76 results on '"neo-antigen"'
Search Results
52. T-cell 'induced-self' MHC class I/peptide complexes may enable 'de novo' tolerance induction to neo-antigens occurring outside of the thymus.
- Author
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Oelert, Thilo, Gilhar, Amos, and Paus, Ralf
- Subjects
- *
HAIR follicles , *T cells , *MAJOR histocompatibility complex , *PEPTIDES , *ANTIGENS - Abstract
The hair follicle ( HF) epithelium can present self-antigens to cognate CD8+ T cells. These cells express periodically during the hair cycle arising or age-related immunogenic proteins including HF-specific neo-antigens. We propose that IFN-gamma derived from the respective antigen-specific T cells spotting the particular self-peptides may thereby significantly induce and alter self-antigen presentation ('induced-self'). This induction, at first, may silence T cells, including neo-epitope-specific T cells. As the thymus cannot significantly recapitulate neo-epitopes evolving in the periphery, we propose that peripheral tissue-specific induction of MHC molecules presenting exactly these neo-epitopes by self- MHC/peptide-reactive CD8+ T cells is a key element of self-tolerance. Subsequently, however, the local perpetuation and modification of the same crosstalk in the context of HF immune privilege collapse can invite HF immunopathology, as typically seen in alopecia areata. This concept may essentially complement thymus-based regulation models of self/non-self-discrimination beyond 'missing-self' to the fine-tuned 'induced-self' to ensure peripheral needs to maintain self-tolerance in the case of 'danger' and any 'alteration of self'. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
53. Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury.
- Author
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Slone, Emily Archer and Fleming, Sherry D.
- Subjects
- *
MEMBRANE lipids , *INTESTINAL ischemia , *REPERFUSION injury , *AMERICANS , *DEATH rate , *NEUTROPHILS , *EICOSANOIDS , *DISEASES - Abstract
Abstract: Ischemia, lack of blood flow, and reperfusion, return of blood flow, are a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that antibodies recognize exposure of neo-antigens, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed. [Copyright &y& Elsevier]
- Published
- 2014
- Full Text
- View/download PDF
54. Treatment and Prevention of Lung Cancer Using a Virus-Infected Reprogrammed Somatic Cell-Derived Tumor Cell Vaccination (VIReST) Regime
- Author
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Louisa S Chard Dunmall, Shuangshuang Lu, Zhizhong Wang, Lirong Zhang, Zhenguo Cheng, Yunshu Dong, Yang Li, Zhongxian Zhang, Wenli Yan, Duanqing Pei, Danyang Shan, Dongling Gao, Na Wang, Jianzeng Dong, Yaohe Wang, Yupei Ji, Panpan Wang, Nicholas R. Lemoine, Jiwei Wang, Zhe Zhang, Keke Li, Yuenan Li, and Yongchao Chu
- Subjects
lcsh:Immunologic diseases. Allergy ,Oncolytic adenovirus ,Male ,Lung Neoplasms ,Survival ,induced pluripotent stem cells ,T cell ,Immunology ,Genetic Vectors ,Gene Expression ,Vaccinia virus ,Mice, Transgenic ,Cancer Vaccines ,Mice ,Antigens, Neoplasm ,T-Lymphocyte Subsets ,Transduction, Genetic ,Pancreatic cancer ,vaccine ,medicine ,KRAS ,Immunology and Allergy ,Animals ,TP53 ,Progenitor cell ,Lung cancer ,Induced pluripotent stem cell ,Original Research ,business.industry ,Cancer ,adenovirus ,neo-antigen ,medicine.disease ,Tumor Burden ,lung cancer ,Disease Models, Animal ,Oncolytic Viruses ,medicine.anatomical_structure ,Treatment Outcome ,Cancer research ,Immunization ,Stem cell ,lcsh:RC581-607 ,business - Abstract
Lung cancer is one of the most commonly diagnosed cancer and despite therapeutic advances, mortality remains high. The long period of clinical latency associated with lung cancer provides an ideal window of opportunity to administer vaccines to at-risk individuals that can prevent tumor progression and initiate long-term anti-tumor immune surveillance. Here we describe a personalized vaccination regime that could be applied for both therapeutic and prophylactic prevention of lung cancer, based on the derivation of lung cancer cells from induced pluripotent stem cells. Stem cells from healthy mice were modified to express Cre-dependent KRASG12D and Trp53R172H prior to differentiation to lung progenitor cells. Subsequent viral delivery of Cre caused activation of exogenous driver mutations, resulting in transformation and development of lung cancer cells. iPSC-derived lung cancer cells were highly antigenically related to lung cancer cells induced in LSL-KRASG12D/+; Trp53R172H/+ transgenic mice and were antigenically unrelated to original pluripotent stem cells or pancreatic cancer cells derived using the same technological platform. For vaccination, induced lung cancer cells were infected with oncolytic Adenovirus or Vaccinia virus, to act as vaccine adjuvants, prior to delivery of vaccines sequentially to a murine inducible transgenic model of lung cancer. Application of this Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime primed tumor-specific T cell responses that significantly prolonged survival in both subcutaneous post-vaccine challenge models and induced transgenic models of lung cancer, demonstrating that stem cell-derived prophylactic vaccines may be a feasible intervention for treatment or prevention of lung cancer development in at-risk individuals.
