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1
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Maj M, Hernik K, Tyszkiewicz K, Owe-Larsson M, Sztokfisz-Ignasiak A, Malejczyk J, Janiuk I. A complex role of chromogranin A and its peptides in inflammation, autoimmunity, and infections. Front Immunol 2025; 16:1567874. [PMID: 40370467 PMCID: PMC12074958 DOI: 10.3389/fimmu.2025.1567874] [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: 01/28/2025] [Accepted: 04/09/2025] [Indexed: 05/16/2025] Open
Abstract
Chromogranin A (CgA), mostly known as a nonspecific neuroendocrine tumor marker, was the first glycoprotein from the granin family characterized as a prohormone for various bioactive peptides including vasostatin I/II (VS-I, VS-II), catestatin (CST), chromofungin (CHR), pancreastatin (PST), WE-14, and others. CgA and its derivatives present various functions, often antagonistic, in maintaining body homeostasis and influencing the immune system. This review aims to summarize the not fully understood role of CgA and its derivatives in inflammation, autoimmunity, and infections. CgA seems to be involved in the complex pathophysiology of cardiovascular disorders, neurodegenerative diseases, and other conditions where immune system dysfunction plays a role in the onset and development of the disease (e.g. systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), or rheumatoid arthritis (RA)). However, the direct immunomodulatory role of CgA is difficult to assess since many of its activities may be linked with its peptides. CST and VS-I are considered anti-inflammatory molecules, due to M2 macrophage polarization stimulation and downregulation of certain proinflammatory cytokines. Conversely, PST is reported to stimulate proinflammatory M1 macrophage polarization and Th1 lymphocyte response. Thus, the final effects of CgA in inflammation may depend on its cleavage pattern. Additionally, peptides like CST, VS-I, or CHR exert direct antimicrobial/antifungal activities. CgA, WE-14, and other less-known CgA-derived peptides have also been reported to trigger autoimmune responses, highly studied in type 1 diabetes mellitus. Overall, CgA and its derivatives have an interesting but complex role in immunity, however, their specific roles require further research.
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Affiliation(s)
- Maciej Maj
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Karolina Hernik
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Kaja Tyszkiewicz
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Maja Owe-Larsson
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Alicja Sztokfisz-Ignasiak
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
| | - Jacek Malejczyk
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
- Institute of Health Sciences, Faculty of Medical and Health Sciences, University of Siedlce, Siedlce, Poland
| | - Izabela Janiuk
- Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
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2
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Niri T, Inoue SI, Akazawa S, Nishikido S, Miwa M, Kobayashi M, Yui K, Okita M, Kawakami A, Abiru N. Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice. Clin Exp Immunol 2025; 219:uxae093. [PMID: 39432837 PMCID: PMC11773818 DOI: 10.1093/cei/uxae093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 09/16/2024] [Accepted: 10/19/2024] [Indexed: 10/23/2024] Open
Abstract
Haploinsufficiency of the transcription factor interferon-regulatory factor 4 (IRF4) prevents the onset of spontaneous diabetes in NOD mice. However, the immunological mechanisms of the IRF4-mediated disease regulation remain unclear. This study aims to investigate the role of IRF4 in the pathogenesis of autoimmune diabetes by conducting adoptive transfer experiments using donor IRF4 gene-deficient CD4+ T cells from BDC2.5-transgenic (Tg) NOD mice and recipient Rag1-knockout NOD mice, respectively. Through this approach, we analyzed both clinical and immunological phenotypes of the recipient mice. Additionally, IRF4-deficient BDC2.5 CD4+ T cells were stimulated to assess their immunological and metabolic phenotypes in vitro. The findings revealed that diabetes was completely prevented in the recipients with Irf4-/- T cells and was approximately 50% lower in those with Irf4+/- T cells than in wild type (WT) controls, whereas Irf4-/- recipients with WT T cells only showed a delayed onset of diabetes. Islet-infiltrating T cells isolated from recipients with Irf4+/- T cells exhibited significantly lower proliferation and IFN-γ/IL-17 double-positive cell fraction rates compared with those in WT controls. Irf4-/- BDC2.5 CD4+ T cells stimulated in vitro showed a reduced number of cell divisions, decreased antigen-specific T-cell markers, and impairment of glycolytic capacity compared with those observed in WT controls. We concluded that IRF4 predominantly regulates the diabetogenic potential in a dose-dependent manner by mediating the proliferation and differentiation of islet-infiltrating T cells while playing an adjunctive role in the innate immune responses toward diabetes progression in NOD mice.
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Affiliation(s)
- Tetsuro Niri
- Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shin-Ichi Inoue
- Division of Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Satoru Akazawa
- Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinpei Nishikido
- Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaki Miwa
- Diabetes Care Support Center, Nagasaki University Hospital, Nagasaki, Japan
| | | | - Katsuyuki Yui
- Shionogi Global Infectious Diseases Division, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
| | - Minoru Okita
- Department of Physical Therapy Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Atsushi Kawakami
- Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Norio Abiru
- Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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3
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Agrawal N, Kumar G, Pandey SP, Yadav S, Kumar M, Sudheesh MS, Pandey RS. Immunotherapy for Type 1 Diabetes: Mechanistic Insights and Impact of Delivery Systems. Curr Pharm Des 2025; 31:925-933. [PMID: 39694966 DOI: 10.2174/0113816128343081241030054303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/14/2024] [Accepted: 09/19/2024] [Indexed: 12/20/2024]
Abstract
Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, leading to hyperglycemia and various complications. Despite insulin replacement therapy, there is a need for therapies targeting the underlying autoimmune response. This review aims to explore the mechanistic insights into T1D pathogenesis and the impact of delivery systems on immunotherapy. Genetic predisposition and environmental factors contribute to T1D development, triggering an immune-mediated attack on β-cells. T cells, particularly CD4+ and CD8+ T cells, play a central role in β-cell destruction. Antigen- specific immunotherapy is a unique way to modify the immune system by targeting specific antigens (substances that trigger the immune system) for immunotherapy. It aims to restore immune tolerance by targeting autoantigens associated with T1D. Nanoparticle-based delivery systems offer precise antigen delivery, promoting immune tolerance induction. Various studies have demonstrated the efficacy of nanoparticle-mediated delivery of autoantigens and immunomodulatory agents in preclinical models, and several patents have been made in T1D. Combining antigen-specific immunotherapy with β-cell regeneration strategies presents a promising approach for T1D treatment. However, challenges remain in optimizing delivery systems for targeted immune modulation while ensuring safety and efficacy.
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Affiliation(s)
- Nishi Agrawal
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
| | - Ganesh Kumar
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
| | - Sree Prakash Pandey
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
| | - Shweta Yadav
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
| | - Manoj Kumar
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
| | - M S Sudheesh
- Department of Pharmaceutics, Amrita School of Pharmacy, Kochi, India
| | - Ravi Shankar Pandey
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya, Bilaspur (C.G.) 495009, India
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4
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Rojas M, Acosta-Ampudia Y, Heuer LS, Zang W, M Monsalve D, Ramírez-Santana C, Anaya JM, M Ridgway W, A Ansari A, Gershwin ME. Antigen-specific T cells and autoimmunity. J Autoimmun 2024; 148:103303. [PMID: 39141985 DOI: 10.1016/j.jaut.2024.103303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024]
Abstract
Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.
