Sci U S A 2021; 118:e2107208118. [PMID: 34611019 PMCID: PMC8521679 DOI: 10.1073/pnas.2107208118] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2021] [Indexed: 01/29/2023] Open
Abstract
Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.
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Affiliation(s)
- Amanda M Anderson
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Laurie G Landry
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Aimon A Alkanani
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
| | - Laura Pyle
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Biostatistics and Informatics, University of Colorado School of Public Health, Aurora, CO 80045
| | - Alvin C Powers
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
- Medical Service, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Clayton E Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Bart O Roep
- Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA 91010
- Department of Internal Medicine, Leiden University Medical Center, 2300RC Leiden, The Netherlands
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045
| | - Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045;
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045
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29
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Kahn SE, Chen YC, Esser N, Taylor AJ, van Raalte DH, Zraika S, Verchere CB. The β Cell in Diabetes: Integrating Biomarkers With Functional Measures. Endocr Rev 2021; 42:528-583. [PMID: 34180979 PMCID: PMC9115372 DOI: 10.1210/endrev/bnab021] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 02/08/2023]
Abstract
The pathogenesis of hyperglycemia observed in most forms of diabetes is intimately tied to the islet β cell. Impairments in propeptide processing and secretory function, along with the loss of these vital cells, is demonstrable not only in those in whom the diagnosis is established but typically also in individuals who are at increased risk of developing the disease. Biomarkers are used to inform on the state of a biological process, pathological condition, or response to an intervention and are increasingly being used for predicting, diagnosing, and prognosticating disease. They are also proving to be of use in the different forms of diabetes in both research and clinical settings. This review focuses on the β cell, addressing the potential utility of genetic markers, circulating molecules, immune cell phenotyping, and imaging approaches as biomarkers of cellular function and loss of this critical cell. Further, we consider how these biomarkers complement the more long-established, dynamic, and often complex measurements of β-cell secretory function that themselves could be considered biomarkers.
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Affiliation(s)
- Steven E Kahn
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Yi-Chun Chen
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Nathalie Esser
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - Austin J Taylor
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Daniël H van Raalte
- Department of Internal Medicine, Amsterdam University Medical Center (UMC), Vrije Universiteit (VU) University Medical Center, 1007 MB Amsterdam, The Netherlands.,Department of Experimental Vascular Medicine, Amsterdam University Medical Center (UMC), Academic Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Sakeneh Zraika
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, 98108 WA, USA
| | - C Bruce Verchere
- BC Children's Hospital Research Institute and Centre for Molecular Medicine and Therapeutics, Vancouver, BC, V5Z 4H4, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
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30
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Shan Y, Kong Y, Zhou Y, Guo J, Shi Q, Li S, Guo H, Huang Y, Ding S, Liu C, Cao L, Huang Y, Fang C, Hu J. Decreased expression of programmed death-1 on CD8 + effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes. Acta Diabetol 2021; 58:1239-1249. [PMID: 33890177 DOI: 10.1007/s00592-021-01711-z] [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: 11/20/2020] [Accepted: 03/24/2021] [Indexed: 11/25/2022]
Abstract
AIMS Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. METHODS A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet's inflammation in NOD mice. RESULTS Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95 ± 12.72%, *p < 0.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb-33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = - 0.2992, *p < 0.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. CONCLUSIONS It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.
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Affiliation(s)
- Yimei Shan
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Clinical Medicine Research Center, Affiliated Hospital 2 of Nantong University, Nantong, China
| | - Yinghong Kong
- Department of Endocrinology, Changshu No. 2 People's Hospital, Changshu, China
| | - Yan Zhou
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Guo
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Qiyun Shi
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Sicheng Li
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Heming Guo
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yiting Huang
- Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Sisi Ding
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
| | - Cuiping Liu
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
| | - Lei Cao
- Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
| | - Yun Huang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Chen Fang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
- Department of Clinical Nutrition, The Second Affiliated Hospital of Soochow University, Suzhou, China.
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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31
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Pagni PP, Chaplin J, Wijaranakula M, Wesley JD, Granger J, Cracraft J, O'Brien C, Perdue N, Kumar V, Li S, Ratliff SS, Roach A, Misquith A, Chan CL, Coppieters K, von Herrath M. Multicomponent Plasmid Protects Mice From Spontaneous Autoimmune Diabetes. Diabetes 2021; 71:db210327. [PMID: 34389610 PMCID: PMC8763876 DOI: 10.2337/db21-0327] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/08/2021] [Indexed: 11/13/2022]
Abstract
Type 1 diabetes is an autoimmune disease in which insulin-secreting β-cells are destroyed, leading to a life-long dependency on exogenous insulin. There are no approved disease-modifying therapies available, and future immunotherapies would need to avoid generalized immune suppression. We developed a novel plasmid expressing preproinsulin2 and a combination of immune-modulatory cytokines (transforming growth factor-beta-1, interleukin [IL] 10 and IL-2) capable of near-complete prevention of autoimmune diabetes in non-obese diabetic mice. Efficacy depended on preproinsulin2, suggesting antigen-specific tolerization, and on the cytokine combination encoded. Diabetes suppression was achieved following either intramuscular or subcutaneous injections. Intramuscular plasmid treatment promoted increased peripheral levels of endogenous IL-10 and modulated myeloid cell types without inducing global immunosuppression. To prepare for first-in-human studies, the plasmid was modified to allow for selection without the use of antibiotic resistance; this modification had no impact on efficacy. This pre-clinical study demonstrates that this multi-component, plasmid-based antigen-specific immunotherapy holds potential for inducing self-tolerance in persons at risk of developing type 1 diabetes. Importantly, the study also informs on relevant cytokine and immune cell biomarkers that may facilitate clinical trials. This therapy is currently being tested for safety and tolerability in a phase 1 trial (ClinicalTrials.gov Identifier: NCT04279613).