- Published
- 2020
55. MHC class II restricted neoantigen peptides predicted by clonal mutation analysis in lung adenocarcinoma patients: implications on prognostic immunological biomarker and vaccine design
- Author
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Dapeng Zhou, Jiaqian Wang, Wen Ling Tan, Weibo Wu, Weijing Cai, Caicun Zhou, and Yanyan Lou
- Subjects
0301 basic medicine ,lcsh:QH426-470 ,medicine.medical_treatment ,lcsh:Biotechnology ,DNA Mutational Analysis ,Adenocarcinoma of Lung ,PD1 checkpoint blocking antibody ,Human leukocyte antigen ,Immunologic Tests ,Biology ,medicine.disease_cause ,Major histocompatibility complex ,03 medical and health sciences ,Cancer immunotherapy ,Antigens, Neoplasm ,Neo-antigen ,lcsh:TP248.13-248.65 ,Databases, Genetic ,MHC class I ,Biomarkers, Tumor ,Genetics ,medicine ,Cancer vaccine ,Humans ,HLA-DRB1 ,MHC class II ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Immune checkpoint ,lcsh:Genetics ,030104 developmental biology ,Cancer research ,biology.protein ,Immunotherapy ,KRAS ,Lung cancer ,Peptides ,HLA-DRB1 Chains ,Research Article ,Biotechnology - Abstract
Background Mutant peptides presented by MHC (major histocompatibility complex) Class II in cancer are important targets for cancer immunotherapy. Both animal studies and clinical trials in cancer patients showed that CD4 T cells specific to tumor-derived mutant peptides are essential for the efficacy of immune checkpoint blockade therapy by PD1 antibody. Results In this study, we analyzed the next generation sequencing data of 147 lung adenocarcinoma patients from The Cancer Genome Atlas and predicted neoantigens presented by MHC Class I and Class II molecules. We found 18,175 expressed clonal somatic mutations, with an average of 124 per patient. The presentation of mutant peptides by an HLA(human leukocyte antigen) Class II molecule, HLA DRB1, were predicted by NetMHCIIpan3.1. 8804 neo-peptides, including 375 strong binders and 8429 weak binders were found. For HLA DRB1*01:01, 54 strong binders and 896 weak binders were found. The most commonly mutated genes with predicted neo-antigens are KRAS, TTN, RYR2, MUC16, TP53, USH2A, ZFHX4, KEAP1, STK11, FAT3, NAV3 and EGFR. Conclusions Our results support the feasibility of discovering individualized HLA Class II presented mutant peptides as candidates for immunodiagnosis and immunotherapy of lung adenocarcinoma. Electronic supplementary material The online version of this article (10.1186/s12864-018-4958-5) contains supplementary material, which is available to authorized users.
- Published
- 2018
56. Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome
- Author
-
Ian M. Dick, Catherine A. Forbes, Vanessa S. Fear, Jonathan Chee, Louis Boon, Bruce W. S. Robinson, Shaokang Ma, and Jenette Creaney
- Subjects
0301 basic medicine ,T cell ,Immunology ,T cells ,Cancer Vaccines ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Antigen ,Neo-antigen ,Antigens, Neoplasm ,Neoplasms ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Animals ,Humans ,Lymph node ,Immune Checkpoint Inhibitors ,RC254-282 ,Original Research ,business.industry ,Intracellular Signaling Peptides and Proteins ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,Immune checkpoint ,3. Good health ,Blockade ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,mesothelioma ,Cancer research ,Biomarker (medicine) ,checkpoint blockade ,biomarker ,Lymph Nodes ,Immunologic diseases. Allergy ,business ,T-Lymphocytes, Cytotoxic - Abstract
Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.