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Affiliation(s)
- Manuel Rojas
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA; Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia.
| | - Yeny Acosta-Ampudia
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Luke S Heuer
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Weici Zang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Diana M Monsalve
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | - Carolina Ramírez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota, Colombia
| | | | - William M Ridgway
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - Aftab A Ansari
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, 95616, USA.
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5
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Dwyer AJ, Shaheen ZR, Fife BT. Antigen-specific T cell responses in autoimmune diabetes. Front Immunol 2024; 15:1440045. [PMID: 39211046 PMCID: PMC11358097 DOI: 10.3389/fimmu.2024.1440045] [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: 05/28/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting β-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.
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Affiliation(s)
- Alexander J. Dwyer
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Zachary R. Shaheen
- Center for Immunology, Department of Pediatrics, Pediatric Rheumatology, Allergy, & Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Brian T. Fife
- Center for Immunology, Department of Medicine, Division of Rheumatic and Autoimmune Diseases, University of Minnesota Medical School, Minneapolis, MN, United States
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6
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Firdessa-Fite R, Johnson SN, Bechi Genzano C, Leon MA, Ku A, Ocampo Gonzalez FA, Milner JD, Sestak JO, Berkland C, Creusot RJ. Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy. Front Immunol 2024; 15:1258369. [PMID: 38933266 PMCID: PMC11199391 DOI: 10.3389/fimmu.2024.1258369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 05/21/2024] [Indexed: 06/28/2024] Open
Abstract
Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but clinical implementation has been challenging. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA used (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Over time, the peptides induced an IgE-independent anaphylactic reaction, the incidence of which was significantly delayed when peptides were in SAgA form rather than in free form. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Immunologic anaphylaxis occurred in NOD mice in a dose-dependent manner but not in C57BL/6 or BALB/c mice; however, its incidence did not correlate with the level of anti-peptide antibodies. We provide evidence that SAgAs significantly improve the efficacy of peptides to induce tolerance and prevent autoimmune diabetes while at the same time reducing their anaphylactogenic potential.
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Affiliation(s)
- Rebuma Firdessa-Fite
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, United States
| | - Stephanie N. Johnson
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
| | - Camillo Bechi Genzano
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, United States
| | - Martin A. Leon
- Department of Chemistry, University of Kansas, Lawrence, KS, United States
| | - Amy Ku
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY, United States
| | - Fernando A. Ocampo Gonzalez
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, NY, United States
| | - Joshua D. Milner
- Department of Pediatrics, Division of Allergy and Immunology, Columbia University Irving Medical Center, New York, NY, United States
| | - Joshua O. Sestak
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
| | - Cory Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
- Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS, United States
| | - Remi J. Creusot
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, United States
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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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8
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Stern LJ, Clement C, Galluzzi L, Santambrogio L. Non-mutational neoantigens in disease. Nat Immunol 2024; 25:29-40. [PMID: 38168954 PMCID: PMC11075006 DOI: 10.1038/s41590-023-01664-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 09/29/2023] [Indexed: 01/05/2024]
Abstract
The ability of mammals to mount adaptive immune responses culminating with the establishment of immunological memory is predicated on the ability of the mature T cell repertoire to recognize antigenic peptides presented by syngeneic MHC class I and II molecules. Although it is widely believed that mature T cells are highly skewed towards the recognition of antigenic peptides originating from genetically diverse (for example, foreign or mutated) protein-coding regions, preclinical and clinical data rather demonstrate that novel antigenic determinants efficiently recognized by mature T cells can emerge from a variety of non-mutational mechanisms. In this Review, we describe various mechanisms that underlie the formation of bona fide non-mutational neoantigens, such as epitope mimicry, upregulation of cryptic epitopes, usage of non-canonical initiation codons, alternative RNA splicing, and defective ribosomal RNA processing, as well as both enzymatic and non-enzymatic post-translational protein modifications. Moreover, we discuss the implications of the immune recognition of non-mutational neoantigens for human disease.
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Affiliation(s)
- Lawrence J Stern
- Department of Pathology, UMass Chan Medical School, Worcester, MA, USA
- Immunology and Microbiology Program, UMass Chan Medical School, Worcester, MA, USA
| | - Cristina Clement
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
| | - Laura Santambrogio
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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Firdessa Fite R, Bechi Genzano C, Mallone R, Creusot RJ. Epitope-based precision immunotherapy of Type 1 diabetes. Hum Vaccin Immunother 2023; 19:2154098. [PMID: 36656048 PMCID: PMC9980607 DOI: 10.1080/21645515.2022.2154098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Antigen-specific immunotherapies (ASITs) address important clinical needs in treating autoimmune diseases. However, Type 1 diabetes is a heterogeneous disease wherein patient characteristics influence responsiveness to ASITs. Targeting not only disease-relevant T cell populations, but also specific groups of patients using precision medicine is a new goal toward achieving effective treatment. HLA-restricted peptides provide advantages over protein as antigens, however, methods for profiling antigen-specific T cells need to improve in sensitivity, depth, and throughput to facilitate epitope selection. Delivery approaches are highly diverse, illustrating the many ways relevant antigen-presenting cell populations and anatomical locations can be targeted for tolerance induction. The role of persistence of antigen presentation in promoting durable antigen-specific tolerance requires further investigation. Based on the outcome of ASIT trials, the field is moving toward using patient-specific variations to improve efficacy, but challenges still lie on the path to delivering more effective and safer treatment to the T1D patient population.
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Affiliation(s)
- Rebuma Firdessa Fite
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Camillo Bechi Genzano
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.,Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Hôpitaux Universitaires de Paris Centre-Université de Paris, Paris, France
| | - Remi J Creusot
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
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10
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Firdessa-Fite R, Johnson SN, Leon MA, Sestak JO, Berkland C, Creusot RJ. Soluble antigen arrays improve the efficacy and safety of peptide-based tolerogenic immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.05.539161. [PMID: 37205572 PMCID: PMC10187310 DOI: 10.1101/2023.05.05.539161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but the limited in vivo stability and uptake of peptides impedes clinical implementation. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA (hydrolysable (hSAgA) and non-hydrolysable 'click' SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Both SAgA variants significantly delayed anaphylaxis compared to their respective free peptides. The anaphylaxis, which occurred in NOD mice but not in C57BL/6 mice, was dose-dependent but did not correlate with the production of IgG1 or IgE against the peptides. We provide evidence that SAgAs significantly improve the efficacy and safety of peptide-based immunotherapy.
