|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Tuffs SW, Dufresne K, Rishi A, Walton NR, McCormick JK. Novel insights into the immune response to bacterial T cell superantigens. Nat Rev Immunol 2024; 24:417-434. [PMID: 38225276 DOI: 10.1038/s41577-023-00979-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2023] [Indexed: 01/17/2024]
Abstract
Bacterial T cell superantigens (SAgs) are a family of microbial exotoxins that function to activate large numbers of T cells simultaneously. SAgs activate T cells by direct binding and crosslinking of the lateral regions of MHC class II molecules on antigen-presenting cells with T cell receptors (TCRs) on T cells; these interactions alter the normal TCR-peptide-MHC class II architecture to activate T cells in a manner that is independent of the antigen specificity of the TCR. SAgs have well-recognized, central roles in human diseases such as toxic shock syndrome and scarlet fever through their quantitative effects on the T cell response; in addition, numerous other consequences of SAg-driven T cell activation are now being recognized, including direct roles in the pathogenesis of endocarditis, bloodstream infections, skin disease and pharyngitis. In this Review, we summarize the expanding family of bacterial SAgs and how these toxins can engage highly diverse adaptive immune receptors. We highlight recent findings regarding how SAg-driven manipulation of the adaptive immune response may operate in multiple human diseases, as well as contributing to the biology and life cycle of SAg-producing bacterial pathogens.
Collapse
Affiliation(s)
- Stephen W Tuffs
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada
| | - Karine Dufresne
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Aanchal Rishi
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - Nicholas R Walton
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
| | - John K McCormick
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
| |
Collapse
|
|
3
|
Minniakhmetov I, Yalaev B, Khusainova R, Bondarenko E, Melnichenko G, Dedov I, Mokrysheva N. Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem. Biomedicines 2024; 12:399. [PMID: 38398001 PMCID: PMC10886892 DOI: 10.3390/biomedicines12020399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus.
Collapse
Affiliation(s)
- Ildar Minniakhmetov
- Endocrinology Research Centre, Dmitry Ulyanov Street, 11, 117292 Moscow, Russia; (R.K.); (E.B.); (G.M.); (I.D.); (N.M.)
| | - Bulat Yalaev
- Endocrinology Research Centre, Dmitry Ulyanov Street, 11, 117292 Moscow, Russia; (R.K.); (E.B.); (G.M.); (I.D.); (N.M.)
| | | | | | | | | | | |
Collapse
|
|
4
|
Ye C, Clements SA, Gu W, Geurts AM, Mathews CE, Serreze DV, Chen YG, Driver JP. Deletion of Vβ3 +CD4 + T cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8 + T cells. Proc Natl Acad Sci U S A 2023; 120:e2312039120. [PMID: 38015847 PMCID: PMC10710095 DOI: 10.1073/pnas.2312039120] [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: 07/18/2023] [Accepted: 09/23/2023] [Indexed: 11/30/2023] Open
Abstract
In both humans and NOD mice, type 1 diabetes (T1D) develops from the autoimmune destruction of pancreatic beta cells by T cells. Interactions between both helper CD4+ and cytotoxic CD8+ T cells are essential for T1D development in NOD mice. Previous work has indicated that pathogenic T cells arise from deleterious interactions between relatively common genes which regulate aspects of T cell activation/effector function (Ctla4, Tnfrsf9, Il2/Il21), peptide presentation (H2-A g7, B2m), and T cell receptor (TCR) signaling (Ptpn22). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus (Mtv)3 provirus as a genetic element affecting CD4+/CD8+ T cell interactions through an additional mechanism, altering the TCR repertoire. Mtv3 encodes a superantigen (SAg) that deletes the majority of Vβ3+ thymocytes in NOD mice. Ablating Mtv3 and restoring Vβ3+ T cells has no effect on spontaneous T1D development in NOD mice. However, transferring Mtv3 to C57BL/6 (B6) mice congenic for the NOD H2 g7 MHC haplotype (B6.H2 g7) completely blocks their normal susceptibility to T1D mediated by transferred CD8+ T cells transgenically expressing AI4 or NY8.3 TCRs. The entire genetic effect is manifested by Vβ3+CD4+ T cells, which unless deleted by Mtv3, accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8+ T cells. Our findings provide evidence that endogenous Mtv SAgs can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vβ repertoire due to Mtvs, it raises questions about the role of Mtvs in other mouse models designed to reflect human immune disorders.
Collapse
Affiliation(s)
- Cheng Ye
- Department of Animal Sciences, University of Florida, Gainesville, FL32611
| | - Sadie A. Clements
- Division of Animal Sciences, University of Missouri, Columbia, MO65201
| | - Weihong Gu
- Division of Animal Sciences, University of Missouri, Columbia, MO65201
| | - Aron M. Geurts
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI53226
| | - Clayton E. Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL32610
| | | | - Yi-Guang Chen
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI53226
| | - John P. Driver
- Division of Animal Sciences, University of Missouri, Columbia, MO65201
| |
Collapse
|
|
5
|
Younger DS. Adult and childhood vasculitis. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:653-705. [PMID: 37562892 DOI: 10.1016/b978-0-323-98818-6.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability, making this a disorder of paramount importance to all clinicians. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary CNS and PNS vasculitides, predicated on achievement in primary systemic forms. Primary neurological vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, unfortunately without the benefit of RCTs, and tempered by the recognition of anticipated medication side effects. It may be said that efforts to define a disease are attempts to understand the very concept of the disease. This has been especially evident in systemic and neurological disorders associated with vasculitis. For the past 100 years, since the first description of granulomatous angiitis of the brain, the CNS vasculitides have captured the attention of generations of clinical investigators around the globe to reach a better understanding of vasculitides involving the central and peripheral nervous system. Since that time it has become increasingly evident that this will necessitate an international collaborative effort.
Collapse
Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
| |
Collapse
|
|
6
|
Redondo MJ, Steck AK, Pugliese A. Genetics of type 1 diabetes. Pediatr Diabetes 2018; 19:346-353. [PMID: 29094512 PMCID: PMC5918237 DOI: 10.1111/pedi.12597] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 09/18/2017] [Accepted: 09/20/2017] [Indexed: 12/23/2022] Open
Abstract
Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.
Collapse
Affiliation(s)
- Maria J. Redondo
- Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030
| | - Andrea K. Steck
- University of Colorado School of Medicine, Barbara Davis Center for Childhood Diabetes, Aurora, CO, 80045
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology and Metabolism, Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136
| |
Collapse
|
|
7
|
Streptococcal pharyngitis and rheumatic heart disease: the superantigen hypothesis revisited. INFECTION GENETICS AND EVOLUTION 2018. [PMID: 29530660 DOI: 10.1016/j.meegid.2018.03.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Streptococcus pyogenes is a human-specific and globally prominent bacterial pathogen that despite causing numerous human infections, this bacterium is normally found in an asymptomatic carrier state. This review provides an overview of both bacterial and human factors that likely play an important role in nasopharyngeal colonization and pharyngitis, as well as the development of acute rheumatic fever and rheumatic heart disease. Here we highlight a recently described role for bacterial superantigens in promoting acute nasopharyngeal infection, and discuss how these immune system activating toxins could be crucial to initiate the autoimmune process in rheumatic heart disease.