- Published
- 2019
57. Diminished neo-antigen response to keyhole limpet hemocyanin (KLH) vaccines in patients after treatment with chemotherapy or hematopoietic cell transplantation
- Author
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Miller, Jeffrey S., Curtsinger, Julie, Berthold, Melinda, Malvey, Kirsten, Bliss, Robin L., Le, Chap T., Fautsch, Susan K., Dudek, Arkadiusz Z., Blazar, Bruce R., and Panoskaltsis-Mortari, Angela
- Subjects
- *
CANCER treatment , *CANCER patients , *CANCER , *PREVENTIVE medicine - Abstract
Abstract: Relapse is the most common cause of treatment failure for advanced cancer, even those treated with autologous hematopoietic cell transplantation (HCT). Effective tumor-specific immunotherapy may decrease relapse, however, this will fail if the immune system is unable to respond. We developed a strategy to test immune responses with a single injection of the bona fide neo-antigen KLH. The model was first tested in 37 normal volunteers using three KLH vaccines: Intracel KLH, Biosyn KLH, and Biosyn KLH + adjuvant. Despite finding the immunogenic epitope conserved in both products, intact Intracel KLH induced a better response compared to a purified 350/390 kDA subunit of KLH contained in the Biosyn KLH product. Addition of a synthetic oil adjuvant (Montanide ISA51) restored the response to a single injection of Biosyn KLH. A quantitative readout measured by a KLH-specific cellular and humoral response with isotype switching 1 month after KLH vaccination was established. To test the integrity of the adaptive immune response in cancer patients, we vaccinated 14 patients post-HCT and 19 patients with advanced cancer with KLH vaccines that elicited a 100% response rate in normal volunteers. In marked contrast to normal subjects, both responses were significantly impaired up to 16 months after autologous HCT with an intermediate response in advanced cancer patients. KLH vaccines are safe and require only a single injection to test neo-antigen responses providing an optimal platform for definitive testing of strategies to improve diminished immune recovery after chemotherapy or post-HCT. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
58. Neo-Antigen mRNA Vaccines
- Author
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Lorenzo Franceschini, Kris Thielemans, Arthur Esprit, Rajendra Bahadur Shahi, Karine Breckpot, Wout De Mey, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Laboratory for Medical and Molecular Oncology, Vriendenkring VUB, and Laboratory of Molecullar and Cellular Therapy
- Subjects
0301 basic medicine ,dendritic cell ,mRNA ,T cell ,Immunology ,lcsh:Medicine ,Review ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,vaccine ,Drug Discovery ,medicine ,cancer ,Pharmacology (medical) ,Pharmacology ,Tumor microenvironment ,business.industry ,lcsh:R ,Cancer ,Dendritic cell ,neo-antigen ,medicine.disease ,neoantigen ,Vaccination ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Central tolerance ,business - Abstract
The interest in therapeutic cancer vaccines has caught enormous attention in recent years due to several breakthroughs in cancer research, among which the finding that successful checkpoint blockade treatments reinvigorate neo-antigen-specific T cells and that successful adoptive cell therapies are directed towards neo-antigens. Neo-antigens are cancer-specific antigens, which develop from somatic mutations in the cancer cell genome that can be highly immunogenic and are not subjected to central tolerance. As the majority of neo-antigens are unique to each patient’s cancer, a vaccine technology that is flexible and potent is required to develop personalized neo-antigen vaccines. In vitro transcribed mRNA is such a technology platform and has been evaluated for delivery of neo-antigens to professional antigen-presenting cells both ex vivo and in vivo. In addition, strategies that support the activity of T cells in the tumor microenvironment have been developed. These represent a unique opportunity to ensure durable T cell activity upon vaccination. Here, we comprehensively review recent progress in mRNA-based neo-antigen vaccines, summarizing critical milestones that made it possible to bring the promise of therapeutic cancer vaccines within reach.
- Published
- 2020
59. Identification and Ranking of Recurrent Neo-Epitopes in Cancer
- Author
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Eric Blanc, Manuel Holtgrewe, Gerald Willimsky, Thomas Blankenstein, Clemens Messerschmidt, Dieter Beule, and Arunraj Dhamodaran
- Subjects
lcsh:Internal medicine ,Cancer Research ,Neo-epitope ,lcsh:QH426-470 ,Databases, Factual ,Computer science ,Somatic cell ,In silico ,T cell ,medicine.medical_treatment ,Genes, MHC Class I ,Genomics ,Computational biology ,Epitope ,Epitopes ,Mice ,Cancer immunotherapy ,Neo-antigen ,Neoplasms ,MHC class I ,medicine ,Cytotoxic T cell ,Animals ,Humans ,lcsh:RC31-1245 ,Alleles ,Precision treatment ,Cancer ,chemistry.chemical_classification ,biology ,Computational Biology ,medicine.disease ,Amino acid ,lcsh:Genetics ,medicine.anatomical_structure ,chemistry ,Cardiovascular and Metabolic Diseases ,biology.protein ,Immunotherapy ,Technology Platforms ,Research Article - Abstract
Immune escape is one of the hallmarks of cancer and several new treatment approaches attempt to modulate and restore the immune system’s capability to target cancer cells. At the heart of the immune recognition process lies antigen presentation from somatic mutations. These neo-epitopes are emerging as attractive targets for cancer immunotherapy and new strategies for rapid identification of relevant candidates have become a priority. We carefully screen TCGA data sets for recurrent somatic amino acid exchanges and apply MHC class I binding predictions. We propose a method for in silico selection and prioritization of candidates which have a high potential for neo-antigen generation and are likely to appear in multiple patients. While the percentage of patients carrying a specific neo-epitope and HLA-type combination is relatively small, the sheer number of new patients leads to surprisingly high reoccurence numbers. We identify 769 epitopes which are expected to occur in 77629 patients per year. While our candidate list will definitely contain false positives, the results provide an objective order for wet-lab testing of reusable neo-epitopes. Thus recurrent neo-epitopes may be suitable to supplement existing personalized T cell treatment approaches with precision treatment options.