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Affiliation(s)
- Rebuma Firdessa-Fite
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Medical Center, 650 West 168 St, New York, NY 10032
| | - Stephanie N. Johnson
- Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047
| | - Martin A. Leon
- Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045
| | - Joshua O. Sestak
- Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047
| | - Cory Berkland
- Department of Pharmaceutical Chemistry, University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047
- Department of Chemical and Petroleum Engineering, University of Kansas,1530 West 15 Street, Lawrence, KS 66045
| | - Remi J. Creusot
- Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University Medical Center, 650 West 168 St, New York, NY 10032
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Ochocińska A, Wysocka-Mincewicz M, Świderska J, Cukrowska B. Selected Serum Markers Associated with Pathogenesis and Clinical Course of Type 1 Diabetes in Pediatric Patients-The Effect of Disease Duration. J Clin Med 2023; 12:2151. [PMID: 36983153 PMCID: PMC10051659 DOI: 10.3390/jcm12062151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/24/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
Biochemical abnormalities in the course of type 1 diabetes (T1D) may cause the production/activation of various proteins and peptides influencing treatment and causing a risk of complications. The aim of this study was to assess concentrations of selected serum substances involved in the pathogenesis and course of T1D and to correlate their concentrations with the duration of T1D. The study included patients with T1D (n = 156) at the age of 3-17, who were divided according to the duration of the disease into those newly diagnosed (n = 30), diagnosed after 3-5 (n = 77), 6-7 (n = 25), and over 7 (n = 24) years from the onset of T1D, and age-matched healthy controls (n = 30). Concentrations of amylin (IAPP), proamylin (proIAPP), catestatin (CST), chromogranin A (ChgA), nerve growth factor (NFG), platelet-activating factor (PAF), uromodulin (UMOD), and intestinal fatty acid binding protein (I-FABP) were measured in sera using immunoenzymatic tests. There were significant differences in concentrations of all the substances except UMOD and NGF between T1D patients and healthy children. The duration of the disease affected concentrations of CST, ChgA, PAF, and NGF, i.e., proteins/peptides which could have an impact on the course of T1D and the development of complications. In long-term patients, a decrease in concentrations of CST and ChgA, and an increase in PAF concentrations were found. In the case of NGF, a decrease was observed after the initial high values, followed by an increase over 7 years after T1D diagnosis. Concluding, the results show that concentrations of selected serum indicators may change in the course of T1D. Further studies are needed to establish whether these indicators could be used in the context of predicting long-term complications.
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Affiliation(s)
- Agnieszka Ochocińska
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - Marta Wysocka-Mincewicz
- Clinic of Endocrinology and Diabetology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - Jolanta Świderska
- Clinic of Endocrinology and Diabetology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
| | - Bożena Cukrowska
- Department of Pathomorphology, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20, 04-730 Warsaw, Poland
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12
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Lichti CF, Wan X. Using mass spectrometry to identify neoantigens in autoimmune diseases: The type 1 diabetes example. Semin Immunol 2023; 66:101730. [PMID: 36827760 PMCID: PMC10324092 DOI: 10.1016/j.smim.2023.101730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023]
Abstract
In autoimmune diseases, recognition of self-antigens presented by major histocompatibility complex (MHC) molecules elicits unexpected attack of tissue by autoantibodies and/or autoreactive T cells. Post-translational modification (PTM) may alter the MHC-binding motif or TCR contact residues in a peptide antigen, transforming the tolerance to self to autoreactivity. Mass spectrometry-based immunopeptidomics provides a valuable mechanism for identifying MHC ligands that contain PTMs and can thus provide valuable insights into pathogenesis and therapeutics of autoimmune diseases. A plethora of PTMs have been implicated in this process, and this review highlights their formation and identification.
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Affiliation(s)
- Cheryl F Lichti
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
| | - Xiaoxiao Wan
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
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13
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Li W, Li R, Wang Y, Zhang Y, Tomar MS, Dai S. Calcitonin gene-related peptide is a potential autoantigen for CD4 T cells in type 1 diabetes. Front Immunol 2022; 13:951281. [PMID: 36189304 PMCID: PMC9523785 DOI: 10.3389/fimmu.2022.951281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/04/2022] [Indexed: 12/01/2022] Open
Abstract
The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide with critical roles in the development of peripheral sensitization and pain. One of the CGRP family peptides, islet amyloid polypeptide (IAPP), is an important autoantigen in type 1 diabetes. Due to the high structural and chemical similarity between CGRP and IAPP, we expected that the CGRP peptide could be recognized by IAPP-specific CD4 T cells. However, there was no cross-reactivity between the CGRP peptide and the diabetogenic IAPP-reactive T cells. A set of CGRP-specific CD4 T cells was isolated from non-obese diabetic (NOD) mice. The T-cell receptor (TCR) variable regions of both α and β chains were highly skewed towards TRAV13 and TRBV13, respectively. The clonal expansion of T cells suggested that the presence of activated T cells responded to CGRP stimulation. None of the CGRP-specific CD4 T cells were able to be activated by the IAPP peptide. This established that CGRP-reactive CD4 T cells are a unique type of autoantigen-specific T cells in NOD mice. Using IAg7-CGRP tetramers, we found that CGRP-specific T cells were present in the pancreas of both prediabetic and diabetic NOD mice. The percentages of CGRP-reactive T cells in the pancreas of NOD mice were correlated to the diabetic progression. We showed that the human CGRP peptide presented by IAg7 elicited strong CGRP-specific T-cell responses. These findings suggested that CGRP is a potential autoantigen for CD4 T cells in NOD mice and probably in humans. The CGRP-specific CD4 T cells could be a unique marker for type 1 diabetes. Given the ubiquity of CGRP in nervous systems, it could potentially play an important role in diabetic neuropathy.
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Affiliation(s)
- Wei Li
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- National Health Commission (NHC) Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Ronghui Li
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- National Health Commission (NHC) Key Laboratory of Pulmonary Immune-related Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yang Wang
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Yan Zhang
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Munendra S. Tomar
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Shaodong Dai
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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14
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Li W, Zhang Y, Li R, Wang Y, Chen L, Dai S. A Novel Tolerogenic Antibody Targeting Disulfide-Modified Autoantigen Effectively Prevents Type 1 Diabetes in NOD Mice. Front Immunol 2022; 13:877022. [PMID: 36032077 PMCID: PMC9406144 DOI: 10.3389/fimmu.2022.877022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/06/2022] [Indexed: 11/15/2022] Open
Abstract
Increasing evidence suggested that the islet amyloid polypeptide (IAPP) is an essential autoantigen in the pathogenesis of type 1 diabetes (T1D) in humans and non-obese diabetic (NOD) mice. A unique disulfide containing IAPP-derived peptide KS20 is one of the highly diabetogenic peptides in NOD mice. The KS20-reactive T cells, including prototypic pathogenic BDC5.2.9, accumulate in the pancreas of prediabetic and diabetic mice and contribute to disease development. We generated a monoclonal antibody (LD96.24) that interacts with IAg7-KS20 complexes with high affinity and specificity. LD96.24 recognized the IAg7-KS20 disulfide loop and blocked the interaction between IAg7-KS20 tetramers and cognate T cells but not other autoantigen-reactive T cells. The in vivo LD96.24 studies, at either early or late stages, drastically induced tolerance and delayed the onset of T1D disease in NOD mice by reducing the infiltration of not only IAPP-specific T cells but also chromogranin A and insulin-specific T cells in the pancreas, together with B cells and dendritic cells. LD96.24 can also significantly increase the ratio of Foxp3+ regulatory T cells with Interferon-gamma-secreting effector T cells. Our data suggested the important role of disulfide-modified peptides in the development of T1D. Targeting the complexes of Major histocompatibility complex (MHC)/disulfide modified antigens would influence the thiol redox balance and could be a novel immunotherapy for T1D.