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Affiliation(s)
- Philippe P Pagni
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Jay Chaplin
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Michael Wijaranakula
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Johnna D Wesley
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Jaimie Granger
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Justen Cracraft
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Conor O'Brien
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Nikole Perdue
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Vijetha Kumar
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Shangjin Li
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | | | - Allie Roach
- Type 1 Diabetes & Kidney Disease, Global Drug Discovery, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Ayesha Misquith
- Discovery Biologics, Global Research Technologies, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Chung-Leung Chan
- Discovery Biologics, Global Research Technologies, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, U.S.A
| | - Ken Coppieters
- Project and Alliance Management, Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Matthias von Herrath
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Global Chief Medical Office, Novo Nordisk A/S, Søborg, Denmark
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32
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Thomas R, Carballido JM, Wesley JD, Ahmed ST. Overcoming Obstacles in the Development of Antigen-Specific Immunotherapies for Type 1 Diabetes. Front Immunol 2021; 12:730414. [PMID: 34421931 PMCID: PMC8375663 DOI: 10.3389/fimmu.2021.730414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 07/22/2021] [Indexed: 01/01/2023] Open
Abstract
Antigen-specific immunotherapy (ASI) holds great promise for type 1 diabetes (T1D). Preclinical success for this approach has been demonstrated in vivo, however, clinical translation is still pending. Reasons explaining the slow progress to approve ASI are complex and span all stages of research and development, in both academic and industry environments. The basic four hurdles comprise a lack of translatability of pre-clinical research to human trials; an absence of robust prognostic and predictive biomarkers for therapeutic outcome; a need for a clear regulatory path addressing ASI modalities; and the limited acceptance to develop therapies intervening at the pre-symptomatic stages of disease. The core theme to address these challenges is collaboration-early, transparent, and engaged interactions between academic labs, pharmaceutical research and clinical development teams, advocacy groups, and regulatory agencies to drive a fundamental shift in how we think and treat T1D.
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Affiliation(s)
- Ranjeny Thomas
- University of Queensland Diamantina Institute, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - José M. Carballido
- Translational Medicine/Preclinical Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Johnna D. Wesley
- Type 1 Diabetes, Immunology, & Kidney Disease Research, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, United States
| | - Simi T. Ahmed
- Strategic Partnerships, The New York Stem Cell Foundation Research Institute, New York, NY, United States
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Abstract
PURPOSE OF REVIEW Loss of tolerance to insulin likely contributes to the immunopathogenesis of type 1 diabetes (T1D). Several large clinical trials and smaller mechanistic studies have failed to demonstrate the efficacy of insulin antigen therapy. The growing awareness of the heterogeneity of T1D likely affects the response to various immune therapies including insulin. Identification of biomarkers of clinical response will provide further insight into mechanisms leading to the disease and classify responders in the quest for personalized therapy. RECENT FINDINGS Several biomarkers have identified subpopulations in posthoc analyses that showed benefit from oral insulin even though the placebo-controlled study was as a whole unsuccessful. High insulin autoantibody titer, low first phase insulin response, and high Diabetes Prevention Trial-Type 1 Risk Score identify at-risk relatives more likely to benefit from oral insulin. Future incorporation of human leukocyte antigen and the variable number of tandem repeats polymorphism located in the insulin gene promoter (INS VNTR) is of interest for both primary and secondary prevention studies. SUMMARY Although primary and secondary prevention trials using oral insulin are ongoing, those completed have been largely unsuccessful. However, we believe that oral insulin should be considered in future trials as part of combination therapies as prerandomization biomarker testing is refined.
