Review
Immunology
Karthik Dhatchinamoorthy, Jeff D. Colbert, Kenneth L. Rock
Summary: Loss of MHC I antigen presentation is common in many cancers, which may impair immune responses and affect the efficacy of immunotherapy. Studies have discussed underlying mechanisms through which some cancers evade immune killing by shutting down the MHC I pathway, and proposed potential strategies to overcome this limitation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemical Research Methods
Laura C. Demmers, Wei Wu, Albert J. R. Heck
Summary: HLA molecules play critical roles in the adaptive immune system by presenting small peptides to signal cell health status to the immune system. This study investigated the adaptive response of a B lymphoblastic cell line to high temperature treatment, revealing potential preparations for immune-like responses in the absence of invading pathogenic peptides. The findings suggest intriguing temperature-sensitive adaptations in this particular B cell line.
MOLECULAR & CELLULAR PROTEOMICS
(2021)
Article
Oncology
Lei Zhan, Junhui Zhang, Jing Zhang, Xiaojing Liu, Suding Zhu, Yuchuan Shi, Yu He, Wenyan Wang, Yijing Wei, Zhenhai Tang, Guo Chen, Bing Wei, Yunxia Cao
Summary: In this study, the researchers found that upregulated autophagy and decreased expression of MHC-I and NLRC5 were associated with endometrial cancer (EC). Inhibition of autophagy was found to suppress MHC-I gene expression. They also discovered that LC3 interacted with NLRC5 to inhibit the NLRC5-mediated MHC-I antigen presentation pathway. These findings suggest that inhibiting LC3 and promoting NLRC5 may be a promising immunotherapy strategy for EC management.
Article
Cell Biology
Maria C. Tovar Fernandez, Ewa M. Sroka, Mathilde Lavigne, Aikaterini Thermou, Chrysoula Daskalogianni, Benedicte Manoury, Rodrigo Prado Martins, Robin Fahraeus
Summary: The accumulation of protein aggregates is toxic and its relation to diseases is still unclear. This study reveals that certain antigenic peptides can be presented to the MHC class I pathway via autophagy. The presentation of peptides derived from the viral EBNA1 protein was not affected by autophagy suppression, while the presentation of ovalbumin was suppressed. The study also suggests that the relative levels of protein expression do not affect autophagy-mediated antigen presentation.
CELLULAR IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Haiyin Liu, Kayla R. Wilson, Ashley M. Firth, Christophe Macri, Patrick Schriek, Annabelle B. Blum, Javiera Villar, Samuel Wormald, Mitch Shambrook, Bangyan Xu, Hui Jing Lim, Hamish E. G. McWilliam, Andrew F. Hill, Laura E. Edgington-Mitchell, Irina Caminschi, Mireille H. Lahoud, Elodie Segura, Marco J. Herold, Jose A. Villadangos, Justine D. Mintern
Summary: This study reveals the critical role of ubiquitin-like protein 3 (UBL3) in the trafficking process controlled by MARCH1. UBL3 has wide-ranging immunological consequences and is essential for immune responses.
NATURE COMMUNICATIONS
(2022)
Review
Cell Biology
Irina A. Ishina, Maria Y. Zakharova, Inna N. Kurbatskaia, Azad E. Mamedov, Alexey A. A. Belogurov Jr, Alexander G. G. Gabibov
Summary: Antigen presentation by MHC-II is crucial for immune response and self-antigen tolerance. Certain MHC-II alleles are associated with autoimmune diseases. The process of MHC-II-mediated presentation plays a significant role in understanding the mechanisms of autoimmune diseases and the protective effect of certain MHC-II alleles.