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Affiliation(s)
- Wei Li
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- National Health Commission (NHC) Key Laboratory of Pulmonary Immune-Related Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yan Zhang
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Ronghui Li
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- National Health Commission (NHC) Key Laboratory of Pulmonary Immune-Related Diseases, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yang Wang
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Lan Chen
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Shaodong Dai
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
- *Correspondence: Shaodong Dai,
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15
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Joyce S, Ternette N. Know thy immune self and non-self: Proteomics informs on the expanse of self and non-self, and how and where they arise. Proteomics 2021; 21:e2000143. [PMID: 34310018 PMCID: PMC8865197 DOI: 10.1002/pmic.202000143] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/30/2021] [Accepted: 07/19/2021] [Indexed: 12/30/2022]
Abstract
T cells play an important role in the adaptive immune response to a variety of infections and cancers. Initiation of a T cell mediated immune response requires antigen recognition in a process termed MHC (major histocompatibility complex) restri ction. A T cell antigen is a composite structure made up of a peptide fragment bound within the antigen-binding groove of an MHC-encoded class I or class II molecule. Insight into the precise composition and biology of self and non-self immunopeptidomes is essential to harness T cell mediated immunity to prevent, treat, or cure infectious diseases and cancers. T cell antigen discovery is an arduous task! The pioneering work in the early 1990s has made large-scale T cell antigen discovery possible. Thus, advancements in mass spectrometry coupled with proteomics and genomics technologies make possible T cell antigen discovery with ease, accuracy, and sensitivity. Yet we have only begun to understand the breadth and the depth of self and non-self immunopeptidomes because the molecular biology of the cell continues to surprise us with new secrets directly related to the source, and the processing and presentation of MHC ligands. Focused on MHC class I molecules, this review, therefore, provides a brief historic account of T cell antigen discovery and, against a backdrop of key advances in molecular cell biologic processes, elaborates on how proteogenomics approaches have revolutionised the field.
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Affiliation(s)
- Sebastian Joyce
- Department of Veterans AffairsTennessee Valley Healthcare System and the Department of PathologyMicrobiology and ImmunologyVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Nicola Ternette
- Centre for Cellular and Molecular PhysiologyNuffield Department of MedicineUniversity of OxfordOxfordUK
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16
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Reed B, Crawford F, Hill RC, Jin N, White J, Krovi SH, Marrack P, Hansen K, Kappler JW. Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation. J Exp Med 2021; 218:211485. [PMID: 33095259 PMCID: PMC7590512 DOI: 10.1084/jem.20192135] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 08/06/2020] [Accepted: 09/10/2020] [Indexed: 01/15/2023] Open
Abstract
The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.
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Affiliation(s)
- Brendan Reed
- Department of Biomedical Research, National Jewish Health, Denver, CO.,Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO.,Research Division, Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - Frances Crawford
- Department of Biomedical Research, National Jewish Health, Denver, CO
| | - Ryan C Hill
- Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - Niyun Jin
- Department of Biomedical Research, National Jewish Health, Denver, CO.,Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO.,Research Division, Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - Janice White
- Department of Biomedical Research, National Jewish Health, Denver, CO
| | - S Harsha Krovi
- Department of Biomedical Research, National Jewish Health, Denver, CO.,Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - Philippa Marrack
- Department of Biomedical Research, National Jewish Health, Denver, CO.,Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO.,Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - Kirk Hansen
- Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO
| | - John W Kappler
- Department of Biomedical Research, National Jewish Health, Denver, CO.,Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado, Aurora, CO.,Research Division, Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO.,Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Aurora, CO
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17
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Herold Z, Doleschall M, Somogyi A. Role and function of granin proteins in diabetes mellitus. World J Diabetes 2021; 12:1081-1092. [PMID: 34326956 PMCID: PMC8311481 DOI: 10.4239/wjd.v12.i7.1081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
The granin glycoprotein family consists of nine acidic proteins; chromogranin A (CgA), chromogranin B (CgB), and secretogranin II-VIII. They are produced by a wide range of neuronal, neuroendocrine, and endocrine cells throughout the human body. Their major intracellular function is to sort peptides and proteins into secretory granules, but their cleavage products also take part in the extracellular regulation of diverse biological processes. The contribution of granins to carbohydrate metabolism and diabetes mellitus is a recent research area. CgA is associated with glucose homeostasis and the progression of type 1 diabetes. WE-14, CgA10-19, and CgA43-52 are peptide derivates of CgA, and act as CD4+ or CD8+ autoantigens in type 1 diabetes, whereas pancreastatin (PST) and catestatin have regulatory effects in carbohydrate metabolism. Furthermore, PST is related to gestational and type 2 diabetes. CgB has a crucial role in physiological insulin secretion. Secretogranins II and III have angiogenic activity in diabetic retinopathy (DR), and are novel targets in recent DR studies. Ongoing studies are beginning to investigate the potential use of granin derivatives as drugs to treat diabetes based on the divergent relationships between granins and different types of diabetes.
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Affiliation(s)
- Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest 1083, Hungary
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
| | - Marton Doleschall
- Molecular Medicine Research Group, Eotvos Lorand Research Network and Semmelweis University, Budapest 1089, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest 1088, Hungary
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18
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Reed BK, Kappler JW. Hidden in Plain View: Discovery of Chimeric Diabetogenic CD4 T Cell Neo-Epitopes. Front Immunol 2021; 12:669986. [PMID: 33986758 PMCID: PMC8111216 DOI: 10.3389/fimmu.2021.669986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/01/2021] [Indexed: 11/13/2022] Open
Abstract
The T cell antigens driving autoimmune Type 1 Diabetes (T1D) have been pursued for more than three decades. When diabetogenic CD4 T cell clones and their relevant MHCII antigen presenting alleles were first identified in rodents and humans, the path to discovering the peptide epitopes within pancreatic beta cell proteins seemed straightforward. However, as experimental results accumulated, definitive data were often absent or controversial. Work within the last decade has helped to clear up some of the controversy by demonstrating that a number of the important MHCII presented epitopes are not encoded in the natural beta cell proteins, but in fact are fusions between peptide fragments derived from the same or different proteins. Recently, the mechanism for generating these MHCII diabetogenic chimeric epitopes has been attributed to a form of reverse proteolysis, called transpeptidation, a process that has been well-documented in the production of MHCI presented epitopes. In this mini-review we summarize these data and their implications for T1D and other autoimmune responses.
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Affiliation(s)
- Brendan K Reed
- Research Division, Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, United States.,Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, United States.,Department of Immunology and Microbiology, University of Colorado, Aurora, CO, United States
| | - John W Kappler
- Research Division, Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, United States.,Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, United States.,Department of Immunology and Microbiology, University of Colorado, Aurora, CO, United States.,Biochemistry and Molecular Genetics, University of Colorado, Aurora, CO, United States
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19
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A biomimetic five-module chimeric antigen receptor ( 5MCAR) designed to target and eliminate antigen-specific T cells. Proc Natl Acad Sci U S A 2020; 117:28950-28959. [PMID: 33139567 DOI: 10.1073/pnas.2012495117] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
T cells express clonotypic T cell receptors (TCRs) that recognize peptide antigens in the context of class I or II MHC molecules (pMHCI/II). These receptor modules associate with three signaling modules (CD3γε, δε, and ζζ) and work in concert with a coreceptor module (either CD8 or CD4) to drive T cell activation in response to pMHCI/II. Here, we describe a first-generation biomimetic five-module chimeric antigen receptor (5MCAR). We show that 1) chimeric receptor modules built with the ectodomains of pMHCII assemble with CD3 signaling modules into complexes that redirect cytotoxic T lymphocyte (CTL) specificity and function in response to the clonotypic TCRs of pMHCII-specific CD4+ T cells, and 2) surrogate coreceptor modules enhance the function of these complexes. Furthermore, we demonstrate that adoptively transferred 5MCAR-CTLs can mitigate type I diabetes by targeting autoimmune CD4+ T cells in NOD mice. This work provides a framework for the construction of biomimetic 5MCARs that can be used as tools to study the impact of particular antigen-specific T cells in immune responses, and may hold potential for ameliorating diseases mediated by pathogenic T cells.