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Affiliation(s)
- Laura M. Jacobsen
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Desmond A. Schatz
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
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34
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Musthaffa Y, Hamilton-Williams EE, Nel HJ, Bergot AS, Mehdi AM, Harris M, Thomas R. Proinsulin-specific T-cell responses correlate with estimated c-peptide and predict partial remission duration in type 1 diabetes. Clin Transl Immunology 2021; 10:e1315. [PMID: 34336205 PMCID: PMC8312239 DOI: 10.1002/cti2.1315] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/20/2021] [Accepted: 06/27/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Type 1 diabetes (T1D) is an autoimmune disorder in which autoreactive T cells destroy insulin-producing β-cells. Interventions that preserve β-cell function represent a fundamental therapeutic goal in T1D and biomarkers that predict and monitor β-cell function, and changes in islet autoantigenic signatures are needed. As proinsulin and neoantigens derived from proinsulin peptides (hybrid insulin peptides, HIPs) are important T1D autoantigens, we analysed peripheral blood CD4+ T-cell autoantigen-specific proliferative responses and their relationship to estimated β-cell function. Methods We recruited 72 people with and 42 without T1D, including 17 pre-diabetic islet antibody-positive and 9 antibody-negative first-degree relatives and 16 unrelated healthy controls with T1D-risk HLA types. We estimated C-peptide level at 3-month intervals for 2 years post-diagnosis and measured CD4+ T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay. Results We show that CD4+ T-cell proliferation to any islet peptide and to multiple epitopes were significantly more frequent in pre-diabetic islet antibody-positive siblings and participants with T1D ≤ 3 months of duration, than in participants with T1D > 3 months or healthy controls. Among participants with T1D and first-degree relatives, CD4+ T-cell proliferation occurred most frequently in response to proinsulin33-63 (full-length C-peptide). Proinsulin33-63-specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/DQ8. In children with T1D, proinsulin33-63-specific T-cell proliferation positively associated with concurrent estimated C-peptide and predicted survival in honeymoon. Conclusion CD4+ T-cell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin33-63-specific CD4+ T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.
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Affiliation(s)
- Yassmin Musthaffa
- Department of Endocrinology and Diabetes Queensland Children's Hospital South Brisbane QLD Australia.,The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Emma E Hamilton-Williams
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Hendrik J Nel
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Anne-Sophie Bergot
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Ahmed M Mehdi
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Mark Harris
- Department of Endocrinology and Diabetes Queensland Children's Hospital South Brisbane QLD Australia.,The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Ranjeny Thomas
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
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35
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Frontino G, Guercio Nuzio S, Scaramuzza AE, D'Annunzio G, Toni S, Citriniti F, Bonfanti R. Prevention of type 1 diabetes: where we are and where we are going. Minerva Pediatr (Torino) 2021; 73:486-503. [PMID: 34286946 DOI: 10.23736/s2724-5276.21.06529-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
T1D (T1D) is one of the most frequent chronic disease in children and is associated to the risk of severe acute and chronic complications. There are about 550000 children with T1D in the world and about 86000 children are diagnosed with T1D every year and its incidence is ever increasing. In this narrative review we will discuss current and future perspectives in T1D prevention strategies as well as their pitfalls. It is important to remember that for the first time one drug, in particular Teplizumab (antibody anti CD3) is going to be accepted for treatment in stage 2 of type 1 diabetes mellitus: this represent the onset of a new era.
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Affiliation(s)
- Giulio Frontino
- Diabetes Research Institute, Department of Pediatrics, IRCCS San Raffaele Scientific Institute, Milano, Italy
| | - Salvatore Guercio Nuzio
- Division of Pediatric, Santa Maria della Speranza Hospital, Battipaglia, ASL Salerno, Salerno, Italy
| | | | - Giuseppe D'Annunzio
- Pediatric Clinic and Endocrinology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Sonia Toni
- Diabetology and Endocrinology Unit, Meyer Children Hospital, Firenze, Italy
| | - Felice Citriniti
- Department of Pediatrics, Pugliese-Ciaccio Hospital, Catanzaro, Italy
| | - Riccardo Bonfanti
- Diabetes Research Institute, Department of Pediatrics, IRCCS San Raffaele Scientific Institute, Milano, Italy - .,Università Vita-Salute San Raffaele, Milan, Italy
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Borg DJ, Faridi P, Giam KL, Reeves P, Fotheringham AK, McCarthy DA, Leung S, Ward MS, Harcourt BE, Ayala R, Scheijen JL, Briskey D, Dudek NL, Schalkwijk CG, Steptoe R, Purcell AW, Forbes JM. Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model. Metabolites 2021; 11:426. [PMID: 34203471 PMCID: PMC8305727 DOI: 10.3390/metabo11070426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/21/2021] [Accepted: 06/22/2021] [Indexed: 12/17/2022] Open
Abstract
Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50-100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10-12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function.
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Affiliation(s)
- Danielle J. Borg
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
- Pregnancy and Development, Mater Research Institute, The University of Queensland, South Brisbane, QLD 4101, Australia
| | - Pouya Faridi
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Kai Lin Giam
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Peta Reeves
- Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; (P.R.); (R.S.)
| | - Amelia K. Fotheringham
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Domenica A. McCarthy
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Sherman Leung
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Micheal S. Ward
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
| | - Brooke E. Harcourt
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
| | - Rochelle Ayala
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Jean L. Scheijen
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands; (J.L.S.); (C.G.S.)
- Cardiovascular Research Institute Maastricht, 6211 Maastricht, The Netherlands
| | - David Briskey
- School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD 4067, Australia;
| | - Nadine L. Dudek
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Casper G. Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, 6211 Maastricht, The Netherlands; (J.L.S.); (C.G.S.)