- Published
- 2018
- Full Text
- View/download PDF
60. Non-Genetically Encoded Epitopes Are Relevant Targets in Autoimmune Diabetes.
- Author
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Nguyen, Hai, Guyer, Perrin, Ettinger, Ruth A., James, Eddie A., and Alleva, David G.
- Subjects
EPITOPES ,TYPE 1 diabetes ,T cells ,PANCREATIC beta cells ,ANTIGENS - Abstract
Islet antigen reactive T cells play a key role in promoting beta cell destruction in type 1 diabetes (T1D). Self-reactive T cells are typically deleted through negative selection in the thymus or deviated to a regulatory phenotype. Nevertheless, those processes are imperfect such that even healthy individuals have a reservoir of potentially autoreactive T cells. What remains less clear is how tolerance is lost to insulin and other beta cell specific antigens. Islet autoantibodies, the best predictor of disease risk, are known to recognize classical antigens such as proinsulin, GAD65, IA-2, and ZnT8. These antibodies are thought to be supported by the expansion of autoreactive CD4
+ T cells that recognize these same antigenic targets. However, recent studies have identified new classes of non-genetically encoded epitopes that may reflect crucial gaps in central and peripheral tolerance. Notably, some of these specificities, including epitopes from enzymatically post-translationally modified antigens and hybrid insulin peptides, are present at relatively high frequencies in the peripheral blood of patients with T1D. We conclude that CD4+ T cells that recognize non-genetically encoded epitopes are likely to make an important contribution to the progression of islet autoimmunity in T1D. We further propose that these classes of neo-epitopes should be considered as possible targets for strategies to induce antigen specific tolerance. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
61. Neo-Antigen mRNA Vaccines.
- Author
-
Esprit, Arthur, de Mey, Wout, Bahadur Shahi, Rajendra, Thielemans, Kris, Franceschini, Lorenzo, and Breckpot, Karine
- Subjects
CANCER vaccines ,T cells ,VACCINES ,MESSENGER RNA ,SOMATIC mutation - Abstract
The interest in therapeutic cancer vaccines has caught enormous attention in recent years due to several breakthroughs in cancer research, among which the finding that successful checkpoint blockade treatments reinvigorate neo-antigen-specific T cells and that successful adoptive cell therapies are directed towards neo-antigens. Neo-antigens are cancer-specific antigens, which develop from somatic mutations in the cancer cell genome that can be highly immunogenic and are not subjected to central tolerance. As the majority of neo-antigens are unique to each patient's cancer, a vaccine technology that is flexible and potent is required to develop personalized neo-antigen vaccines. In vitro transcribed mRNA is such a technology platform and has been evaluated for delivery of neo-antigens to professional antigen-presenting cells both ex vivo and in vivo. In addition, strategies that support the activity of T cells in the tumor microenvironment have been developed. These represent a unique opportunity to ensure durable T cell activity upon vaccination. Here, we comprehensively review recent progress in mRNA-based neo-antigen vaccines, summarizing critical milestones that made it possible to bring the promise of therapeutic cancer vaccines within reach. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
62. Immunotherapy for human cancer : from bedside to bench and back
- Author
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Kelderman, S., Schumacher, T.N.M., Blank, C.U., Burg, S.H. van der, Haanen, J.B.A.G., Heemskerk, M.H.M., Borst, J., Kenter, G.G., and Leiden University
- Subjects
T-cell antigen ,Immune-checkpoint blockade ,Neo-antigen ,Cancer immunotherapy ,TCR ,TIL therapy - Abstract
Cancer immunotherapy has taken up its place in oncological practice and it is likely there to stay. Although the field has come from far, much is still to learn as oncologists observe that not all patients with the same disease type respond to cancer immunotherapy, Furthermore, in some cancer types, no clinical benefit is observed at all, despite the presence of an abundant local immune infiltrate, indicating that our understanding of cancer – immune interaction is still incomplete. The overall goal of this thesis is to help address these matters in three ways. First, we have retrospectively analyzed a cohort of melanoma patients treated with ipilimumab, an anti-CTLA-4 antibody, for markers of responsiveness and review the literature to explore the limitations and curative potential of treatment strategies currently used in the clinic or under development. Second, we have developed several technology platforms that allow us to characterize and compare different types of T-cell responses that are directed against tumor-specific antigens in patient tumor material. Third, we aim to increase our understanding of the potential of cancer immunotherapy in ovarian and colorectal cancer, by analysis of the tumor-reactive compartment within these diseases.