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20
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Eiden LE, Gundlach AL, Grinevich V, Lee MR, Mecawi AS, Chen D, Buijs RM, Hernandez VS, Fajardo-Dolci G, Zhang L. Regulatory peptides and systems biology: A new era of translational and reverse-translational neuroendocrinology. J Neuroendocrinol 2020; 32:e12844. [PMID: 32307768 DOI: 10.1111/jne.12844] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/15/2022]
Abstract
Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation. The third is the explosion in defined structures of the G-protein coupled receptors to which most regulatory peptides bind and exert their actions. These trends have closely wedded basic systems biology to drug discovery and development, creating a "two-way street" on which translational advances travel from basic research to the clinic, and, equally importantly, "reverse-translational" information is gathered, about the molecular, cellular and circuit-level mechanisms of action of regulatory peptides, comprising information required for the fine-tuning of drug development through testing in animal models. This review focuses on a small group of 'influential' peptides, including oxytocin, vasopressin, pituitary adenylate cyclase-activating polypeptide, ghrelin, relaxin-3 and glucagon-like peptide-1, and how basic discoveries and their application to therapeutics have intertwined over the past decade.
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Affiliation(s)
- Lee E Eiden
- Section on Molecular Neuroscience, National Institute of Mental Heath-Intramural Research Program, NIH, Bethesda, MD, USA
| | - Andrew L Gundlach
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Valery Grinevich
- Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, University Heidelberg, Mannheim, Germany
| | - Mary R Lee
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, NIAAA and NIDA, NIH, Bethesda, MD, USA
| | - André S Mecawi
- Laboratory of Neuroendocrinology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Duan Chen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ruud M Buijs
- Department of Cell Biology and Physiology, Institute for Biomedical Research, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico
| | - Vito S Hernandez
- Department of Physiology, School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Germán Fajardo-Dolci
- School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Limei Zhang
- Department of Physiology, School of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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21
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Butalia S, Kaplan GG, Khokhar B, Haubrich S, Rabi DM. The Challenges of Identifying Environmental Determinants of Type 1 Diabetes: In Search of the Holy Grail. Diabetes Metab Syndr Obes 2020; 13:4885-4895. [PMID: 33328748 PMCID: PMC7734044 DOI: 10.2147/dmso.s275080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/15/2020] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes is the result of autoimmune-mediated destruction and inflammation of the insulin-producing β-cells of the pancreas. The excess morbidity and mortality from its complications coupled with its increasing incidence emphasize the importance to better understand the etiology of this condition. It has a strong genetic component, but a genetic predisposition is not the sole contributor to disease development as only 30% to 50% of identical twins both develop the disease. In addition, there are multiple lines of evidence to support that environmental factors contribute to the pathogenesis of type 1 diabetes. Environmental risk factors that have been proposed include infections, dietary factors, air pollution, vaccines, location of residence, childhood obesity, family environment and stress. Researchers have conducted many observational studies to identify and characterize these potential environmental factors, but findings have been inconsistent or inconclusive. Many studies have had inherent methodological issues in recruitment, participation, defining cases and exposures, and/or data analysis which may limit the interpretability of findings. Identifying and addressing these limitations may allow for greatly needed advances in our understanding of type 1 diabetes. As such, the purpose of this article is to review and discuss the limitations of observational studies that aim to determine environmental risk factors for type 1 diabetes and propose recommendations to overcome them.
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Affiliation(s)
- Sonia Butalia
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Correspondence: Sonia ButaliaDivision of Endocrinology and Metabolism, Richmond Road Diagnostic and Treatment Centre, 1820 Richmond Road SW, Calgary, AlbertaT2T 5C7, CanadaTel +1 403-955-8327Fax +1 403-955-8249 Email
| | - Gilaad G Kaplan
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Bushra Khokhar
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Sydney Haubrich
- Ward of the 21st Century, University of Calgary, Calgary, Alberta, Canada
| | - Doreen M Rabi
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Cardiac Sciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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22
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Mahata SK, Corti A. Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation. Ann N Y Acad Sci 2019; 1455:34-58. [PMID: 31588572 PMCID: PMC6899468 DOI: 10.1111/nyas.14249] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 09/09/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
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Affiliation(s)
- Sushil K Mahata
- VA San Diego Healthcare System, San Diego, California.,Metabolic Physiology & Ultrastructural Biology Laboratory, Department of Medicine, University of California, San Diego, La Jolla, California
| | - Angelo Corti
- IRCCS San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
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23
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Ferreira LMR, Muller YD, Bluestone JA, Tang Q. Next-generation regulatory T cell therapy. Nat Rev Drug Discov 2019; 18:749-769. [PMID: 31541224 PMCID: PMC7773144 DOI: 10.1038/s41573-019-0041-4] [Citation(s) in RCA: 330] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2019] [Indexed: 02/08/2023]
Abstract
Regulatory T cells (Treg cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As Treg cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of Treg cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR-Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of Treg cells. In this Review, we describe the key advances and prospects in designing and implementing Treg cell-based therapy in autoimmunity and transplantation.
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Affiliation(s)
- Leonardo M R Ferreira
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, USA
| | - Yannick D Muller
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, USA.
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
- Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
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24
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Wang Y, Sosinowski T, Novikov A, Crawford F, White J, Jin N, Liu Z, Zou J, Neau D, Davidson HW, Nakayama M, Kwok WW, Gapin L, Marrack P, Kappler JW, Dai S. How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes. Sci Immunol 2019; 4:eaav7517. [PMID: 30952805 PMCID: PMC6929690 DOI: 10.1126/sciimmunol.aav7517] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/04/2019] [Accepted: 02/11/2019] [Indexed: 11/03/2022]
Abstract
In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4+ T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IAg7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide grooves and for strong CD4+ T cell stimulation. Here, we present crystal structures showing how these mutations control CD4+ T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal stricking similarities between mouse and human CD4+ TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9-23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation of fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism limited to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.
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MESH Headings
- Amino Acid Sequence/genetics
- Animals
- Autoantigens/genetics
- Autoantigens/immunology
- Autoantigens/metabolism
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cell Line, Tumor
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Epitopes, T-Lymphocyte/genetics
- Epitopes, T-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/metabolism
- HLA-DQ Antigens/immunology
- HLA-DQ Antigens/metabolism
- Humans
- Hybridomas
- Immune Tolerance
- Insulin/genetics
- Insulin/immunology
- Insulin/metabolism
- Lysosomes/immunology
- Lysosomes/metabolism
- Mice
- Mice, Inbred NOD
- Molecular Docking Simulation
- Mutation
- Pancreas/cytology
- Pancreas/immunology
- Pancreas/metabolism
- Peptide Fragments/genetics
- Peptide Fragments/immunology
- Peptide Fragments/metabolism
- Protein Domains/immunology
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- Thymus Gland/cytology
- Thymus Gland/immunology
- Thymus Gland/metabolism
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Affiliation(s)
- Yang Wang
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tomasz Sosinowski
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Andrey Novikov
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
| | - Frances Crawford
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
| | - Janice White
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
| | - Niyun Jin
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Zikou Liu
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
| | - Jinhao Zou
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
| | - David Neau
- Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439, USA
| | - Howard W Davidson
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Maki Nakayama
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - Laurent Gapin
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Philippa Marrack
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - John W Kappler
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA.