- Cardiovascular Research Institute Maastricht, 6211 Maastricht, The Netherlands
| | - Raymond Steptoe
- Tolerance and Autoimmunity Group, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD 4102, Australia; (P.R.); (R.S.)
| | - Anthony W. Purcell
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; (P.F.); (K.L.G.); (R.A.); (N.L.D.); (A.W.P.)
| | - Josephine M. Forbes
- Glycation and Diabetes Complications, Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD 4102, Australia; (D.J.B.); (A.K.F.); (D.A.M.); (S.L.); (M.S.W.); (B.E.H.)
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC 3052, Australia
- Mater Clinical School, The University of Queensland, Brisbane, QLD 4101, Australia
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Bettini M, Bettini ML. Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes. Diabetes 2021; 70:1211-1219. [PMID: 34016597 PMCID: PMC8275894 DOI: 10.2337/dbi18-0058] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 03/10/2021] [Indexed: 12/22/2022]
Abstract
Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.
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MESH Headings
- Animals
- Autoimmunity/physiology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/pathology
- Diabetes Mellitus, Type 1/therapy
- Endocrinology/methods
- Endocrinology/trends
- Humans
- Immune Tolerance/physiology
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/trends
- Mice
- Molecular Targeted Therapy/methods
- Molecular Targeted Therapy/trends
- Pancreas/immunology
- Pancreas/metabolism
- Pancreas/pathology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/physiology
- T-Lymphocytes, Regulatory/transplantation
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Affiliation(s)
- Maria Bettini
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT
| | - Matthew L Bettini
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT
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38
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A Germline-Encoded Structural Arginine Trap Underlies the Anti-DNA Reactivity of a Murine V Gene Segment. Int J Mol Sci 2021; 22:ijms22094541. [PMID: 33926148 PMCID: PMC8123574 DOI: 10.3390/ijms22094541] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 11/30/2022] Open
Abstract
Autoimmunity may have its origins of early repertoire selection in developmental B cells. Such a primary repertoire is probably shaped by selecting B cells that can efficiently perform productive signaling, stimulated by self-antigens in the bone marrow, such as DNA. In support of that idea, we previously found a V segment from VH10 family that can form antibodies that bind to DNA independent of CDR3 usage. In this paper we designed four antibody fragments in a novel single-chain pre-BCR (scpre-BCR) format containing germinal V gene segments from families known to bind DNA (VH10) or not (VH4) connected to a murine surrogate light chain (SLC), lacking the highly charged unique region (UR), by a hydrophilic peptide linker. We also tested the influence of CDR2 on DNA reactivity by shuffling the CDR2 loop. The scpre-BCRs were expressed in bacteria. VH10 bearing scpre-BCR could bind DNA, while scpre-BCR carrying the VH4 segment did not. The CDR2 loop shuffling hampered VH10 reactivity while displaying a gain-of-function in the nonbinding VH4 germline. We modeled the binding sites demonstrating the conservation of a positivity charged pocket in the VH10 CDR2 as the possible cross-reactive structural element. We presented evidence of DNA reactivity hardwired in a V gene, suggesting a structural mechanism for innate autoreactivity. Therefore, while autoreactivity to DNA can lead to autoimmunity, efficiently signaling for B cell development is likely a trade-off mechanism leading to the selection of potentially autoreactive repertoires.
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39
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Rodriguez-Fernandez S, Almenara-Fuentes L, Perna-Barrull D, Barneda B, Vives-Pi M. A century later, still fighting back: antigen-specific immunotherapies for type 1 diabetes. Immunol Cell Biol 2021; 99:461-474. [PMID: 33483995 DOI: 10.1111/imcb.12439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/11/2020] [Accepted: 01/20/2021] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a chronic metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. Ever since the 1920s, the fate of patients suffering from T1D was dramatically improved owing to the isolation and production of insulin, and the scientific field has largely progressed as a result of the evidence gathered about its underpinnings and mechanisms. The last years have seen this knowledge transformed into actual antigen-specific immunotherapies with potential to restore selectively the breach of tolerance to β-cell autoantigens and halt the autoimmune aggression. However, so far, the results of both prevention and reversion trials in T1D have been rather discouraging, so there is still an urgent need to optimize those immunotherapies and their associated factors, for example, posology and administration patterns, route and timing. In this review, we look back on what has been achieved in the last century and identify the main autoantigens driving the autoimmune attack in T1D. Then, we take a deep dive into the numerous antigen-specific immunotherapies trialed and the ones still at a preclinical phase, ranging from peptides, proteins and agent combinations to gene transfer, nanoparticles, cell-based strategies and novel approaches exploiting naturally occurring tolerogenic processes. Finally, we provide insight into the several features to be considered in a T1D clinical trial, the ideal time point for intervention and the biomarkers needed for monitoring the successful regulatory effect of the antigen-specific immunotherapy. Although further research and optimization remain imperative, the development of a therapeutic armamentarium against T1D autoimmunity is certainly advancing with a confident step.
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Affiliation(s)
- Silvia Rodriguez-Fernandez
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
| | - Lidia Almenara-Fuentes
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
| | - David Perna-Barrull
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | | | - Marta Vives-Pi
- Immunology Section, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.,Ahead Therapeutics SL, Barcelona, Spain
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40
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Clark M, Kroger CJ, Ke Q, Tisch RM. The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes. Front Immunol 2021; 11:615371. [PMID: 33603744 PMCID: PMC7884625 DOI: 10.3389/fimmu.2020.615371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.