- Published
- 2016
63. Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis
- Author
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Christina Gerstner, Anatoly Dubnovitsky, Charlotta Sandin, Genadiy Kozhukh, Hannes Uchtenhagen, Eddie A. James, Johan Rönnelid, Anders Jimmy Ytterberg, Jennifer Pieper, Evan Reed, Karolina Tandre, Mary Rieck, Roman A. Zubarev, Lars Rönnblom, Tatyana Sandalova, Jane H. Buckner, Adnane Achour, and Vivianne Malmström
- Subjects
0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,rheumatoid arthritis ,T cell ,Immunology ,Peptide ,HLA-DR4/α-enolase ,HLA-DR4/alpha-enolase ,Epitope ,03 medical and health sciences ,chemistry.chemical_compound ,CD4+ T cell ,crystal structures ,0302 clinical medicine ,medicine ,Citrulline ,CD4(+) T cell ,Immunology and Allergy ,B cell ,030203 arthritis & rheumatology ,chemistry.chemical_classification ,biology ,autoimmunity ,Autoantibody ,Citrullination ,Correction ,Immunology in the medical area ,neo-antigen ,Molecular biology ,cytokines ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Immunologi inom det medicinska området ,biology.protein ,Antibody ,lcsh:RC581-607 - Abstract
Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue. Correction in: Frontiers in Immunology, Volume: 8, Article Number: 1236, DOI: 10.3389/fimmu.2017.01236
- Published
- 2016
64. Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis
- Author
-
Gerstner, Christina, Dubnovitsky, Anatoly, Sandin, Charlotta, Kozhukh, Genadiy, Uchtenhagen, Hannes, James, Eddie A., Rönnelid, Johan, Ytterberg, Anders Jimmy, Pieper, Jennifer, Reed, Evan, Tandre, Carolina, Rieck, Mary, Zubarev, Roman A., Ronnblom, Lars, Sandalova, Tatyana, Buckner, Jane H., Achour, Adnane, Malmstrom, Vivianne, Gerstner, Christina, Dubnovitsky, Anatoly, Sandin, Charlotta, Kozhukh, Genadiy, Uchtenhagen, Hannes, James, Eddie A., Rönnelid, Johan, Ytterberg, Anders Jimmy, Pieper, Jennifer, Reed, Evan, Tandre, Carolina, Rieck, Mary, Zubarev, Roman A., Ronnblom, Lars, Sandalova, Tatyana, Buckner, Jane H., Achour, Adnane, and Malmstrom, Vivianne
- Abstract
Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue., Correction in: Frontiers in Immunology, Volume: 8, Article Number: 1236, DOI: 10.3389/fimmu.2017.01236
- Published
- 2016
- Full Text
- View/download PDF
65. Somatic mutational landscapes of adherens junctions and their functional consequences in cutaneous melanoma development.
- Author
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Korla PK, Chen CC, Gracilla DE, Lai MT, Chen CM, Chen HY, Hwang T, Chen SY, and Sheu JJ
- Subjects
- Adherens Junctions immunology, Adherens Junctions pathology, Antigens, Neoplasm immunology, Cadherins immunology, Cadherins metabolism, Carcinogenesis genetics, Carcinogenesis immunology, Cell Line, Tumor, Cross-Sectional Studies, DNA Mutational Analysis, Datasets as Topic, Disease-Free Survival, Humans, Lymphocytes, Tumor-Infiltrating immunology, Melanoma mortality, Melanoma pathology, Mutagenesis, Site-Directed, Mutation, Protein Binding genetics, Protein Binding immunology, Skin immunology, Skin pathology, Skin Neoplasms mortality, Skin Neoplasms pathology, T-Lymphocytes immunology, beta Catenin metabolism, Adherens Junctions genetics, Antigens, Neoplasm genetics, Cadherins genetics, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Cell-cell interaction in skin homeostasis is tightly controlled by adherens junctions (AJs). Alterations in such regulation lead to melanoma development. However, mutations in AJs and their functional consequences are still largely unknown. Methods: Cadherin mutations in skin cutaneous melanoma were identified using sequencing data from TCGA dataset, followed by cross-validation with data from non-TCGA cohorts. Mutations with significant occurrence were subjected to structural prediction using MODELLER and functional protein simulation using GROMACS software. Neo-antigen prediction was carried out using NetMHCpan tool. Cell-based fluorescence reporter assay was used to validate β-catenin activity in the presence of cadherin mutations. Clinical significance was analyzed using datasets from TCGA and other non-TCGA cohorts. Targeted gene exon sequencing and immunofluorescence staining on melanoma tissues were performed to confirm the in silico findings. Results: Highly frequent mutations in type-II classical cadherins were found in melanoma with one unique recurrent mutation (S524L) in the fifth domain of CDH6, which potentially destabilizes Ca
2+ -binding and cell-cell contacts. Mutational co-occurrence and physical dynamics analyses placed CDH6 at the center of the top-four mutated cadherins (core CDHs; all type-II), suggesting altered heterophilic interactions in melanoma development. Mutations in the intracellular domains significantly disturbed CDH6/β-catenin complex formation, resulting in β-catenin translocation into cytosol or nucleus and dysregulation of canonical Wnt/β-catenin signaling. Although mutations in core CDH genes correlated with advanced cancer stages and lymph node invasion, the overall and disease-free survival times in those patients were longer in patients with wild-type. Peptide/MHC-I binding affinity predictions confirmed overall increased neo-antigen potentials of mutated cadherins, which associated with T-lymphocyte infiltration and better clinical outcomes after immunotherapy. Conclusion: Changes in cell-cell communications by somatic mutations in AJ cadherins function as one of mechanisms to trigger melanoma development. Certain mutations in AJs may serve as potential neo-antigens which conversely benefit patients for longer survival times., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2020
- Full Text
- View/download PDF
66. Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome.