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Structural Biology and Biochemistry program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Shaodong Dai
- Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA.
- Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Structural Biology and Biochemistry program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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25
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A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes. J Autoimmun 2018; 98:13-23. [PMID: 30454875 DOI: 10.1016/j.jaut.2018.11.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/08/2018] [Accepted: 11/12/2018] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes (T1D) is caused by diabetogenic T cells that evaded tolerance mechanisms and react against multiple β-cell antigens. Antigen-specific therapy to reinstate tolerance (typically using a single β-cell antigen) has so far proved unsuccessful in T1D patients. Plasmid DNA (pDNA)-mediated expression of proinsulin has demonstrated transient protection in clinical trials, but long-lasting tolerance is yet to be achieved. We aimed to address whether pDNA delivery of multiple epitopes/mimotopes from several β-cell antigens efficiently presented to CD4+ and CD8+ T cells could also induce tolerance. This approach significantly delayed T1D development, while co-delivery of pDNA vectors expressing four full antigens protected more mice. Delivery of multiple epitopes resulted in a broad engagement of specific T cells, eliciting a response distinct from endogenous epitopes draining from islets. T-cell phenotypes also varied with antigen specificity. Unexpectedly, the repertoire of T cells reactive to the same epitope was highly polyclonal. Despite induction of some CD25+ Foxp3+ regulatory T cells, protection from disease did not persist after treatment discontinuation. These data demonstrate that epitope-based tolerogenic DNA vaccines constitute effective precision medicine tools to target a broad range of specific CD4+ and CD8+ diabetogenic T-cell populations for prevention or treatment of T1D.
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26
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Class II MHC antigen processing in immune tolerance and inflammation. Immunogenetics 2018; 71:171-187. [PMID: 30421030 DOI: 10.1007/s00251-018-1095-x] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 10/31/2018] [Indexed: 01/22/2023]
Abstract
Presentation of peptide antigens by MHC-II proteins is prerequisite to effective CD4 T cell tolerance to self and to recognition of foreign antigens. Antigen uptake and processing pathways as well as expression of the peptide exchange factors HLA-DM and HLA-DO differ among the various professional and non-professional antigen-presenting cells and are modulated by cell developmental state and activation. Recent studies have highlighted the importance of these cell-specific factors in controlling the source and breadth of peptides presented by MHC-II under different conditions. During inflammation, increased presentation of selected self-peptides has implications for maintenance of peripheral tolerance and autoimmunity.
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27
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Muntjewerff EM, Dunkel G, Nicolasen MJT, Mahata SK, van den Bogaart G. Catestatin as a Target for Treatment of Inflammatory Diseases. Front Immunol 2018; 9:2199. [PMID: 30337922 PMCID: PMC6180191 DOI: 10.3389/fimmu.2018.02199] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 09/05/2018] [Indexed: 12/12/2022] Open
Abstract
It is increasingly clear that inflammatory diseases and cancers are influenced by cleavage products of the pro-hormone chromogranin A (CgA), such as the 21-amino acids long catestatin (CST). The goal of this review is to provide an overview of the anti-inflammatory effects of CST and its mechanism of action. We discuss evidence proving that CST and its precursor CgA are crucial for maintaining metabolic and immune homeostasis. CST could reduce inflammation in various mouse models for diabetes, colitis and atherosclerosis. In these mouse models, CST treatment resulted in less infiltration of immune cells in affected tissues, although in vitro monocyte migration was increased by CST. Both in vivo and in vitro, CST can shift macrophage differentiation from a pro- to an anti-inflammatory phenotype. Thus, the concept is emerging that CST plays a role in tissue homeostasis by regulating immune cell infiltration and macrophage differentiation. These findings warrant studying the effects of CST in humans and make it an interesting therapeutic target for treatment and/or diagnosis of various metabolic and immune diseases.
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Affiliation(s)
- Elke M Muntjewerff
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Gina Dunkel
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Mara J T Nicolasen
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Sushil K Mahata
- VA San Diego Healthcare System, San Diego, CA, United States.,Department of Medicine, University of California at San Diego, La Jolla, CA, United States
| | - Geert van den Bogaart
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands
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28
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Eissa N, Hussein H, Hendy GN, Bernstein CN, Ghia JE. Chromogranin-A and its derived peptides and their pharmacological effects during intestinal inflammation. Biochem Pharmacol 2018; 152:315-326. [PMID: 29656116 DOI: 10.1016/j.bcp.2018.04.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023]
Abstract
The gastrointestinal tract is the largest endocrine organ that produces a broad range of active peptides. Mucosal changes during inflammation alter the distribution and products of enteroendocrine cells (EECs) that play a role in immune activation and regulation of gut homeostasis by mediating communication between the nervous, endocrine and immune systems. Patients with inflammatory bowel disease (IBD) typically have altered expression of chromogranin (CHG)-A (CHGA), a major soluble protein secreted by EECs that functions as a pro-hormone. CHGA gives rise to several bioactive peptides that have direct or indirect effects on intestinal inflammation. In IBD, CHGA and its derived peptides are correlated with the disease activity. In this review we describe the potential immunomodulatory roles of CHGA and its derived peptides and their clinical relevance during the progression of intestinal inflammation. Targeting CHGA and its derived peptides could be of benefit for the diagnosis and clinical management of IBD patients.
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Affiliation(s)
- Nour Eissa
- Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, MB, Canada; Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada; IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Hayam Hussein
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, OH, USA
| | - Geoffrey N Hendy
- Metabolic Disorders and Complications, McGill University Health Centre-Research Institute, Departments of Medicine, Physiology, and Human Genetics, McGill University, Montréal, QC, Canada
| | - Charles N Bernstein
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada; Section of Gastroenterology, Department of Internal Medicine, College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Jean-Eric Ghia
- Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, MB, Canada; Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada; IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada; Section of Gastroenterology, Department of Internal Medicine, College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
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29
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Tarbell KV, Egen JG. Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation. J Leukoc Biol 2018; 103:1117-1129. [PMID: 29393979 DOI: 10.1002/jlb.3mir1017-400r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 12/18/2017] [Accepted: 12/21/2017] [Indexed: 02/28/2024] Open
Abstract
The generation and regulation of innate immune signals are key determinants of autoimmune pathogenesis. Emerging evidence suggests that parallel processes operating in the setting of solid tumors can similarly determine the balance between tolerance and immunity and ultimately the effectiveness of the antitumor immune response. In both contexts, self-specific responses start with innate immune cell activation that leads to the initial break in self-tolerance, which can be followed by immune response amplification and maturation through innate-adaptive crosstalk, and finally immune-mediated tissue/tumor destruction that can further potentiate inflammation. Of particular importance for these processes is type I IFN, which is induced in response to endogenous ligands, such as self-nucleic acids, and acts on myeloid cells to promote the expansion of autoreactive or tumor-specific T cells and their influx into the target tissue. Evidence from the study of human disease pathophysiology and genetics and mouse models of disease has revealed an extensive and complex network of negative regulatory pathways that has evolved to restrain type I IFN production and activity. Here, we review the overlapping features of self- and tumor-specific immune responses, including the central role that regulators of the type I IFN response and innate immune cell activation play in maintaining tolerance, and discuss how a better understanding of the pathophysiology of autoimmunity can help to identify new approaches to promote immune-mediated tumor destruction.