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Affiliation(s)
- Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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41
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Molecular Imaging of Autoimmune Diseases. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00055-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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42
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Chuzho N, Kumar N, Mishra N, Tandon N, Kanga U, Kaur G, Singh P, Mishra G, Sharma S, Mehra NK. Differential HLA Association of GAD65 and IA2 Autoantibodies in North Indian Type 1 Diabetes Patients. J Diabetes Res 2021; 2021:4012893. [PMID: 34988229 PMCID: PMC8723877 DOI: 10.1155/2021/4012893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/23/2021] [Accepted: 12/02/2021] [Indexed: 11/17/2022] Open
Abstract
The human leucocyte antigen (HLA) association with type 1 diabetes (T1D) is well known but there are limited studies investigating the association between β-cell autoantibodies and HLA genes. We evaluated the prevalence of GAD65 and IA-2 autoantibodies (GADA and IA2A) in 252 T1D patients from North India and investigated the genetic association of GADA and IA2A with HLA class I and class II genes/haplotypes. GADA and IA2A were detected in 50.79% and 15.87% of T1D patients, respectively, while only 8.73% had both GADA and IA2A. HLA-DRB1∗03 was observed to be significantly higher in GADA+ T1D patients as compared to GADA- (91.41% vs. 66.13%, Bonferroni-corrected P (P c) = 1.11 × 10-5; OR = 5.45; 95% CI: 2.67-11.08). Similarly, HLA-DQB1∗02 was found to be significantly increased in GADA+ patients (94.53%, P c = 2.19 × 10-5; OR = 6.27; 95% CI: 2.7-14.49) as compared to GADA- (73.39%). The frequencies of HLA-DRB1∗04 and DQB1∗03 were increased in IA2A+ patients (45.0% and 52.5%, respectively) as compared to that in IA2A- (25.94% and 33.96%, respectively). Further, the frequency of DRB1∗03-DQB1∗02 haplotype was found to be significantly increased in GADA+ T1D patients as compared to GADA- (60.55% vs. 41.94%, P = 3.94 × 10-5; OR = 2.13; 95%CI = 1.49-3.03). Similarly, HLA-DRB1∗04-DQB1∗03 haplotype was found to be significantly increased in IA2A+ T1D patients compared to IA2A- patients (22.5% vs. 12.97%; P = 0.041; OR = 1.95; 95%CI = 1.08-3.52). None of the HLA class I genes (HLA-A, B, and Cw) was found to be associated with GADA or IA2A in people with T1D. Our findings suggest that HLA-DRB1∗03/DQB1∗02 and HLA-DRB1∗04/DQB1∗03 might play an important role in the development of GADA and IA2A, respectively.
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Affiliation(s)
- Neihenuo Chuzho
- Indian Council of Medical Research (ICMR)-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Neeraj Kumar
- Indian Council of Medical Research (ICMR)-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India
| | - Neetu Mishra
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Nikhil Tandon
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
| | - Uma Kanga
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Gurvinder Kaur
- Laboratory Oncology Unit, Dr BR Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Paras Singh
- Department of Molecular Medicine, National Institute of Tuberculosis and Respiratory Diseases, Sri Aurobindo Marg, New Delhi, India
| | - Gunja Mishra
- Indian Council of Medical Research (ICMR)-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India
| | - Shreya Sharma
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India
| | - Narinder K. Mehra
- Emeritus Scientist (ICMR), and Former Dean (Research), All India Institute of Medical Sciences, New Delhi, India
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43
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Wen X, Yang J, James E, Chow IT, Reijonen H, Kwok WW. Increased islet antigen-specific regulatory and effector CD4 + T cells in healthy individuals with the type 1 diabetes-protective haplotype. Sci Immunol 2020; 5:5/44/eaax8767. [PMID: 32060144 DOI: 10.1126/sciimmunol.aax8767] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 01/24/2020] [Indexed: 12/13/2022]
Abstract
The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127-FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen-specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope-specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10-producing T effectors and CD25+CD127-FOXP3+ regulatory T cells.