- Author
-
Ma S, Chee J, Fear VS, Forbes CA, Boon L, Dick IM, Robinson BWS, and Creaney J
- Subjects
- Animals, Antigens, Neoplasm genetics, Humans, Intracellular Signaling Peptides and Proteins genetics, Lymph Nodes, Mice, T-Lymphocytes, Cytotoxic, Cancer Vaccines, Immune Checkpoint Inhibitors pharmacology, Neoplasms genetics, Neoplasms therapy
- Abstract
Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2019
- Full Text
- View/download PDF
67. Robust Iterative Stimulation with Self-Antigens Overcomes CD8+ T Cell Tolerance to Self- and Tumor Antigens.
- Author
-
Nelson, Christine E., Thompson, Emily A., Quarnstrom, Clare F., Fraser, Kathryn A., Seelig, Davis M., Bhela, Siddheshvar, Burbach, Brandon J., Masopust, David, and Vezys, Vaiva
- Abstract
The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8
+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment. • Iterative stimulation with antigen and inflammation reverses CD8+ T cell tolerance • Tolerance reversal results in avidity maturation and enhanced antigen sensing • Expanded self-specific CD8+ T cells form T RM in lymphoid and non-lymphoid tissues • Self-specific CD8+ T cells control tumor growth without concomitant autoimmunity Nelson et al. show that immune tolerance to self is not a fixed state and can be overcome with robust, iterative stimulation in the context of infection. Autoreactive CD8+ T cells expanded with this method can be co-opted to target tumors bearing shared self-antigen without associated autoimmunity. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
68. β cell ER stress and the implications for immunogenicity in type 1 diabetes
- Author
-
Eddie A. James, Meghan L. Marré, and Jon D. Piganelli
- Subjects
Cell physiology ,type 1 diabetes ,Autoimmunity ,Cell ,β cell ,Review ,medicine.disease_cause ,Cell and Developmental Biology ,medicine ,Secretion ,Antigen-presenting cell ,lcsh:QH301-705.5 ,Autoimmune disease ,business.industry ,Endoplasmic reticulum ,autoimmunity ,Cell Biology ,neo-antigen ,medicine.disease ,medicine.anatomical_structure ,lcsh:Biology (General) ,post-translational modification ,Immunology ,Unfolded protein response ,business ,ER stress ,Developmental Biology - Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of insulin-producing pancreatic islet β cells. Although many elegant studies have identified β cell autoantigens that are targeted by the autoimmune response, the mechanisms by which these autoantigens are generated remain poorly understood. Normal β cell physiology includes a high demand for insulin production and secretion in response to dynamic glucose sensing. This secretory function predisposes β cells to significantly higher levels of endoplasmic reticulum (ER) stress compared to nonsecretory cells. In addition, many environmental triggers associated with T1D onset further augment this inherent ER stress in β cells. ER stress may increase abnormal post-translational modification (PTM) of endogenous β cell proteins. Indeed, in other autoimmune disorders such as celiac disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, abnormally modified neo-antigens are presented by antigen presenting cells (APCs) in draining lymph nodes. In the context of genetic susceptibility to autoimmunity, presentation of neo-antigens activates auto-reactive T cells and pathology ensues. Therefore, the ER stress induced by normal β cell secretory physiology and environmental triggers may be sufficient to generate neo-antigens for the autoimmune response in T1D. This review summarizes what is currently known about ER stress and protein PTM in target organs of other autoimmune disease models, as well as the data supporting a role for ER stress-induced neo-antigen formation in β cells in T1D.