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Affiliation(s)
- Kristin V Tarbell
- Department of Oncology, Amgen, Inc., South San Francisco, California, USA
| | - Jackson G Egen
- Department of Oncology, Amgen, Inc., South San Francisco, California, USA
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30
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Dendrou CA, Petersen J, Rossjohn J, Fugger L. HLA variation and disease. Nat Rev Immunol 2018; 18:325-339. [PMID: 29292391 DOI: 10.1038/nri.2017.143] [Citation(s) in RCA: 491] [Impact Index Per Article: 70.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fifty years since the first description of an association between HLA and human disease, HLA molecules have proven to be central to physiology, protective immunity and deleterious, disease-causing autoimmune reactivity. Technological advances have enabled pivotal progress in the determination of the molecular mechanisms that underpin the association between HLA genetics and functional outcome. Here, we review our current understanding of HLA molecules as the fundamental platform for immune surveillance and responsiveness in health and disease. We evaluate the scope for personalized antigen-specific disease prevention, whereby harnessing HLA-ligand interactions for clinical benefit is becoming a realistic prospect.
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Affiliation(s)
- Calliope A Dendrou
- Nuffield Department of Medicine, The Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Jan Petersen
- Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.,Infection and Immunity Programme and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, Victoria 3800, Australia
| | - Jamie Rossjohn
- Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.,Infection and Immunity Programme and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.,Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Lars Fugger
- Danish National Research Foundation Centre PERSIMUNE, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark.,Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford OX3 9DS, UK
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31
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C-terminal modification of the insulin B:11-23 peptide creates superagonists in mouse and human type 1 diabetes. Proc Natl Acad Sci U S A 2017; 115:162-167. [PMID: 29255035 PMCID: PMC5776820 DOI: 10.1073/pnas.1716527115] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Insulin is a target of CD4 T cells in type 1 diabetes in mice and humans. Why the major epitope in the insulin B chain is presented poorly to the diabetogenic CD4 T cells by the disease-associated major histocompatibility class II (MHCII) alleles has been highly debated. Here we present high-resolution mouse and human MHCII structures and T-cell functional data to show that C-terminal modifications of this epitope are required for binding and presentation in the appropriate position in the MHCII binding groove. These results suggest that pancreas-specific posttranslational modifications of this peptide may play a role in the induction of diabetes and explain how the pathogenic T cells escape deletion in the thymus. A polymorphism at β57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9–23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the β57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.
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32
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Spanier JA, Sahli NL, Wilson JC, Martinov T, Dileepan T, Burrack AL, Finger EB, Blazar BR, Michels AW, Moran A, Jenkins MK, Fife BT. Increased Effector Memory Insulin-Specific CD4 + T Cells Correlate With Insulin Autoantibodies in Patients With Recent-Onset Type 1 Diabetes. Diabetes 2017; 66:3051-3060. [PMID: 28842400 PMCID: PMC5697953 DOI: 10.2337/db17-0666] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 08/18/2017] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) results from T cell-mediated destruction of insulin-producing β-cells. Insulin represents a key self-antigen in disease pathogenesis, as recent studies identified proinsulin-responding T cells from inflamed pancreatic islets of organ donors with recent-onset T1D. These cells respond to an insulin B-chain (InsB) epitope presented by the HLA-DQ8 molecule associated with high T1D risk. Understanding insulin-specific T-cell frequency and phenotype in peripheral blood is now critical. We constructed fluorescent InsB10-23:DQ8 tetramers, stained peripheral blood lymphocytes directly ex vivo, and show DQ8+ patients with T1D have increased tetramer+ CD4+ T cells compared with HLA-matched control subjects without diabetes. Patients with a shorter disease duration had higher frequencies of insulin-reactive CD4+ T cells, with most of these cells being antigen experienced. We also demonstrate that the number of insulin tetramer+ effector memory cells is directly correlated with insulin antibody titers, suggesting insulin-specific T- and B-cell interactions. Notably, one of four control subjects with tetramer+ cells was a first-degree relative who had insulin-specific cells with an effector memory phenotype, potentially representing an early marker of T-cell autoimmunity. Our results suggest that studying InsB10-23:DQ8 reactive T-cell frequency and phenotype may provide a biomarker of disease activity in patients with T1D and those at risk.
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Affiliation(s)
- Justin A Spanier
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Nathanael L Sahli
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Joseph C Wilson
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Tijana Martinov
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Thamotharampillai Dileepan
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Adam L Burrack
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Erik B Finger
- Department of Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - Bruce R Blazar
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
| | - Aaron W Michels
- Department of Pediatrics and Medicine, University of Colorado, Denver, CO
| | - Antoinette Moran
- Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN
| | - Marc K Jenkins
- Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
| | - Brian T Fife
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
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33
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Buckner JH, Greenbaum CJ. Stacking the Deck: Studies of Patients with Multiple Autoimmune Diseases Propelled Our Understanding of Type 1 Diabetes as an Autoimmune Disease. THE JOURNAL OF IMMUNOLOGY 2017; 199:3011-3013. [DOI: 10.4049/jimmunol.1701299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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34
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Harbige J, Eichmann M, Peakman M. New insights into non-conventional epitopes as T cell targets: The missing link for breaking immune tolerance in autoimmune disease? J Autoimmun 2017; 84:12-20. [PMID: 28803690 DOI: 10.1016/j.jaut.2017.08.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/29/2017] [Accepted: 08/01/2017] [Indexed: 12/15/2022]
Abstract
The mechanism by which immune tolerance is breached in autoimmune disease is poorly understood. One possibility is that post-translational modification of self-antigens leads to peripheral recognition of neo-epitopes against which central and peripheral tolerance is inadequate. Accumulating evidence points to multiple mechanisms through which non-germline encoded sequences can give rise to these non-conventional epitopes which in turn engage the immune system as T cell targets. In particular, where these modifications alter the rules of epitope engagement with MHC molecules, such non-conventional epitopes offer a persuasive explanation for associations between specific HLA alleles and autoimmune diseases. In this review article, we discuss current understanding of mechanisms through which non-conventional epitopes may be generated, focusing on several recently described pathways that can transpose germline-encoded sequences. We contextualise these discoveries around type 1 diabetes, the prototypic organ-specific autoimmune disease in which specific HLA-DQ molecules confer high risk. Non-conventional epitopes have the potential to act as tolerance breakers or disease drivers in type 1 diabetes, prompting a timely re-evaluation of models of a etiopathogenesis. Future studies are required to elucidate the disease-relevance of a range of potential non-germline epitopes and their relationship to the natural peptide repertoire.