Review
Immunology
Karolina D. Witt
Summary: MHC class I antigen processing is a less recognized area in nonviral host-pathogen interactions, involving immunology and cell biology. This review focuses on the MHC-I antigen processing pathway and alternative sources of antigens, particularly in the context of Mycobacterium tuberculosis (Mtb) as an intracellular pathogen. It explores how Mtb manipulates host immunity for survival and proposes directions for MHC-I-focused approaches in developing vaccines against tuberculosis.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2023)
Article
Immunology
Jimena Alvarez Freile, Yuzhu Qi, Lisa Jacob, Maria Franceskin Lobo, Harm Jan Lourens, Gerwin Huls, Edwin Bremer
Summary: Investigations into the strength of antigen-specific responses in vitro are crucial for early-phase research of immunotherapeutic approaches. This study presents a rapid luminescence-based method using HPV16 E7(11-20) peptide as a model antigen to evaluate MHC-dependent antigen-specific T cell responses in vitro. The method has important implications for assessing the impact of tumor microenvironment and immune checkpoint inhibitors, as well as accelerating the development of novel immunotherapies.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Agnes Ulfig, Verian Bader, Marharyta Varatnitskaya, Natalie Lupilov, Konstanze F. Winklhofer, Lars Leichert
Summary: Studies have shown that N-chlorinated HSA can significantly impair the ability of macrophages to present antigens to T cells via MHC class II proteins at multiple stages, potentially preventing antigen processing by immune cells at the initial stage of infection and leading to chronic infection and inflammation.
Article
Pharmacology & Pharmacy
Carley Tasker, Jenny Patel, Vibha Jawa, Jad Maamary
Summary: A novel cell-based assay has been proposed for investigating the endosomal processing and MHC class II presentation capabilities of antigens, utilizing competition between epitopes for MHC class II binding and labeled soluble T cell receptors as detectors for epitope presentation.
Article
Biochemistry & Molecular Biology
Onur Oezer, Tobias L. Lenz
Summary: The diversity of pathogens affects different MHC variants binding selectively to different antigenic peptides, providing a key factor for maintaining the diversity of MHC genes in populations.
MOLECULAR BIOLOGY AND EVOLUTION
(2021)
Review
Immunology
David H. Margulies, Jiansheng Jiang, Javeed Ahmad, Lisa F. Boyd, Kannan Natarajan
Summary: Peptide loading of MHC-I molecules plays a critical role in the response of T cells to infections and tumors. Recent advances in structural methods have improved our understanding of the biophysical parameters that govern peptide selection, binding, and surface display. The current understanding of this cellular process is based on various approaches, and further studies are needed to explore its details and potential applications in immunization and therapy.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
M. L. M. Jongsma, J. Neefjes, R. M. Spaapen
Summary: MHC-I molecules present a blueprint of the intracellular proteome to T cells for immune response, but pathogens and tumor cells can downmodulate MHC-I mediated antigen presentation to evade immune surveillance. While the fundamental rules of antigen presentation are well understood, new modules of regulation in this system continue to be uncovered.