Collapse
|
|
8
|
Gieras A, Gehbauer C, Perna-Barrull D, Engler JB, Diepenbruck I, Glau L, Joosse SA, Kersten N, Klinge S, Mittrücker HW, Friese MA, Vives-Pi M, Tolosa E. Prenatal Administration of Betamethasone Causes Changes in the T Cell Receptor Repertoire Influencing Development of Autoimmunity. Front Immunol 2017; 8:1505. [PMID: 29181000 PMCID: PMC5693859 DOI: 10.3389/fimmu.2017.01505] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 10/25/2017] [Indexed: 12/15/2022] Open
Abstract
Prenatal glucocorticoids are routinely administered to pregnant women at risk of preterm delivery in order to improve survival of the newborn. However, in half of the cases, birth occurs outside the beneficial period for lung development. Glucocorticoids are potent immune modulators and cause apoptotic death of immature T cells, and we have previously shown that prenatal betamethasone treatment at doses eliciting lung maturation induce profound thymocyte apoptosis in the offspring. Here, we asked if there are long-term consequences on the offspring’s immunity after this treatment. In the non-obese diabetic mouse model, prenatal betamethasone clearly decreased the frequency of pathogenic T cells and the incidence of type 1 diabetes (T1D). In contrast, in the lupus-prone MRL/lpr strain, prenatal glucocorticoids induced changes in the T cell repertoire that resulted in more autoreactive cells. Even though glucocorticoids transiently enhanced regulatory T cell (Treg) development, these cells did not have a protective effect in a model for multiple sclerosis which relies on a limited repertoire of pathogenic T cells for disease induction that were not affected by prenatal betamethasone. We conclude that prenatal steroid treatment, by inducing changes in the T cell receptor repertoire, has unforeseeable consequences on development of autoimmune disease. Our data should encourage further research to fully understand the consequences of this widely used treatment.
Collapse
Affiliation(s)
- Anna Gieras
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Gehbauer
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Perna-Barrull
- Immunology Division, Germans Trias i Pujol Research Institute and Hospital, Universitat Autonoma de Barcelona, Badalona, Spain
| | - Jan Broder Engler
- Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, Hamburg, Germany
| | - Ines Diepenbruck
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Glau
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Simon A Joosse
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nora Kersten
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefanie Klinge
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Willi Mittrücker
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manuel A Friese
- Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, Hamburg, Germany
| | - Marta Vives-Pi
- Immunology Division, Germans Trias i Pujol Research Institute and Hospital, Universitat Autonoma de Barcelona, Badalona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Eva Tolosa
- Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
9
|
Choi IY, Lee C, Longo VD. Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence. Mol Cell Endocrinol 2017; 455:4-12. [PMID: 28137612 PMCID: PMC5862044 DOI: 10.1016/j.mce.2017.01.042] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 01/25/2017] [Accepted: 01/25/2017] [Indexed: 02/04/2023]
Abstract
Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the generation, survival and function of lymphocytes and therefore can affect several autoimmune diseases. Here, we review the dysregulation of lymphocytes during autoimmunity and aging, the mechanisms associated with loss of immune function, and how fasting mimicking diets and other dietary interventions affect autoimmunity and immunosenescence.
Collapse
Affiliation(s)
- In Young Choi
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Department of Microbiology, Immunology, Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Changhan Lee
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
| | - Valter D Longo
- Longevity Institute, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA; Department of Neuroscience, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA; IFOM, FIRC Institute of Molecular Oncology, 20139, Milan, Italy.
| |
Collapse
|
|
10
|
Abstract
PURPOSE OF REVIEW By necessity, the vast majority of information we have on autoreactive T cells in human type 1 diabetes (T1D) has come from the study of peripheral blood of donors with T1D. It is not clear how representative the peripheral autoreactive T-cell repertoire is of the autoreactive T cells infiltrating the islets in T1D. We will summarize and discuss what is known of the immunohistopathology of insulitis, the T-cell receptor repertoire expressed by islet-infiltrating T cells, and the autoreactivity and function of islet-infiltrating T cells in T1D. RECENT FINDINGS Recovery and analysis of live, islet-infiltrating T cells from the islets of cadaveric donors with T1D revealed a broad repertoire and proinflammatory phenotype of CD4 T-cell autoreactivity to peptide targets from islet proteins, including proinsulin, as well as CD4 T-cell reactivity to a number of post-translationally modified peptides, including peptides with citrullinations and hybrid insulin peptide fusions. Islet-infiltrating CD8 T cells were also derived and required further isolation and characterization. SUMMARY The recovery of live, islet-infiltrating T cells from donors with T1D, reactive with a broad range of known targets and post-translationally modified peptides, allows for the specific functional analysis of islet-infiltrating T cells for the development of antigen-specific immunotherapies.
Collapse
Affiliation(s)
- Sally C Kent
- Division of Diabetes, Department of Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | | |
Collapse
|
|
11
|
Seay HR, Yusko E, Rothweiler SJ, Zhang L, Posgai AL, Campbell-Thompson M, Vignali M, Emerson RO, Kaddis JS, Ko D, Nakayama M, Smith MJ, Cambier JC, Pugliese A, Atkinson MA, Robins HS, Brusko TM. Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI Insight 2016; 1:e88242. [PMID: 27942583 DOI: 10.1172/jci.insight.88242] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The adaptive immune repertoire plays a critical role in type 1 diabetes (T1D) pathogenesis. However, efforts to characterize B cell and T cell receptor (TCR) profiles in T1D subjects have been largely limited to peripheral blood sampling and restricted to known antigens. To address this, we collected pancreatic draining lymph nodes (pLN), "irrelevant" nonpancreatic draining lymph nodes, peripheral blood mononuclear cells (PBMC), and splenocytes from T1D subjects (n = 18) and control donors (n = 9) as well as pancreatic islets from 1 T1D patient; from these tissues, we collected purified CD4+ conventional T cells (Tconv), CD4+ Treg, CD8+ T cells, and B cells. By conducting high-throughput immunosequencing of the TCR β chain (TRB) and B cell receptor (BCR) immunoglobulin heavy chain (IGH) on these samples, we sought to analyze the molecular signature of the lymphocyte populations within these tissues and of T1D. Ultimately, we observed a highly tissue-restricted CD4+ repertoire, while up to 24% of CD8+ clones were shared among tissues. We surveyed our data set for previously described proinsulin- and glutamic acid decarboxylase 65-reactive (GAD65-reactive) receptors, and interestingly, we observed a TRB with homology to a known GAD65-reactive TCR (clone GAD4.13) present in 7 T1D donors (38.9%), representing >25% of all productive TRB within Tconv isolated from the pLN of 1 T1D subject. These data demonstrate diverse receptor signatures at the nucleotide level and enriched autoreactive clones at the amino acid level, supporting the utility of coupling immunosequencing data with knowledge of characterized autoreactive receptors.
Collapse
Affiliation(s)
- Howard R Seay
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Erik Yusko
- Adaptive Biotechnologies Corporation, Seattle, Washington, USA
| | - Stephanie J Rothweiler
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Lin Zhang
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Marissa Vignali
- Adaptive Biotechnologies Corporation, Seattle, Washington, USA
| | - Ryan O Emerson
- Adaptive Biotechnologies Corporation, Seattle, Washington, USA
| | - John S Kaddis
- Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA
| | - Dave Ko
- Department of Information Sciences, City of Hope National Medical Center, Duarte, California, USA
| | | | - Mia J Smith
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - John C Cambier
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alberto Pugliese
- Diabetes Research Institute and Departments of Medicine, Microbiology, and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Harlan S Robins
- Adaptive Biotechnologies Corporation, Seattle, Washington, USA.,Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| |
Collapse
|
|
12
|
Torres BA, Kominsky S, Perrin GQ, Hobeika AC, Johnson HM. Superantigens: The Good, the Bad, and the Ugly. Exp Biol Med (Maywood) 2016; 226:164-76. [PMID: 11361034 DOI: 10.1177/153537020122600303] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Increasing evidence suggests that superantigens play a role in Immune-mediated diseases. Superantigens are potent activators of CD4* T cells, causing rapid and massive proliferation of cells and cytokine production. This characteristic of superantigens can be exploited in diseases where strong immunologic responses are required, such as in the B16F10 animal model of melanoma. Superantigen administration is able to significantly enhance Ineffective anti-tumor Immune responses, resulting in potent and long-lived protective anti-tumor immunity. However, superantigens are more well-known for the role they play in diseases. Studies using an animal model for neurologic demy-elinatlng diseases such as multiple sclerosis show that superantigens can induce severe relapses and activate auto-reactive T cells not involved in the Initial bout of disease. This may also involve epitope spreading of disease. Superantigens have also been implicated in acute diseases such as food poisoning and TSS, and in chronic diseases such as psoriasis and rheumatoid arthritis. Viral superantigens are also involved in the disease process, including superantigens derived from human Immunodeficiency virus and mouse mammary tumor virus. Finally, immunotherapies that ameliorate the role played by superantigens in disease are discussed.