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Affiliation(s)
- James Harbige
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, UK.
| | - Martin Eichmann
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, UK
| | - Mark Peakman
- Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, UK; Division of Diabetes and Nutritional Sciences, King's College London, UK; Institute of Diabetes, Endocrinology and Obesity, King's Health Partners, London, UK.
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Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin and other pancreatic β cells proteins including GAD65 (GADA), islet antigen 2 (IA-2A), and zinc transporter 8 (ZnT8A). The assay technology for IAbs has made great progress; however, several important aspects still need to be addressed and improved. RECENT FINDINGS Currently a radio-binding assay has been well established as the 'gold' standard assay for all four IAbs. New generation of nonradioactive IAb assay with electrochemiluminescence technology has been shown to further improve sensitivity and disease specificity. Recently, multiplexed assays have opened the possibility of more efficient screening in large populations. Identification of potential new autoantibodies to neo-antigens or neo-epitopes posttranslational modification is a new important field to be explored. SUMMARY Individuals having a single positive autoantibody are at low risk for progression to T1D, whereas individuals expressing two or more positive autoantibodies, especially on multiple tests over time, have nearly 100% risk of developing clinical T1D when followed for over two decades. More efficient and cost effective IAb assays will hopefully lead to point-of-care screening in the general population.
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Affiliation(s)
- Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
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Weissert R. Adaptive Immunity Is the Key to the Understanding of Autoimmune and Paraneoplastic Inflammatory Central Nervous System Disorders. Front Immunol 2017; 8:336. [PMID: 28386263 PMCID: PMC5362596 DOI: 10.3389/fimmu.2017.00336] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 03/08/2017] [Indexed: 12/25/2022] Open
Abstract
There are common aspects and mechanisms between different types of autoimmune diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), and autoimmune encephalitis (AE) as well as paraneoplastic inflammatory disorders of the central nervous system. To our present knowledge, depending on the disease, T and B cells as well as antibodies contribute to various aspects of the pathogenesis. Possibly the events leading to the breaking of tolerance between the different diseases are of great similarity and so far, only partially understood. Beside endogenous factors (genetics, genomics, epigenetics, malignancy) also exogenous factors (vitamin D, sun light exposure, smoking, gut microbiome, viral infections) contribute to susceptibility in such diseases. What differs between these disorders are the target molecules of the immune attack. For T cells, these target molecules are presented on major histocompatibility complex (MHC) molecules as MHC-bound ligands. B cells have an important role by amplifying the immune response of T cells by capturing antigen with their surface immunoglobulin and presenting it to T cells. Antibodies secreted by plasma cells that have differentiated from B cells are highly structure specific and can have important effector functions leading to functional impairment or/and lesion evolvement. In MS, the target molecules are mainly myelin- and neuron/axon-derived proteins; in NMOSD, mainly aquaporin-4 expressed on astrocytes; and in AE, various proteins that are expressed by neurons and axons.
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Affiliation(s)
- Robert Weissert
- Department of Neurology, Neuroimmunology, University of Regensburg , Regensburg , Germany
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37
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Burrack AL, Martinov T, Fife BT. T Cell-Mediated Beta Cell Destruction: Autoimmunity and Alloimmunity in the Context of Type 1 Diabetes. Front Endocrinol (Lausanne) 2017; 8:343. [PMID: 29259578 PMCID: PMC5723426 DOI: 10.3389/fendo.2017.00343] [Citation(s) in RCA: 207] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 11/21/2017] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes (T1D) results from destruction of pancreatic beta cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for T1D, and some individuals develop life-threatening complications. Pancreas and islet transplantation have been attractive therapeutic approaches; however, transplants containing insulin-producing cells are vulnerable to both recurrent autoimmunity and conventional allograft rejection. Current immune suppression treatments subdue the immune system, but not without complications. Ideally a successful approach would target only the destructive immune cells and leave the remaining immune system intact to fight foreign pathogens. This review discusses the autoimmune diabetes disease process, diabetic complications that warrant a transplant, and alloimmunity. First, we describe the current understanding of autoimmune destruction of beta cells including the roles of CD4 and CD8 T cells and several possibilities for antigen-specific tolerance induction. Second, we outline diabetic complications necessitating beta cell replacement. Third, we discuss transplant recognition, potential sources for beta cell replacement, and tolerance-promoting therapies under development. We hypothesize that a better understanding of autoreactive T cell targets during disease pathogenesis and alloimmunity following transplant destruction could enhance attempts to re-establish tolerance to beta cells.
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Affiliation(s)
- Adam L. Burrack
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Tijana Martinov
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Brian T. Fife
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States
- *Correspondence: Brian T. Fife,
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Bandyopadhyay GK, Mahata SK. Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity. Front Endocrinol (Lausanne) 2017; 8:20. [PMID: 28228748 PMCID: PMC5296320 DOI: 10.3389/fendo.2017.00020] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 01/23/2017] [Indexed: 01/15/2023] Open
Abstract
Chromogranin A (CgA) is a prohormone and granulogenic factor in endocrine and neuroendocrine tissues, as well as in neurons, and has a regulated secretory pathway. The intracellular functions of CgA include the initiation and regulation of dense-core granule biogenesis and sequestration of hormones in neuroendocrine cells. This protein is co-stored and co-released with secreted hormones. The extracellular functions of CgA include the generation of bioactive peptides, such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin. CgA knockout mice (Chga-KO) display: (i) hypertension with increased plasma catecholamines, (ii) obesity, (iii) improved hepatic insulin sensitivity, and (iv) muscle insulin resistance. These findings suggest that individual CgA-derived peptides may regulate different physiological functions. Indeed, additional studies have revealed that the pro-inflammatory PST influences insulin sensitivity and glucose tolerance, whereas CST alleviates adiposity and hypertension. This review will focus on the different metabolic roles of PST and CST peptides in insulin-sensitive and insulin-resistant models, and their potential use as therapeutic targets.
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Affiliation(s)
| | - Sushil K. Mahata
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, Metabolic Physiology and Ultrastructural Biology Laboratory, VA San Diego Healthcare System, San Diego, CA, USA
- *Correspondence: Sushil K. Mahata,
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Dastagir SR, Postigo-Fernandez J, Xu C, Stoeckle JH, Firdessa-Fite R, Creusot RJ. Efficient Presentation of Multiple Endogenous Epitopes to Both CD4 + and CD8 + Diabetogenic T Cells for Tolerance. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2016; 4:27-38. [PMID: 28344989 PMCID: PMC5363322 DOI: 10.1016/j.omtm.2016.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 12/13/2016] [Indexed: 10/28/2022]
Abstract
Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native β cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple β cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells.
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Affiliation(s)
- Shamael R Dastagir
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Jorge Postigo-Fernandez
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Chunliang Xu
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - James H Stoeckle
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Rebuma Firdessa-Fite
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Rémi J Creusot
- Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
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40
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Abstract
The incidence of type 1 diabetes has risen considerably in the past 30 years due to changes in the environment that have been only partially identified. In this Series paper, we critically discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes. We revisit previously proposed hypotheses to explain the growth in the incidence of type 1 diabetes in light of current data. Finally, we suggest a unified model in which immune tolerance to β cells can be broken by several environmental exposures that induce generation of hybrid peptides acting as neoautoantigens.
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Affiliation(s)
- Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University and Linköping University Hospital, Linköping, Sweden.
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