- Published
- 2015
69. Robust Iterative Stimulation with Self-Antigens Overcomes CD8 + T Cell Tolerance to Self- and Tumor Antigens.
- Author
-
Nelson CE, Thompson EA, Quarnstrom CF, Fraser KA, Seelig DM, Bhela S, Burbach BJ, Masopust D, and Vezys V
- Subjects
- Animals, CD8-Positive T-Lymphocytes pathology, Cell Line, Tumor, Melanoma pathology, Melanoma therapy, Mice, Mice, Transgenic, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Immune Tolerance, Immunity, Cellular, Melanoma immunology
- Abstract
The immune system adapts to constitutive antigens to preserve self-tolerance, which is a major barrier for anti-tumor immunity. Antigen-specific reversal of tolerance constitutes a major goal to spur therapeutic applications. Here, we show that robust, iterative, systemic stimulation targeting tissue-specific antigens in the context of acute infections reverses established CD8
+ T cell tolerance to self, including in T cells that survive negative selection. This strategy results in large numbers of circulating and resident memory self-specific CD8+ T cells that are widely distributed and can be co-opted to control established malignancies bearing self-antigen without concomitant autoimmunity. Targeted expansion of both self- and tumor neoantigen-specific T cells acts synergistically to boost anti-tumor immunity and elicits protection against aggressive melanoma. Our findings demonstrate that T cell tolerance can be re-adapted to responsiveness through robust antigenic exposure, generating self-specific CD8+ T cells that can be used for cancer treatment., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
70. Immunotherapeutic Challenges for Pediatric Cancers.
- Author
-
Hutzen B, Ghonime M, Lee J, Mardis ER, Wang R, Lee DA, Cairo MS, Roberts RD, Cripe TP, and Cassady KA
- Abstract
Solid tumors contain a mixture of malignant cells and non-malignant infiltrating cells that often create a chronic inflammatory and immunosuppressive microenvironment that restricts immunotherapeutic approaches. Although childhood and adult cancers share some similarities related to microenvironmental changes, pediatric cancers are unique, and adult cancer practices may not be wholly applicable to our pediatric patients. This review highlights the differences in tumorigenesis, viral infection, and immunologic response between children and adults that need to be considered when trying to apply experiences from experimental therapies in adult cancer patients to pediatric cancers., (© 2019 The Authors.)
- Published
- 2019
- Full Text
- View/download PDF
71. A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma
- Author
-
Xiao-Jing Tang, Zhi-Bin Gao, Jie Zhou, Zhan Zhou, Jun Lai, and Shuqing Chen
- Subjects
0301 basic medicine ,Pathology ,Lung Neoplasms ,medicine.medical_treatment ,Targeted therapy ,Major Histocompatibility Complex ,lcsh:Chemistry ,Peritoneal Neoplasm ,personalized immunotherapy target ,Mesothelioma ,Precision Medicine ,Frameshift Mutation ,lcsh:QH301-705.5 ,Peritoneal Neoplasms ,Spectroscopy ,Antigen Presentation ,BAP1 ,High-Throughput Nucleotide Sequencing ,General Medicine ,neo-antigen ,Immunohistochemistry ,Computer Science Applications ,mesothelioma ,Biomarker (medicine) ,Female ,Ubiquitin Thiolesterase ,Signal Transduction ,medicine.medical_specialty ,Blotting, Western ,Biology ,Models, Biological ,Article ,Catalysis ,Frameshift mutation ,Inorganic Chemistry ,03 medical and health sciences ,Antigens, Neoplasm ,Biomarkers, Tumor ,medicine ,Humans ,Amino Acid Sequence ,Physical and Theoretical Chemistry ,Molecular Biology ,Aged ,Tumor Suppressor Proteins ,Mesothelioma, Malignant ,Organic Chemistry ,Reproducibility of Results ,Cancer ,medicine.disease ,Molecular Weight ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 - Abstract
Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient's HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM.
- Published
- 2016
72. Corrigendum: Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis.
- Subjects
RHEUMATOID arthritis ,T cells ,ENOLASE - Published
- 2017
- Full Text
- View/download PDF
73. Corrigendum: Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis.
- Author
-
Gerstner C, Dubnovitsky A, Sandin C, Kozhukh G, Uchtenhagen H, James EA, Rönnelid J, Ytterberg AJ, Pieper J, Reed E, Tandre K, Rieck M, Zubarev RA, Rönnblom L, Sandalova T, Buckner JH, Achour A, and Malmström V
- Abstract
[This corrects the article on p. 494 in vol. 7, PMID: 27895642.].