Collapse
Affiliation(s)
- B A Torres
- Department of Microbiology and Cell Science, University of Florida, Gainesville 32611, USA
| | | | | | | | | |
Collapse
|
|
13
|
Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 2016; 22:1482-1487. [PMID: 27798614 DOI: 10.1038/nm.4203] [Citation(s) in RCA: 242] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 09/14/2016] [Indexed: 12/13/2022]
Abstract
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8+ T cells in situ, in islets of human leukocyte antigen (HLA)-A2+ donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4+ T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4+ and CD8+ T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.
Collapse
|
|
14
|
Root-Bernstein R. Autoimmunity and the microbiome: T-cell receptor mimicry of "self" and microbial antigens mediates self tolerance in holobionts: The concepts of "holoimmunity" (TcR-mediated tolerance for the holobiont) and "holoautoimmunity" (loss of tolerance for the holobiont) are introduced. Bioessays 2016; 38:1068-1083. [PMID: 27594308 PMCID: PMC7161894 DOI: 10.1002/bies.201600083] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
I propose a T-cell receptor (TcR)-based mechanism by which immunity mediates both "genetic self" and "microbial self" thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross-reactivity with "self," resulting in selection for a TcR repertoire mimicking "genetic self." Second, evolution has selected for a "microbial self" that mimics "genetic self" so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR-microbiome mimicry "holoimmunity" to denote immune tolerance to the "holobiont self." Logically, microbiome-host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross-react with host antigens producing "holoautoimmunity."
Collapse
|
|
15
|
Yosaee S, Akbari Fakhrabadi M, Shidfar F. Positive evidence for vitamin A role in prevention of type 1 diabetes. World J Diabetes 2016; 7:177-188. [PMID: 27162582 PMCID: PMC4856890 DOI: 10.4239/wjd.v7.i9.177] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 03/23/2016] [Accepted: 04/07/2016] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) as one of the most well-known autoimmune disease, results from the destruction of β-cells in pancreas by autoimmune process. T1DM is fatal without insulin treatment. The expansion of alternative treatment to insulin is a dream to be fulfilled. Currently autoimmunity is considered as main factor in development of T1DM. So manipulation of the immune system can be considered as alternative treatment to insulin. For the past decades, vitamin A has been implicated as an essential dietary micronutrient in regulator of immune function. Despite major advantage in the knowledge of vitamin A biology, patients who present T1DM are at risk for deficiency in vitamin A and carotenoids. Applying such evidences, vitamin A treatment may be the key approach in preventing T1DM.
Collapse
|
|
16
|
Bioinformatics evaluation of the possibility of heat shock proteins as autoantigens in multiple sclerosis based on molecular mimicry hypothesis. J Neuroimmunol 2016; 295-296:100-21. [PMID: 27235356 DOI: 10.1016/j.jneuroim.2016.03.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/19/2016] [Accepted: 03/29/2016] [Indexed: 01/22/2023]
Abstract
Molecular mimicry is the explanatory link between the heat shock proteins (HSPs) of infectious agents and triggering multiple sclerosis. Considering that there are many similarities between self- and bacterial-HSPs, the goal was to investigate a panel of 60- and 70kDa HSPs from a variety of bacteria in order to predict the role of each microorganism in triggering or progression of the disease under the molecular mimicry hypothesis. By clarifying the peptides meeting criteria for cross-reactivity and elucidating the role of each microorganism in MS pathogenesis, it would be easier to suggest more effective treatment and preventive strategies for this disease.
Collapse
|
|
17
|
Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med 2015; 42:42-60. [PMID: 25579746 PMCID: PMC4548800 DOI: 10.1016/j.mam.2014.12.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/20/2014] [Accepted: 12/15/2014] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and immunologic factors. Similar to the majority of autoimmune diseases, T1DM usually has a relapsing remitting disease course with autoantibody and T cellular responses to islet autoantigens, which precede the clinical onset of the disease process. The immunological diagnosis of autoimmune diseases relies primarily on the detection of autoantibodies in the serum of T1DM patients. Although their pathogenic significance remains uncertain, they have the practical advantage of serving as surrogate biomarkers for predicting the clinical onset of T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (i.e. HLA), and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3) or DRB1*04-DQB1*0302 (DR4)]. In addition, HLA alleles such as DQB1*0602 are associated with dominant protection from T1DM in multiple populations. A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development. Viral infections may play a role in the chain of events leading to disease, albeit conclusive evidence linking infections with T1DM remains to be firmly established. Two syndromes have been described in which an immune-mediated form of diabetes occurs as the result of a single gene defect. These syndromes are termed autoimmune polyglandular syndrome type I (APS-I) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and X-linked poyendocrinopathy, immune dysfunction and diarrhea (XPID). These two syndromes are unique models to understand the mechanisms involved in the loss of tolerance to self-antigens in autoimmune diabetes and its associated organ-specific autoimmune disorders. A growing number of animal models of these diseases have greatly helped elucidate the immunologic mechanisms leading to autoimmune diabetes.
Collapse
Affiliation(s)
- Michael P Morran
- Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Andrew Vonberg
- Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Anmar Khadra
- Department of Physiology, McGill University, Montreal, QC, Canada
| | - Massimo Pietropaolo
- Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
| |
Collapse
|
|
18
|
Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami, Miami, FL
| |
Collapse
|
|
19
|
Szablewski L. Role of immune system in type 1 diabetes mellitus pathogenesis. Int Immunopharmacol 2014; 22:182-91. [PMID: 24993340 DOI: 10.1016/j.intimp.2014.06.033] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 12/26/2022]
Abstract
The immune system is the body's natural defense system against invading pathogens. It protects the body from infection and works to communicate an individual's well-being through a complex network of interconnected cells and cytokines. This system is an associated host defense. An uncontrolled immune system has the potential to trigger negative complications in the host. Type 1 diabetes results from the destruction of pancreatic β-cells by a β-cell-specific autoimmune process. Examples of β-cell autoantigens are insulin, glutamic acid decarboxylase, tyrosine phosphatase, and insulinoma antigen. There are many autoimmune diseases, but type 1 diabetes mellitus is one of the well-characterized autoimmune diseases. The mechanisms involved in the β-cell destruction are still not clear; it is generally believed that β-cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes are involved in the β-cell-specific autoimmune process. It is necessary to determine what exact factors are causing the immune system to become unregulated in such a manner as to promote an autoimmune response.
Collapse
Affiliation(s)
- Leszek Szablewski
- General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland.
| |
Collapse
|
|
20
|
Zhou J, Kong C, Wang X, Jia Y, Wang L, Chang H, Sun L. In silico Analysis of TCR Vβ7 of Two Patients with Type 1 Diabetes Mellitus. J Lab Physicians 2014; 5:79-82. [PMID: 24701098 PMCID: PMC3968635 DOI: 10.4103/0974-2727.119845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To compare the sequences and crystal structures of variable region of beta chain 7 (Vβ7) of T cell receptor (TCR) of two patients with type 1 diabetes mellitus (T1DM). PATIENTS AND METHODS The skewness of TCR Vβ7 of two T1DM patients were detected with real-time florescence quantitative polymerase chain reaction (FQ-PCR) and deoxyribonucleic acid (DNA) melting curve analysis technique followed by being sequenced, the crystal structures of them were simulated according to CPH models 2.0 Server, IMGT database, and RasMol 2 software. RESULTS The whole sequences of TCR Vβ7 of T1DM patient-1 were "CASRTAGQYEQYFGPGTR", that of patient-2 were "CASRTAGQYEQFFGPGTR"; the only difference between them lied on the 12(th) amino acid. The crystal structures of Vβ7 of the two patients simulated with backbone model were rather similar, while that with sphere model were obviously different. CONCLUSION Although the TCR Vβ7 of the T1DM patients share the similar gene sequences, their crystal structures simulated with sphere model are different, and the mechanism needs further study.