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Affiliation(s)
- Xiaomin Wen
- Benaroya Research Institute, Seattle, WA 98101, USA
| | - Junbao Yang
- Benaroya Research Institute, Seattle, WA 98101, USA
| | - Eddie James
- Benaroya Research Institute, Seattle, WA 98101, USA
| | - I-Ting Chow
- Benaroya Research Institute, Seattle, WA 98101, USA
| | - Helena Reijonen
- Department of Diabetes Immunology, City of Hope Beckman Research Institute, Duarte, CA 91010, USA
| | - William W Kwok
- Benaroya Research Institute, Seattle, WA 98101, USA. .,Department of Medicine, University of Washington, Seattle, WA 98109, USA
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44
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Sadeqi Nezhad M, Seifalian A, Bagheri N, Yaghoubi S, Karimi MH, Adbollahpour-Alitappeh M. Chimeric Antigen Receptor Based Therapy as a Potential Approach in Autoimmune Diseases: How Close Are We to the Treatment? Front Immunol 2020; 11:603237. [PMID: 33324420 PMCID: PMC7727445 DOI: 10.3389/fimmu.2020.603237] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite significant breakthroughs in understanding of immunological and physiological features of autoimmune diseases, there is currently no specific therapeutic option with prolonged remission. Cell-based therapy using engineered-T cells has attracted tremendous attention as a practical treatment for autoimmune diseases. Genetically modified-T cells armed with chimeric antigen receptors (CARs) attack autoreactive immune cells such as B cells or antibody-secreting plasma cells. CARs can further guide the effector and regulatory T cells (Tregs) to the autoimmune milieu to traffic, proliferate, and exert suppressive functions. The genetically modified-T cells with artificial receptors are a promising option to suppress autoimmune manifestation and autoinflammatory events. Interestingly, CAR-T cells are modified to a new chimeric auto-antibody receptor T (CAAR-T) cell. This cell, with its specific-antigen, recognizes and binds to the target autoantibodies expressing autoreactive cells and, subsequently, destroy them. Preclinical studies of CAR-T cells demonstrated satisfactory outcomes against autoimmune diseases. However, the lack of target autoantigens remains one of the pivotal problems in the field of CAR-T cells. CAR-based therapy has to pass several hurdles, including stability, durability, trafficking, safety, effectiveness, manufacturing, and persistence, to enter clinical use. The primary goal of this review was to shed light on CAR-T immunotherapy, CAAR-T cell therapy, and CAR-Treg cell therapy in patients with immune system diseases.
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Affiliation(s)
- Muhammad Sadeqi Nezhad
- Department of Clinical Laboratory Science, Young Researchers and Elites Club, Gorgan Branch, Islamic Azad University, Gorgan, Iran.,Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Gorgan, Iran
| | - Alexander Seifalian
- Nanotechnology & Regenerative Medicine Commercialization Centre (Ltd), The London BioScience Innovation Centre, London, United Kingdom
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sajad Yaghoubi
- Department of Clinical Microbiology, Iranshahr University of Medical Sciences, Iranshahr, Iran
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45
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Dickerson MT, Dadi PK, Butterworth RB, Nakhe AY, Graff SM, Zaborska KE, Schaub CM, Jacobson DA. Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls pancreatic β-cell insulin secretion. J Physiol 2020; 598:4887-4905. [PMID: 32790176 PMCID: PMC8095317 DOI: 10.1113/jp279941] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/20/2020] [Indexed: 12/20/2022] Open
Abstract
KEY POINTS Tetraspanin (TSPAN) proteins regulate many biological processes, including intracellular calcium (Ca2+ ) handling. TSPAN-7 is enriched in pancreatic islet cells; however, the function of islet TSPAN-7 has not been identified. Here, we characterize how β-cell TSPAN-7 regulates Ca2+ handling and hormone secretion. We find that TSPAN-7 reduces β-cell glucose-stimulated Ca2+ entry, slows Ca2+ oscillation frequency and decreases glucose-stimulated insulin secretion. TSPAN-7 controls β-cell function through a direct interaction with L-type voltage-dependent Ca2+ channels (CaV 1.2 and CaV 1.3), which reduces channel Ca2+ conductance. TSPAN-7 slows activation of CaV 1.2 and accelerates recovery from voltage-dependent inactivation; TSPAN-7 also slows CaV 1.3 inactivation kinetics. These findings strongly implicate TSPAN-7 as a key regulator in determining the set-point of glucose-stimulated Ca2+ influx and insulin secretion. ABSTRACT Glucose-stimulated insulin secretion (GSIS) is regulated by calcium (Ca2+ ) entry into pancreatic β-cells through voltage-dependent Ca2+ (CaV ) channels. Tetraspanin (TSPAN) transmembrane proteins control Ca2+ handling, and thus they may also modulate GSIS. TSPAN-7 is the most abundant islet TSPAN and immunostaining of mouse and human pancreatic slices shows that TSPAN-7 is highly expressed in β- and α-cells; however, the function of islet TSPAN-7 has not been determined. Here, we show that TSPAN-7 knockdown (KD) increases glucose-stimulated Ca2+ influx into mouse and human β-cells. Additionally, mouse β-cell Ca2+ oscillation frequency was accelerated by TSPAN-7 KD. Because TSPAN-7 KD also enhanced Ca2+ entry when membrane potential was clamped with depolarization, the effect of TSPAN-7 on CaV channel activity was examined. TSPAN-7 KD enhanced L-type CaV currents in mouse and human β-cells. Conversely, heterologous expression of TSPAN-7 with CaV 1.2 and CaV 1.3 L-type CaV channels decreased CaV currents and reduced Ca2+ influx through both channels. This was presumably the result of a direct interaction of TSPAN-7 and L-type CaV channels because TSPAN-7 coimmunoprecipitated with both CaV 1.2 and CaV 1.3 from primary human β-cells and from a heterologous expression system. Finally, TSPAN-7 KD in human β-cells increased basal (5.6 mM glucose) and stimulated (45 mM KCl + 14 mM glucose) insulin secretion. These findings strongly suggest that TSPAN-7 modulation of β-cell L-type CaV channels is a key determinant of β-cell glucose-stimulated Ca2+ entry and thus the set-point of GSIS.