- Published
- 2017
- Full Text
- View/download PDF
74. A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity.
- Author
-
Walters JN, Ferraro B, Duperret EK, Kraynyak KA, Chu J, Saint-Fleur A, Yan J, Levitsky H, Khan AS, Sardesai NY, and Weiner DB
- Subjects
- Amino Acid Sequence, Animals, Antibodies immunology, Cancer Vaccines immunology, Cell Line, Tumor, Cytokines metabolism, Disease Models, Animal, Epitopes, T-Lymphocyte immunology, Female, Gene Expression, Humans, Immunodominant Epitopes chemistry, Immunodominant Epitopes immunology, Lymphocyte Subsets metabolism, Macaca mulatta, Male, Mice, Neoplasms mortality, Neoplasms pathology, Neoplasms therapy, Peptides immunology, Vaccination, Antigens, Neoplasm immunology, Immune Tolerance, Lymphocyte Subsets immunology, Neoplasms immunology, Vaccines, DNA immunology, WT1 Proteins immunology
- Abstract
Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms' tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency. This approach induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens for driving T cell immunity and breaking tolerance. Non-human primates (NHPs) vaccinated with SynCon WT1 antigens elicited immune responses against native rhesus WT1 peptides. When delivered by electroporation (EP) in mice, SynCon-based WT1 constructs elicited strong CD4 and CD8 T cell responses (including IFN-γ, CD107a, and TNF-α) to both native and consensus peptides. In addition, SynCon WT1 vaccine-induced antibodies recognized native WT1 in vitro. Vaccination with the SynCon WT1 immunogens was capable of slowing tumor growth in therapeutic models in vivo. These data support the further study of synthetic consensus DNA vaccines for breaking tolerance to important germline antigens., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
75. A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma.
- Author
-
Lai J, Zhou Z, Tang XJ, Gao ZB, Zhou J, and Chen SQ
- Subjects
- Aged, Amino Acid Sequence, Antigen Presentation immunology, Blotting, Western, Female, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Major Histocompatibility Complex, Mesothelioma, Malignant, Models, Biological, Molecular Weight, Reproducibility of Results, Signal Transduction, Tumor Suppressor Proteins chemistry, Ubiquitin Thiolesterase chemistry, Antigens, Neoplasm genetics, Biomarkers, Tumor genetics, Frameshift Mutation genetics, Lung Neoplasms genetics, Mesothelioma genetics, Peritoneal Neoplasms genetics, Precision Medicine, Tumor Suppressor Proteins genetics, Ubiquitin Thiolesterase genetics
- Abstract
Malignant peritoneal mesothelioma (MPM) is an aggressive rare malignancy associated with asbestos exposure. A better understanding of the molecular pathogenesis of MPM will help develop a targeted therapy strategy. Oncogene targeted depth sequencing was performed on a tumor sample and paired peripheral blood DNA from a patient with malignant mesothelioma of the peritoneum. Four somatic base-substitutions in NOTCH2, NSD1, PDE4DIP, and ATP10B and 1 insert frameshift mutation in BAP1 were validated by the Sanger method at the transcriptional level. A 13-amino acids neo-peptide of the truncated Bap1 protein, which was produced as a result of this novel frameshift mutation, was predicted to be presented by this patient's HLA-B protein. The polyclonal antibody of the synthesized 13-mer neo-peptide was produced in rabbits. Western blotting results showed a good antibody-neoantigen specificity, and Immunohistochemistry (IHC) staining with the antibody of the neo-peptide clearly differentiated neoplastic cells from normal cells. A search of the Catalogue of Somatic Mutations in Cancer (COSMIC) database also revealed that 53.2% of mutations in BAP1 were frameshift indels with neo-peptide formation. An identified tumor-specific neo-antigen could be the potential molecular biomarker for personalized diagnosis to precisely subtype rare malignancies such as MPM.
- Published
- 2016
- Full Text
- View/download PDF
76. β cell ER stress and the implications for immunogenicity in type 1 diabetes.
- Author
-
Marré ML, James EA, and Piganelli JD
- Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by hyperglycemia due to progressive immune-mediated destruction of insulin-producing pancreatic islet β cells. Although many elegant studies have identified β cell autoantigens that are targeted by the autoimmune response, the mechanisms by which these autoantigens are generated remain poorly understood. Normal β cell physiology includes a high demand for insulin production and secretion in response to dynamic glucose sensing. This secretory function predisposes β cells to significantly higher levels of endoplasmic reticulum (ER) stress compared to nonsecretory cells. In addition, many environmental triggers associated with T1D onset further augment this inherent ER stress in β cells. ER stress may increase abnormal post-translational modification (PTM) of endogenous β cell proteins. Indeed, in other autoimmune disorders such as celiac disease, systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, abnormally modified neo-antigens are presented by antigen presenting cells (APCs) in draining lymph nodes. In the context of genetic susceptibility to autoimmunity, presentation of neo-antigens activates auto-reactive T cells and pathology ensues. Therefore, the ER stress induced by normal β cell secretory physiology and environmental triggers may be sufficient to generate neo-antigens for the autoimmune response in T1D. This review summarizes what is currently known about ER stress and protein PTM in target organs of other autoimmune disease models, as well as the data supporting a role for ER stress-induced neo-antigen formation in β cells in T1D.
- Published
- 2015
- Full Text
- View/download PDF
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