Collapse
Affiliation(s)
- Jianwei Zhou
- Clinic Laboratory, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| | - Cui Kong
- Department of Cardiovascular Disease, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| | - Xiukui Wang
- Department of Stomatology, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| | - Yinfeng Jia
- Clinic Laboratory, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| | - Li Wang
- Department of Pharmocology, The First People's Hospital, Jining, Shandong Province, China
| | - Hong Chang
- Clinic Laboratory, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| | - Lin Sun
- Department of Endocrinology, The Affiliated Hospital of Jining Medical College, Jining, Shandong Province, China
| |
Collapse
|
|
21
|
Di Caro V, Giannoukakis N, Trucco M. In vivo delivery of nucleic acid-formulated microparticles as a potential tolerogenic vaccine for type 1 diabetes. Rev Diabet Stud 2012; 9:348-56. [PMID: 23804272 PMCID: PMC3740702 DOI: 10.1900/rds.2012.9.348] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 10/31/2012] [Accepted: 11/02/2012] [Indexed: 01/16/2023] Open
Abstract
Originally conceived as a method to silence transcription/translation of nascent RNA, nucleic acids aimed at downregulating gene expression have been shown to act at multiple levels. Some of the intriguing features of these gene-silencing nucleic acids include activation of molecular signals in immune cells which confer tolerogenic properties. We have discovered a method to induce stable tolerogenic ability to dendritic cells ex vivo using a mixture of phosphorothioate-modified antisense DNA targeting the primary transcripts of CD40, CD80 and CD86. Autologous human dendritic cells generated in the presence of these oligonucleotides prevent and reverse type 1 diabetes (T1D) in the non-obese diabetic (NOD) strain mouse model of the human disease, and have been shown to be safe in established diabetic human patients. Even though this ex vivo approach is clinically feasible, we have gone beyond a cell therapy approach to develop a "population-targeting" microsphere formulation of the three antisense oligonucleotides. Effectively, such a product could constitute an "off-the-shelf" vaccine. In this paper, we describe the progress made in developing this approach, as well as providing some insight into potential molecular mechanisms of action.
Collapse
Affiliation(s)
- Valentina Di Caro
- Division of Immunogenetics, Department of Pediatrics, Children´s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
- Ri.Med Foundation, via Bandiera 11, 90133, Palermo, Italy
| | - Nick Giannoukakis
- Division of Immunogenetics, Department of Pediatrics, Children´s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
- Department of Pathology, Children´s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Massimo Trucco
- Division of Immunogenetics, Department of Pediatrics, Children´s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| |
Collapse
|
|
22
|
Abstract
Type 1 diabetes (T1D) represents 10 to 15% of all forms of diabetes. Its incidence shows a consistent rise in all countries under survey. Evidence for autoimmunity in human T1D relies on the detection of insulitis, of islet cell antibodies, of activated β-cell-specific T lymphocytes and on the association of T1D with a restricted set of class II major histocompatibility complex (MHC) alleles. However, mechanisms that initiate the failure of immune tolerance to β-cell autoantigens remain elusive in common forms of T1D. T1D commonly develop as a multifactorial disease in which environmental factors concur with a highly multigenic background. The disease is driven by the activation of T-lymphocytes against pancreatic β-cells. Several years elapse between initial triggering of the autoimmune response to β cells, as evidenced by the appearance or islet cell autoantibodies, and the onset of clinical diabetes, defining a prediabetes stage. Active mechanisms hold back autoreactive effector T-cells in prediabetes, in particular a subset of CD4+ T-cells (T(reg)) and other regulatory T-cells, such as invariant NKT cells. There is evidence in experimental models that systemic or local infections can trigger autoimmune reactions to β-cells. However, epidemiological observations that have accumulated over years have failed to identify undisputable environmental factors that trigger T1D. Moreover, multiple environmental factors may intervene in the disease evolution and protective as weel as triggering environmental factors may be involved. Available models also indicate that local signals within the islets are required for full-blown diabetes to develop. Many autoantigens that are expressed by β-cells but also by the other endocrine islet cells and by neurons are recognized by lymphocytes along the development of T1D. The immune image of β-cells is that of native components of the β-cell membrane, as seen by B-lymphocytes, and of fragments of intracellular β-cell proteins in the form of peptides loaded onto class I MHC molecules on the β-cell surface and class I and class II molecules onto professional antigen presenting cells. Given the key role of T lymphocytes in T1D, the cartography of autoantigen-derived peptides that are presented to class I-restricted CD8(+) T-cells and class II-restricted CD4(+) T-cells is of outmost importance and is a necessary step in the development of diagnostic T-cell assays and of immunotherapy of T1D.
Collapse
|
|
23
|
|
|
24
|
Luce S, Lemonnier F, Briand JP, Coste J, Lahlou N, Muller S, Larger E, Rocha B, Mallone R, Boitard C. Single insulin-specific CD8+ T cells show characteristic gene expression profiles in human type 1 diabetes. Diabetes 2011; 60:3289-99. [PMID: 21998398 PMCID: PMC3219929 DOI: 10.2337/db11-0270] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2011] [Accepted: 09/06/2011] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Both the early steps and the high recurrence of autoimmunity once the disease is established are unexplained in human type 1 diabetes. Because CD8(+) T cells are central and insulin is a key autoantigen in the disease process, our objective was to characterize HLA class I-restricted autoreactive CD8(+) T cells specific for preproinsulin (PPI) in recent-onset and long-standing type 1 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We used HLA-A*02:01 tetramers complexed to PPI peptides to enumerate circulating PPI-specific CD8(+) T cells in patients and characterize them using membrane markers and single-cell PCR. RESULTS Most autoreactive CD8(+) T cells detected in recent-onset type 1 diabetic patients are specific for leader sequence peptides, notably PPI(6-14), whereas CD8(+) T cells in long-standing patients recognize the B-chain peptide PPI(33-42) (B(9-18)). Both CD8(+) T-cell specificities are predominantly naïve, central, and effector memory cells, and their gene expression profile differs from cytomegalovirus-specific CD8(+) T cells. PPI(6-14)-specific CD8(+) T cells detected in one healthy control displayed Il-10 mRNA expression, which was not observed in diabetic patients. CONCLUSIONS PPI-specific CD8(+) T cells in type 1 diabetic patients include central memory and target different epitopes in new-onset versus long-standing disease. Our data support the hypothesis that insulin therapy may contribute to the expansion of autoreactive CD8(+) T cells in the long term.