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Affiliation(s)
- Matthew T Dickerson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Prasanna K Dadi
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Regan B Butterworth
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Arya Y Nakhe
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Sarah M Graff
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Karolina E Zaborska
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - Charles M Schaub
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
| | - David A Jacobson
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B MRB IV, Nashville, TN, USA
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46
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Ma H, Jeppesen JF, Jaenisch R. Human T Cells Expressing a CD19 CAR-T Receptor Provide Insights into Mechanisms of Human CD19-Positive β Cell Destruction. CELL REPORTS MEDICINE 2020; 1:100097. [PMID: 33205073 PMCID: PMC7659530 DOI: 10.1016/j.xcrm.2020.100097] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/24/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022]
Abstract
Autoimmune destruction of pancreatic β cells underlies type 1 diabetes (T1D). To understand T cell-mediated immune effects on human pancreatic β cells, we combine β cell-specific expression of a model antigen, CD19, and anti-CD19 chimeric antigen receptor T (CAR-T) cells. Coculturing CD19-expressing β-like cells and CD19 CAR-T cells results in T cell-mediated β-like cell death with release of activated T cell cytokines. Transcriptome analysis of β-like cells and human islets treated with conditioned medium of the immune reaction identifies upregulation of immune reaction genes and the pyroptosis mediator GSDMD as well as its activator CASP4. Caspase-4-mediated cleaved GSDMD is detected in β-like cells under inflammation and endoplasmic reticulum (ER) stress conditions. Among immune-regulatory genes, PDL1 is one of the most upregulated, and PDL1 overexpression partially protects human β-like cells transplanted into mice. This experimental platform identifies potential mechanisms of β cell destruction and may allow testing of therapeutic strategies.
CD19-expressing β-like cells differentiated from human ES cells are functional Tractable in vitro and in vivo killing of CD19-expressing β-like cells by CAR-T cells Upregulation of pyroptosis factors GSDMD and CAPS4 during β-like cell inflammation PDL1-overexpressing in β-like cells partially protects against reactive T cells
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Affiliation(s)
- Haiting Ma
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Jacob F Jeppesen
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Global Drug Discovery, Novo Nordisk, Cambridge, MA 02142, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.,Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142
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47
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Arribas-Layton D, Guyer P, Delong T, Dang M, Chow IT, Speake C, Greenbaum CJ, Kwok WW, Baker RL, Haskins K, James EA. Hybrid Insulin Peptides Are Recognized by Human T Cells in the Context of DRB1*04:01. Diabetes 2020; 69:1492-1502. [PMID: 32291282 PMCID: PMC7306133 DOI: 10.2337/db19-0620] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 04/09/2020] [Indexed: 12/30/2022]
Abstract
T cells isolated from the pancreatic infiltrates of nonobese diabetic mice have been shown to recognize epitopes formed by the covalent cross-linking of proinsulin and secretory granule peptides. Formation of such hybrid insulin peptides (HIPs) was confirmed through mass spectrometry, and responses to HIPs were observed among the islet-infiltrating T cells of pancreatic organ donors and in the peripheral blood of individuals with type 1 diabetes (T1D). However, questions remain about the prevalence of HIP-specific T cells in humans, the sequences they recognize, and their role in disease. We identified six novel HIPs that are recognized in the context of DRB1*04:01, discovered by using a library of theoretical HIP sequences derived from insulin fragments covalently linked to one another or to fragments of secretory granule proteins or other islet-derived proteins. We demonstrate that T cells that recognize these HIPs are detectable in the peripheral blood of subjects with T1D and exhibit an effector memory phenotype. HIP-reactive T-cell clones produced Th1-associated cytokines and proliferated in response to human islet preparations. These results support the relevance of HIPs in human disease, further establishing a novel posttranslational modification that may contribute to the loss of peripheral tolerance in T1D.
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Affiliation(s)
| | - Perrin Guyer
- Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Thomas Delong
- Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Denver, CO
| | - Mylinh Dang
- Department of Pharmaceutical Sciences, University of Colorado School of Pharmacy, Denver, CO
| | - I-Ting Chow
- Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Cate Speake
- Benaroya Research Institute at Virginia Mason, Seattle, WA
| | - Carla J Greenbaum
- Benaroya Research Institute at Virginia Mason, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Rocky L Baker
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, CO
| | - Kathryn Haskins
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, CO
| | - Eddie A James
- Benaroya Research Institute at Virginia Mason, Seattle, WA
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48
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Korem Kohanim Y, Tendler A, Mayo A, Friedman N, Alon U. Endocrine Autoimmune Disease as a Fragility of Immune Surveillance against Hypersecreting Mutants. Immunity 2020; 52:872-884.e5. [PMID: 32433950 PMCID: PMC7237888 DOI: 10.1016/j.immuni.2020.04.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/14/2020] [Accepted: 04/27/2020] [Indexed: 12/20/2022]
Abstract
Some endocrine organs are frequent targets of autoimmune attack. Here, we addressed the origin of autoimmune disease from the viewpoint of feedback control. Endocrine tissues maintain mass through feedback loops that balance cell proliferation and removal according to hormone-driven regulatory signals. We hypothesized the existence of a dedicated mechanism that detects and removes mutant cells that missense the signal and therefore hyperproliferate and hypersecrete with potential to disrupt organismal homeostasis. In this mechanism, hypersecreting cells are preferentially eliminated by autoreactive T cells at the cost of a fragility to autoimmune disease. The "autoimmune surveillance of hypersecreting mutants" (ASHM) hypothesis predicts the presence of autoreactive T cells in healthy individuals and the nature of self-antigens as peptides from hormone secretion pathway. It explains why some tissues get prevalent autoimmune disease, whereas others do not and instead show prevalent mutant-expansion disease (e.g., hyperparathyroidism). The ASHM hypothesis is testable, and we discuss experimental follow-up.