Collapse
Affiliation(s)
- Sandrine Luce
- INSERM, U986, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
| | - François Lemonnier
- INSERM, U986, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
| | - Jean-Paul Briand
- CNRS-UPR 9021, Institut de Biologie Moléculaire et Cellulaire, Paris, France
| | - Joel Coste
- Unité de Biostatistique et Épidémiologie, Hôpital Cochin, Paris, France
| | - Najiba Lahlou
- CNRS-UPR 9021, Institut de Biologie Moléculaire et Cellulaire, Paris, France
- Laboratoire de Biologie Hormonale, Hôpital Cochin, Paris, France
| | - Sylviane Muller
- CNRS-UPR 9021, Institut de Biologie Moléculaire et Cellulaire, Paris, France
| | - Etienne Larger
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
- Service de Diabétologie, Hôpital Cochin et Hôtel Dieu, Paris, France
| | - Benedita Rocha
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
| | - Roberto Mallone
- INSERM, U986, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
| | - Christian Boitard
- INSERM, U986, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France
- Service de Diabétologie, Hôpital Cochin et Hôtel Dieu, Paris, France
| |
Collapse
|
|
25
|
Brezar V, Carel JC, Boitard C, Mallone R. Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. Endocr Rev 2011; 32:623-69. [PMID: 21700723 DOI: 10.1210/er.2011-0010] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Insulin is not only the hormone produced by pancreatic β-cells but also a key target antigen of the autoimmune islet destruction leading to type 1 diabetes. Despite cultural biases between the fields of endocrinology and immunology, these two facets should not be regarded separately, but rather harmonized in a unifying picture of diabetes pathogenesis. There is increasing evidence suggesting that metabolic factors (β-cell dysfunction, insulin resistance) and immunological components (inflammation and β-cell-directed adaptive immune responses) may synergize toward islet destruction, with insulin standing at the crossroad of these pathways. This concept further calls for a revision of the classical dichotomy between type 1 and type 2 diabetes because metabolic and immune mechanisms may both contribute to different extents to the development of different forms of diabetes. After providing a background on the mechanisms of β-cell autoimmunity, we will explain the role of insulin and its precursors as target antigens expressed not only by β-cells but also in the thymus. Available knowledge on the autoimmune antibody and T-cell responses against insulin will be summarized. A unifying scheme will be proposed to show how different aspects of insulin biology may lead to β-cell destruction and may be therapeutically exploited. We will argue about possible reasons why insulin remains the mainstay of metabolic control in type 1 diabetes but has so far failed to prevent or halt β-cell autoimmunity as an immune modulatory reagent.
Collapse
Affiliation(s)
- Vedran Brezar
- Institut National de la Santé et de la Recherche Médicale, Unité 986, DeAR Lab Avenir, Saint Vincent de Paul Hospital, and Paris Descartes University, 82 avenue Denfert Rochereau, 75674 Paris Cedex 14, France
| | | | | | | |
Collapse
|
|
26
|
T cell recognition of autoantigens in human type 1 diabetes: clinical perspectives. Clin Dev Immunol 2011; 2011:513210. [PMID: 21785617 PMCID: PMC3140193 DOI: 10.1155/2011/513210] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 03/18/2011] [Indexed: 12/20/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease driven by the activation of lymphocytes against pancreatic β-cells. Among β-cell autoantigens, preproinsulin has been ascribed a key role in the T1D process. The successive steps that control the activation of autoreactive lymphocytes have been extensively studied in animal models of T1D, but remains ill defined in man. In man, T lymphocytes, especially CD8+ T cells, are predominant within insulitis. Developing T-cell assays in diabetes autoimmunity is, thus, a major challenge. It is expected to help defining autoantigens and epitopes that drive the disease process, to pinpoint key functional features of epitope-specific T lymphocytes along the natural history of diabetes and to pave the way towards therapeutic strategies to induce immune tolerance to β-cells. New T-cell technologies will allow defining autoreactive T-cell differentiation programs and characterizing autoimmune responses in comparison with physiologically appropriate immune responses. This may prove instrumental in the discovery of immune correlates of efficacy in clinical trials.
Collapse
|
|
27
|
Affiliation(s)
- Patrizia Luppi
- Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
| | | | | |
Collapse
|
|
28
|
Blankier S, McCrindle BW, Ito S, Yeung RSM. The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease. Clin Exp Immunol 2011; 164:193-201. [PMID: 21361911 PMCID: PMC3087911 DOI: 10.1111/j.1365-2249.2011.04331.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2011] [Indexed: 02/06/2023] Open
Abstract
Superantigens have been implicated in a number of diseases including Kawasaki disease (KD), a multi-system vasculitis resulting in coronary artery aneurysms. We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract (LCWE). Using this animal model of KD, we have identified three pathogenic steps leading to coronary artery aneurysm formation. These steps include T cell activation and proliferation, production of the proinflammatory cytokine tumour necrosis factor (TNF)-α and up-regulation of matrix metalloproteinase 9 (MMP-9), an elastolytic protease. In addition to their cholesterol-lowering effects, 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) have pleotropic immunomodulatory properties. Thus, we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model. Atorvastatin inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner. This inhibition was also observed for production of soluble mediators of inflammation including interleukin (IL)-2 and TNF-α. The inhibitory effect on proliferation was rescued completely by mevalonic acid, confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of HMG-CoA reductase. Similarly, TNF-α-induced MMP-9 production was reduced in a dose-dependent manner in response to atorvastatin. Inhibition of extracellular-regulated kinase (ERK) phosphorylation appears to be the mechanism responsible for inhibition of MMP-9 production. In conclusion, atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms, suggesting that statins may have therapeutic benefit in patients with KD.
Collapse
Affiliation(s)
- S Blankier
- Cell Biology Program, The Hospital for Sick Children Research Institute, Toronto, Canada
| | | | | | | |
Collapse
|
|
29
|
Codina-Busqueta E, Scholz E, Muñoz-Torres PM, Roura-Mir C, Costa M, Xufré C, Planas R, Vives-Pi M, Jaraquemada D, Martí M. TCR bias of in vivo expanded T cells in pancreatic islets and spleen at the onset in human type 1 diabetes. THE JOURNAL OF IMMUNOLOGY 2011; 186:3787-97. [PMID: 21325620 DOI: 10.4049/jimmunol.1002423] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Autoreactive T cells, responsible for the destruction of pancreatic β cells in type 1 diabetes, are known to have a skewed TCR repertoire in the NOD mouse. To define the autoreactive T cell repertoire in human diabetes, we searched for intraislet monoclonal expansions from a recent onset in human pancreas to then trace them down to the patient's peripheral blood and spleen. Islet infiltration was diverse, but five monoclonal TCR β-chain variable expansions were detected for Vβ1, Vβ7, Vβ11, Vβ17, and Vβ22 families. To identify any sequence bias in the TCRs from intrapancreatic T cells, we analyzed 139 different CDR3 sequences. We observed amino acid preferences in the NDN region that suggested a skewed TCR repertoire within infiltrating T cells. The monoclonal expanded TCR sequences contained amino acid combinations that fit the observed bias. Using these CDR3 sequences as a marker, we traced some of these expansions in the spleen. There, we identified a Vβ22 monoclonal expansion with identical CDR3 sequence to that found in the islets within a polyclonal TCR β-chain variable repertoire. The same Vβ22 TCR was detected in the patient's PBMCs, making a cross talk between the pancreas and spleen that was reflected in peripheral blood evident. No other pancreatic monoclonal expansions were found in peripheral blood or the spleen, suggesting that the Vβ22 clone may have expanded or accumulated in situ by an autoantigen present in both the spleen and pancreas. Thus, the patient's spleen might be contributing to disease perpetuation by expanding or retaining some autoreactive T cells.
Collapse
Affiliation(s)
- Eva Codina-Busqueta
- Laboratory of Cellular Immunology, Institute of Biotechnology and Biomedicine, Autonomous University of Barcelona, E-08193 Bellaterra, Barcelona, Spain
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Multiple roles of Staphylococcus aureus enterotoxins: pathogenicity, superantigenic activity, and correlation to antibiotic resistance. Toxins (Basel) 2010; 2:2117-31. [PMID: 22069676 PMCID: PMC3153285 DOI: 10.3390/toxins2082117] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2010] [Accepted: 08/09/2010] [Indexed: 12/03/2022] Open
Abstract
Heat-stable enterotoxins are the most notable virulence factors associated with Staphylococcus aureus, a common pathogen associated with serious community and hospital acquired diseases. Staphylococcal enterotoxins (SEs) cause toxic shock-like syndromes and have been implicated in food poisoning. But SEs also act as superantigens that stimulate T-cell proliferation, and a high correlation between these activities has been detected. Most of the nosocomial S. aureus infections are caused by methicillin-resistant S. aureus (MRSA) strains, and those resistant to quinolones or multiresistant to other antibiotics are emerging, leaving a limited choice for their control. This review focuses on these diverse roles of SE, their possible correlations and the influence in disease progression and therapy.
Collapse
|
|
31
|
Balada E, Vilardell-Tarrés M, Ordi-Ros J. Implication of Human Endogenous Retroviruses in the Development of Autoimmune Diseases. Int Rev Immunol 2010; 29:351-70. [DOI: 10.3109/08830185.2010.485333] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
|
|
32
|
Phillips B, Giannoukakis N, Trucco M. Dendritic cell-based therapy in Type 1 diabetes mellitus. Expert Rev Clin Immunol 2010; 5:325-39. [PMID: 20477010 DOI: 10.1586/eci.09.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Dendritic cell (DC) immunotherapy is a clinical reality. Despite two decades of considerable data demonstrating the feasibility of using DCs to prolong transplant allograft survival and to prevent autoimmunity, only now are these cells entering clinical trials in humans. Type 1 diabetes is the first autoimmune disorder to be targeted for treatment in humans using autologous-engineered DCs. This review will highlight the role of DCs in autoimmunity and the manner in which they have been engineered to treat these disorders in rodent models, either via the induction of immune hyporesponsiveness, which may be cell- and/or antigen-specific, or indirectly by upregulation of other immune cell networks.
Collapse
Affiliation(s)
- Brett Phillips
- University of Pittsburgh School of Medicine, Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA.
| | | | | |
Collapse
|
|
33
|
Pugliese A. Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes. Expert Rev Clin Immunol 2010; 2:419-31. [PMID: 20476913 DOI: 10.1586/1744666x.2.3.419] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Insulin is a polypeptide hormone secreted by pancreatic beta-cells and is critical for glucose homeostasis. Abnormalities in insulin secretion result in various forms of diabetes. Type 1A diabetes is an autoimmune form in which insulin has been identified as a critical autoantigen. Recent studies have identified genetic determinants of insulin-specific autoimmune responses and insulin epitopes targeted by autoreactive T lymphocytes. The study of insulin as an autoantigen has also led to discoveries about basic mechanisms of immunological tolerance and autoimmunity. Experimental and clinical evidence suggests that insulin and insulin-derived peptides may delay and perhaps prevent the development of diabetes. Further clinical trials may identify effective treatment modalities for inhibiting diabetogenic autoimmunity and preventing disease development.
Collapse
Affiliation(s)
- Alberto Pugliese
- Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA.
| |
Collapse
|
|
34
|
Atkinson MA, Gianani R. The pancreas in human type 1 diabetes: providing new answers to age-old questions. Curr Opin Endocrinol Diabetes Obes 2009; 16:279-85. [PMID: 19502978 DOI: 10.1097/med.0b013e32832e06ba] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW Although studies of pancreata from type 1 diabetes (T1D) patients largely fell dormant for a period of decades, research efforts have recently been 'rekindled' in this area to address, using modern techniques, many unanswered questions related to the pathogenesis of this disease. RECENT FINDINGS As historically noted, a pancreatic infiltrate commonly referred to as 'insulitis' is present at the symptomatic onset of T1D. Recent studies have further characterized this infiltrate both in terms of its cellular composition as well as the mechanisms that likely underlie beta cell death in T1D. In addition, the notion that the pancreas from T1D patients is completely devoid of insulin producing cells years after the onset of disease has been challenged, whereas the concepts of whether beta cell regeneration or replication are present have also been subject to much debate. Novel concepts regarding the rate and degree of beta cell loss throughout the natural history of the disease have also been put forward to aid in explaining the disorder's pathogenesis. SUMMARY Although answers to many long-standing questions in T1D have recently been addressed, perhaps the main finding has been one supporting a disease of remarkable heterogeneity. However, additional lessons remain to be learned from the pancreas in T1D. Hence, attempts aimed at organizing the scientific community to address these issues are ongoing, particularly those from collaborative efforts, including the Belgium Organ Donor Consortium and the Network for Pancreatic Organ Donors with Diabetes (nPOD).
Collapse
Affiliation(s)
- Mark A Atkinson
- Department of Pathology, University of Florida,1600 SW Archer Road, Gainesville, Florida 32610, USA.
| | | |
Collapse
|
|
35
|
Bargman R, Freedman A, Vogiatzi M, Motaghedi R. Autoimmune type I diabetes mellitus in a perinatally HIV infected patient with a well-preserved immune system. J Pediatr Endocrinol Metab 2009; 22:369-72. [PMID: 19554812 DOI: 10.1515/jpem.2009.22.4.369] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We report an 8 year-old girl with well-controlled perinatally acquired HIV infection who developed autoimmune type 1 diabetes mellitus (DM1A) confirmed by the presence of diabetes-related auto-antibodies. Although non-autoimmune insulin dependent diabetes mellitus (DM1B) and more frequently type 2 DM has been reported in patients affected with HIV, this is the first report of DM1A diagnosed in an HIV positive patient.
Collapse
Affiliation(s)
- Renee Bargman
- Division of Pediatric Endocrinology, Weill Cornell Medical Center, New York, NY 10065, USA.
| | | | | | | |
Collapse
|
|
36
|
Morran MP, Omenn GS, Pietropaolo M. Immunology and genetics of type 1 diabetes. ACTA ACUST UNITED AC 2009; 75:314-27. [PMID: 18729178 DOI: 10.1002/msj.20052] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes is one of the most well-characterized autoimmune diseases. Type 1 diabetes compromises an individual's insulin production through the autoimmune destruction of pancreatic beta-cells. Although much is understood about the mechanisms of this disease, multiple potential contributing factors are thought to play distinct parts in triggering type 1 diabetes. The immunological diagnosis of type 1 diabetes relies primarily on the detection of autoantibodies against islet antigens in the serum of type 1 diabetes mellitus patients. Genetic analyses of type 1 diabetes have linked human leukocyte antigen, specifically class II alleles, to susceptibility to disease onset. Environmental catalysts include various possible factors, such as viral infections, although the evidence linking infections with type 1 diabetes remains inconclusive. Imbalances within the immune system's system of checks and balances may promote immune activation, while undermining immune regulation. A lack of proper regulation and overactive pathogenic responses provide a framework for the development of autoimmune abnormalities. Type 1 diabetes is a predictable and potentially treatable disease that still requires much research to fully understand and pinpoint the exact triggering events leading to autoimmune activation. In silico research can aid the comprehension of the etiology of complex disease pathways, including Type I diabetes, in order to and help predict the outcome of therapeutic strategies aimed at preserving beta-cell function.