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Affiliation(s)
- Yael Korem Kohanim
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Avichai Tendler
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Avi Mayo
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Nir Friedman
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Uri Alon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
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49
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Eichmann M, Baptista R, Ellis RJ, Heck S, Peakman M, Beam CA. Costimulation Blockade Disrupts CD4 + T Cell Memory Pathways and Uncouples Their Link to Decline in β-Cell Function in Type 1 Diabetes. THE JOURNAL OF IMMUNOLOGY 2020; 204:3129-3138. [PMID: 32404353 DOI: 10.4049/jimmunol.1901439] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 04/13/2020] [Indexed: 12/17/2022]
Abstract
We previously reported that costimulation blockade by abatacept limits the decline of β-cell function and the frequency of circulating CD4+ central memory T cells (TCM) (CD45RO+CD62L+) in new-onset type 1 diabetes. In human subjects receiving placebo, we found a significant association between an increase in CD4+ TCM cells and the decline of β-cell function. To extend and refine these findings, we examined changes in human CD4+ and CD8+ naive and memory T cell subsets at greater resolution using polychromatic flow and mass cytometry. In the placebo group, we successfully reproduced the original finding of a significant association between TCM and β-cell function and extended this to other T cell subsets. Furthermore, we show that abatacept treatment significantly alters the frequencies of a majority of CD4+ conventional and regulatory T cell subsets; in general, Ag-naive subsets increase and Ag-experienced subsets decrease, whereas CD8+ T cell subsets are relatively resistant to drug effects, indicating a lesser reliance on CD28-mediated costimulation. Importantly, abatacept uncouples the relationship between changes in T cell subsets and β-cell function that is a component of the natural history of the disease. Although these data suggest immunological markers for predicting change in β-cell function in type 1 diabetes, the finding that abatacept blunts this relationship renders the biomarkers nonpredictive for this type of therapy. In sum, our findings point to a novel mechanism of action for this successful immunotherapy that may guide other disease-modifying approaches for type 1 diabetes.
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Affiliation(s)
- Martin Eichmann
- Peter Gorer Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, United Kingdom;
| | - Roman Baptista
- Peter Gorer Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, United Kingdom.,Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, United Kingdom
| | - Richard J Ellis
- Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, United Kingdom
| | - Susanne Heck
- Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, United Kingdom
| | - Mark Peakman
- Peter Gorer Department of Immunobiology, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, United Kingdom.,Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, United Kingdom.,Institute of Diabetes, Endocrinology and Obesity, King's Health Partners, London, United Kingdom; and
| | - Craig A Beam
- Department of Biomedical Sciences, Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, MI 49008
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50
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Aghaei Zarch SM, Dehghan Tezerjani M, Talebi M, Vahidi Mehrjardi MY. Molecular biomarkers in diabetes mellitus (DM). Med J Islam Repub Iran 2020; 34:28. [PMID: 32617267 PMCID: PMC7320976 DOI: 10.34171/mjiri.34.28] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Background: Diabetes mellitus (DM) is a growing epidemic metabolic syndrome, which affects near 5.6% of the world's population. Almost 12% of health expenditure is dedicated to this disorder. Discovering and developing biomarkers as a practical guideline with high specificity and sensitivity for the diagnosis, prognosis, and clinical management of DM is one of the subjects of great interest among DM researchers due to the long-lasting asymptomatic clinical manifestation of DM. In this study, we described a recently identified molecular biomarker involved in DM. Methods: This review study was done at the Diabetes Research Center affiliated to Shahid Sadoughi University of Medical Sciences. PubMed, Scopus, Google Scholar, and Web of Science were searched using the following keywords: "diabetes mellitus", "biomarker", "microRNA", "diagnostic tool" and "clinical manifestation." Results: A total of 107 studies were finally included in this review. After evaluating numerous articles, including original, metaanalysis, and review studies, we focused on molecular biomarkers involved in DM diagnosis and management. Conclusion: Increasing interest in biomarkers associated with DM goes back to its role in decreasing diabetes-related morbidity and mortality. This review focused on major molecular biomarkers such as proteomic and microRNA (miRNAs) as novel and interesting DM biomarkers that can help achieve timely diagnosis of DM.
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Affiliation(s)
| | - Masoud Dehghan Tezerjani
- Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mehrdad Talebi
- Department of Medical Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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