Collapse
Affiliation(s)
- Michael P Morran
- Department of Internal Medicine, Division of Metabolism, Laboratory of Immunogenetics, Brehm Center for Type 1 Diabetes Research and Analysis, University of Michigan Medical School, Ann Arbor, MI, USA
| | | | | |
Collapse
|
|
37
|
Toma A, Laïka T, Haddouk S, Luce S, Briand JP, Camoin L, Connan F, Lambert M, Caillat-Zucman S, Carel JC, Muller S, Choppin J, Lemonnier F, Boitard C. Recognition of human proinsulin leader sequence by class I-restricted T-cells in HLA-A*0201 transgenic mice and in human type 1 diabetes. Diabetes 2009; 58:394-402. [PMID: 19011169 PMCID: PMC2628613 DOI: 10.2337/db08-0599] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE A restricted region of proinsulin located in the B chain and adjacent region of C-peptide has been shown to contain numerous candidate epitopes recognized by CD8(+) T-cells. Our objective is to characterize HLA class I-restricted epitopes located within the preproinsulin leader sequence. RESEARCH DESIGN AND METHODS Seven 8- to 11-mer preproinsulin peptides carrying anchoring residues for HLA-A1, -A2, -A24, and -B8 were selected from databases. HLA-A2-restricted peptides were tested for immunogenicity in transgenic mice expressing a chimeric HLA-A*0201/beta2-microglobulin molecule. The peptides were studied for binding to purified HLA class I molecules, selected for carrying COOH-terminal residues generated by proteasome digestion in vitro and tested for recognition by human lymphocytes using an ex vivo interferon-gamma (IFN-gamma) ELISpot assay. RESULTS Five HLA-A2-restricted peptides were immunogenic in transgenic mice. Murine T-cell clones specific for these peptides were cytotoxic against cells transfected with the preproinsulin gene. They were recognized by peripheral blood mononuclear cells (PBMCs) from 17 of 21 HLA-A2 type 1 diabetic patients. PBMCs from 25 of 38 HLA-A1, -A2, -A24, or -B8 patients produced IFN-gamma in response to six preproinsulin peptides covering residues 2-25 within the preproinsulin region. In most patients, the response was against several class I-restricted peptides. T-cells recognizing preproinsulin peptide were characterized as CD8(+) T-cells by staining with peptide/HLA-A2 tetramers. CONCLUSIONS We defined class I-restricted epitopes located within the leader sequence of human preproinsulin through in vivo (transgenic mice) and ex vivo (diabetic patients) assays, illustrating the possible role of preproinsulin-specific CD8(+) T-cells in human type 1 diabetes.
Collapse
Affiliation(s)
- Andréa Toma
- Institut National de Santé et de Recherche Médicale U561 et Université Paris N, Hôpital Cochin-Saint Vincent de Paul, Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Affiliation(s)
- Michael P Morran
- Laboratory of Immunogenetics, The Brehm Center for Type 1 Diabetes Research and Analysis, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | | | | |
Collapse
|
|
39
|
Voisset C, Weiss RA, Griffiths DJ. Human RNA "rumor" viruses: the search for novel human retroviruses in chronic disease. Microbiol Mol Biol Rev 2008; 72:157-96, table of contents. [PMID: 18322038 PMCID: PMC2268285 DOI: 10.1128/mmbr.00033-07] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely "human rumor viruses." Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on "novel" retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed.
Collapse
Affiliation(s)
- Cécile Voisset
- CNRS-UMR8161, Institut de Biologie de Lille et Institut Pasteur de Lille, Lille, France
| | | | | |
Collapse
|
|
40
|
Pasquali L, Giannoukakis N, Trucco M. Induction of immune tolerance to facilitate beta cell regeneration in type 1 diabetes. Adv Drug Deliv Rev 2008; 60:106-13. [PMID: 18053613 DOI: 10.1016/j.addr.2007.08.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2007] [Accepted: 08/01/2007] [Indexed: 01/12/2023]
Abstract
A definitive cure for type 1 diabetes is currently being pursued with enormous effort by the scientific community. Different strategies are followed to restore physiologic production of insulin in diabetic patients. Restoration of self-tolerance remains the milestone that must be reached in order to move a step further and recover a cell source capable of independent and functional insulin production. Multiple strategies aimed at modulation of both central and peripheral immunity must be considered. Promising results now show that the immune system can be modulated in a way that acquisition of a "diabetes-suppressive" phenotype is possible. Once self-tolerance is achieved, reversal of the disease may be obtained by simply allowing physiologic rescue and/or regeneration of the beta cells to take place. Given that these outcomes have already been confirmed in humans, refinement of existing protocols along with novel methods adapted to T1DM reversal will allow translation into clinical trials.
Collapse
Affiliation(s)
- Lorenzo Pasquali
- Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
| | | | | |
Collapse
|
|
41
|
Wentzensen N, Coy JF, Knaebel HP, Linnebacher M, Wilz B, Gebert J, von Knebel Doeberitz M. Expression of an endogenous retroviral sequence from the HERV-H group in gastrointestinal cancers. Int J Cancer 2007; 121:1417-23. [PMID: 17546591 DOI: 10.1002/ijc.22826] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human endogenous retroviruses (HERVs) account for approximately 8% of the human genome. Since the majority of HERV elements have accumulated inactivating mutations in the viral genes, only few expressed viral open reading frames (ORFs) have been described. In this study, we have analyzed the expression of a HERV-H copy located on Xp22.3 encompassing a potential ORF immediately downstream of the viral promoter. Conventional and real time RT-PCR based expression analysis of this specific HERV-H sequence showed overexpression in 16 of 34 (47%) colorectal, 25 of 63 (40%) gastric and 2 of 12 (17%) pancreatic cancers, whereas no overexpression was detected in bronchial and cervical cancers. Normal human testis, placenta and breast tissue did not show expression of this sequence. CpG methylation analysis of the viral promoter revealed a loss of methylation in cell lines expressing the HERV-H sequence as compared to nonexpressing cell lines and lymphocyte DNA derived from healthy individuals. Further investigations of the HERV-H long terminal repeat and the HERV-H RNA are necessary to assess the functional relevance of the HERV-H expression.
Collapse
Affiliation(s)
- Nicolas Wentzensen
- Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Abstract
The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361,588 newborns, of which it is anticipated that 17,804 will be eligible for enrollment with just over 7,800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.
Collapse
|
|
43
|
Trucco M, Giannoukakis N. Immunoregulatory dendritic cells to prevent and reverse new-onset Type 1 diabetes mellitus. Expert Opin Biol Ther 2007; 7:951-63. [PMID: 17665986 DOI: 10.1517/14712598.7.7.951] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Herein, the authors provide an overview of where dendritic cells lie in the immunopathology of autoimmune Type 1 diabetes mellitus and how dendritic cell-based therapy may be usefully translated to treat and reverse the disease. The immunopathology of Type 1 diabetes mellitus offers a number of windows at which immunotherapy can be applied to delay, stop and even reverse the autoimmune processes, especially in light of the recent antibody-based accomplishment of improvement in residual beta-cell mass function. As in almost all cell-specific inflammatory processes, dendritic cells are central regulators of diabetes onset and progression. This realisation, along with accumulating data confirming a role for dendritic cells in maintaining and inducing tolerance in multiple therapeutic settings, has prompted a line of investigation to identify the most effective embodiments of dendritic cells for diabetes immunotherapy.
Collapse
Affiliation(s)
- Massimo Trucco
- Children's Hospital of Pittsburgh, Diabetes Institute, Pittsburgh, PA 15213, USA
| | | |
Collapse
|
|
44
|
Ballotti S, de Martino M. Rotavirus infections and development of type 1 diabetes: an evasive conundrum. J Pediatr Gastroenterol Nutr 2007; 45:147-56. [PMID: 17667707 DOI: 10.1097/mpg.0b013e31805fc256] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by altered immune tolerance to specific proteins leading to a selective destruction of insulin-producing beta cells in genetically predisposed individuals. T1D is likely to be triggered by environmental factors, including virus infections in genetically predisposed individuals. Rotaviruses are the main cause of severe diarrhea among children worldwide, but they seem to have a role also in T1D induction. Epidemiological data may be consistent with a similar hypothesis. Mechanisms hypothesized include molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. In this review the authors analyze the factors accounting for rotavirus ability to prime islet autoimmunity and cause T1D. A thorough comprehension of their potential pathogenetic mechanisms may allow preventive strategies to be designed.
Collapse
Affiliation(s)
- Serena Ballotti
- Department of Paediatrics, University of Florence, Anna Meyer Children's Hospital, Florence, Italy
| | | |
Collapse
|
|
45
|
Blancou P, Mallone R, Martinuzzi E, Sévère S, Pogu S, Novelli G, Bruno G, Charbonnel B, Dolz M, Chaillous L, van Endert P, Bach JM. Immunization of HLA Class I Transgenic Mice Identifies Autoantigenic Epitopes Eliciting Dominant Responses in Type 1 Diabetes Patients. THE JOURNAL OF IMMUNOLOGY 2007; 178:7458-66. [PMID: 17513797 DOI: 10.4049/jimmunol.178.11.7458] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells. CD8(+) T cells have recently been assigned a major role in beta cell injury. Consequently, the identification of autoreactive CD8(+) T cells in humans remains essential for development of therapeutic strategies and of assays to identify aggressive cells. However, this identification is laborious and limited by quantities of human blood samples available. We propose a rapid and reliable method to identify autoantigen-derived epitopes recognized by human CD8(+) T lymphocytes in T1D patients. Human histocompatibility leukocyte Ags-A*0201 (HLA-A*0201) transgenic mice were immunized with plasmids encoding the T1D-associated autoantigens: 65 kDa glutamic acid decarboxylase (GAD) or insulinoma-associated protein 2 (IA-2). Candidate epitopes for T1D were selected from peptide libraries by testing the CD8(+) reactivity of vaccinated mice. All of the nine-candidate epitopes (five for GAD and four for IA-2) identified by our experimental approach were specifically recognized by CD8(+) T cells from newly diagnosed T1D patients (n = 19) but not from CD8(+) T cells of healthy controls (n = 20). Among these, GAD(114-123), GAD(536-545) and IA-2(805-813) were recognized by 53%, 25%, and 42% of T1D patients, respectively.
Collapse
Affiliation(s)
- Philippe Blancou
- Immuno-Endocrinology Unité Mixte de Recherche 707, Institut National de la Recherche Agronomique/Ecole Nationale Vétérinaire de Nantes/Université, Nantes, France
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Pietropaolo M, Barinas-Mitchell E, Kuller LH. The heterogeneity of diabetes: unraveling a dispute: is systemic inflammation related to islet autoimmunity? Diabetes 2007; 56:1189-97. [PMID: 17322478 DOI: 10.2337/db06-0880] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Diabetes is an emblematic example of a heterogeneous disease. Systemic inflammation has emerged as a prominent factor in the type 2 diabetes pathoetiology, but it remains ill-defined in type 1 diabetes. There is a wide spectrum of associations between inflammatory responses and diabetic syndromes. At one end of this spectrum, there is type 1 diabetes for which there is convincing evidence that chronic inflammation of pancreatic islets is a central aspect of disease pathogenesis. At the opposite end, is type 2 diabetes that is clearly associated with systemic inflammation, which could be either the cause or simply mark the underlying pathology. Accumulating evidence has substantiated that a subgroup of adult patients clinically diagnosed with type 2 diabetes exhibit autoantibody responses to islet autoantigens. The presence of these immunologic abnormalities is associated with a severe insulin secretory defect and the absence of signs of systemic inflammation as documented by plasma C-reactive protein and fibrinogen levels that are comparable with those of control populations. Islet autoantibody evaluation should be part of the diagnostic assessment for clinically diagnosed type 2 diabetes not only because it might predict the rate of progression to insulin requirement in adult populations but also to identify a pathogenically distinct disease phenotype characterized by the absence of systemic inflammation and its related disorders. A more appropriate characterization of this subgroup of clinically diagnosed type 2 diabetes, diabetes of autoimmune pathogenesis, will promote future research into the etiology, natural history, and treatment.
Collapse
Affiliation(s)
- Massimo Pietropaolo
- Laboratory of Immunogenetics, The Brehm Center for Type 1 Diabetes and Analysis, Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | | | | |
Collapse
|
|
47
|
Abstract
Molecular epidemiologic proof that HERVs and other retroelements are involved in autoimmunity or other disorders is complicated by their large numbers in the human genome. As discussed, most HERVs are no longer functional or active because of the accumulation of mutations, frameshifts, and deletions. Detection or quantification of HERV transcripts that may be pathologically involved in a particular autoimmune disease thus is often compromised by the presence in great excess of related, but nonfunctional, RNA. This phenomenon should not deter active work in the field, although it will require development of improved methods to discriminate accurately between closely related RNA transcripts. Development of improved immunologic methods to precisely identify epitopes on autoantigens or rare self-reactive T-cell clones may further implicate HERVs and the other repetitive elements in regulation of the immune system in health and disease.
Collapse
Affiliation(s)
- Ines Colmegna
- Section of Rheumatology, Department of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA 70112, USA
| | | |
Collapse
|
|
48
|
Li H, Zhao Y, Guo Y, Li Z, Eisele L, Mourad W. Zinc induces dimerization of the class II major histocompatibility complex molecule that leads to cooperative binding to a superantigen. J Biol Chem 2006; 282:5991-6000. [PMID: 17166841 PMCID: PMC3924565 DOI: 10.1074/jbc.m608482200] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Dimerization of class II major histocompatibility complex (MHC) plays an important role in the MHC biological function. Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing specific T cell receptor Vbeta elements. Here we have used structural, sedimentation, and surface plasmon resonance detection approaches to investigate the molecular interactions between MAM and the class II MHC molecule HLA-DR1 in the context of a hemagglutinin peptide-(306-318) (HA). Our results revealed that zinc ion can efficiently induce the dimerization of the HLA-DR1/HA complex. Because the crystal structure of the MAM/HLA-DR1/hemagglutinin complex in the presence of EDTA is nearly identical to the structure of the complex crystallized in the presence of zinc ion, Zn(2+) is evidently not directly involved in the binding between MAM and HLA-DR1. Sedimentation and surface plasmon resonance studies further revealed that MAM binds the HLA-DR1/HA complex with high affinity in a 1:1 stoichiometry, in the absence of Zn(2+). However, in the presence of Zn(2+), a dimerized MAM/HLA-DR1/HA complex can arise through the Zn(2+)-induced DR1 dimer. In the presence of Zn(2+), cooperative binding of MAM to the DR1 dimer was also observed.
Collapse
Affiliation(s)
- Hongmin Li
- Wadsworth Center, New York State Department of Health, University of Albany, State University of New York, Albany, New York 12208, USA.
| | | | | | | | | | | |
Collapse
|
|
49
|
Abstract
Environmental factors appear to play an important role in the pathogenesis of childhood-onset type 1 diabetes (T1D). The most important factors are thought to be infectious, dietary, perinatal, and psychosocial. Enteroviruses (especially Coxsackie B virus), breastfeeding, the early presence or lack of certain foods, birth weight, childhood over-nutrition, maternal islet autoimmunity, and negative stress events have been shown to be related to the prevalence of T1D. However, clear conclusions to date are limited because most studies lacked power to detect exposure/disease associations, were not prospective or long-term, did not start in infancy, had imprecise or infrequent exposure estimates, had confounding exposures, and failed to account for genetic susceptibility. In addition to the identification of specific antigenic triggers, several more general hypotheses, including the accelerator and hygiene hypotheses, are testable approaches worth pursuing.
Collapse
Affiliation(s)
- Hui Peng
- Pacific Northwest Research Institute, Seattle, WA 98122, USA
| | | |
Collapse
|
|
50
|
Ramos-Lopez E, Ghebru S, Van Autreve J, Aminkeng F, Herwig J, Seifried E, Seidl C, Van der Auwera B, Badenhoop K. Neither an intronic CA repeat within the CD48 gene nor the HERV-K18 polymorphisms are associated with type 1 diabetes. ACTA ACUST UNITED AC 2006; 68:147-52. [PMID: 16866884 DOI: 10.1111/j.1399-0039.2006.00637.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.
Collapse
Affiliation(s)
- E Ramos-Lopez
- Department of Internal Medicine I, Division of Endocrinology, Diabetes and Metabolism, University Hospital Frankfurt, Frankfurt am Main, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|