MOLECULAR IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Junki Hirano, Sachiyo Yoshio, Yusuke Sakai, Li Songling, Tatsuya Suzuki, Yumi Itoh, He Zhang, David Virya Chen, Saori Haga, Hiroko Oomori, Takahiro Kodama, Yusuke Maeda, Yoshihiro Ono, Yu Takahashi, Daron M. Standley, Masahiro Yamamoto, Kohji Moriishi, Kyoji Moriya, Tatsuya Kanto, Tetsuo Takehara, Kazuhiko Koike, Yoshiharu Matsuura, Toru Okamoto
Summary: Immunoevasins such as the HCV core protein interfere with the maturation and expression of MHC class I molecules, impairing antigen presentation to CD8(+) T cells and evading immune recognition. Targeting the signal peptide peptidase (SPP) may represent a potential strategy to impair MHC class I molecules by both DNA and RNA viruses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Binkai Chi, Muhammet M. Oeztuerk, Christina L. Paraggio, Claudia E. Leonard, Maria E. Sanita, Mahtab Dastpak, Jeremy D. O'Connell, Jordan A. Coady, Jiuchun Zhang, Steven P. Gygi, Rodrigo Lopez-Gonzalez, Shanye Yin, Robin Reed
Summary: Mutations in RNA/DNA-binding proteins can cause ALS, but the exact disease mechanisms are still unclear. This study found that a group of ALS-associated proteins can affect the expression of genes involved in the MHC II antigen presentation pathway. Additionally, hematopoietic progenitor cells with mutations also exhibit disrupted MHC II expression. These findings suggest that the loss of the MHC II pathway may result in the immune system's failure to protect motor neurons from ALS-related damage.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Surgery
Freya Van Hulle, Kaat De Groot, Robert Hilbrands, Ursule Van de Velde, Krista Suenens, Geert Stange, Ines De Mesmaeker, Diedert L. De Paep, Zhidong Ling, Bart Roep, Pieter Gillard, Daniel Pipeleers, Bart Keymeulen, Daniel Jacobs-Tulleneers-Thevissen
Summary: The study found that omental implants can help restore metabolic control in type 1 diabetes patients, but it may require a higher number of beta cells in the grafts and elimination of immunogenic non-endocrine components in order to establish a metabolically adequate functional beta cell mass in the omentum.
AMERICAN JOURNAL OF TRANSPLANTATION
(2022)
Letter
Endocrinology & Metabolism
John S. Kaddis, Daniel J. Perry, Anh Nguyet Vu, Stephen S. Rich, Mark A. Atkinson, Desmond A. Schatz, Bart O. Roep, Todd M. Brusko
Article
Endocrinology & Metabolism
Rebecca C. Wyatt, William A. Hagopian, Bart O. Roep, Kashyap A. Patel, Brittany Resnick, Rebecca Dobbs, Michelle Hudson, Elisa De Franco, Sian Ellard, Sarah E. Flanagan, Andrew T. Hattersley, Richard A. Oram, Matthew B. Johnson
Summary: This study shows that beta cell stress/dysfunction alone does not lead to the production of islet autoantibodies, even in the context of high-risk HLA types. This suggests that additional factors are required to trigger an autoimmune response towards beta cells.
Article
Biochemistry & Molecular Biology
Angela M. Mitchell, Aaron W. Michels
Summary: Despite progress in understanding the mechanisms behind autoimmune diseases, there is limited knowledge about protective mechanisms against these diseases. In the case of type 1 diabetes, pathogenic T cells that destroy pancreatic islets are well understood, but the immune-mediated mechanisms that contribute to protection against this disease are not fully elucidated. One potential protective mechanism involves regulatory CD4 T cells that suppress immune responses by recognizing self-peptides from islets. This review summarizes current knowledge about the antigenic self-peptides recognized by Tregs in the context of type 1 diabetes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
David B. Dunger, Sylvaine F. A. Bruggraber, Adrian P. Mander, M. Loredana Marcovecchio, Timothy Tree, Piotr Jaroslaw Chmura, Mikael Knip, Anke M. Schulte, Chantal Mathieu
Summary: The INNODIA consortium has established an infrastructure to evaluate clinical data and identify biomarkers for future clinical trials in newly diagnosed type 1 diabetes. They have developed a master protocol to improve phase 2 studies, including standardized assessment, collection of mechanistic data, and evaluation of combination therapies.
Review
Immunology
Chelsea Gootjes, Jaap Jan Zwaginga, Bart O. Roep, Tatjana Nikolic
Summary: Type 1 diabetes is an autoimmune disease caused by the interaction of genetic and environmental factors. In addition to HLA gene composition, over 60 non-HLA gene regions also contribute to the susceptibility of the disease. Combining these risk genes into a score significantly improves the prediction of disease progression. Many minor-risk SNPs associated with immune genes have been identified, but their impact on gene and protein expression and their functional changes at a cellular level require further investigation.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Medicine, General & Internal
Nicoline H. M. den Hollander, Bart O. O. Roep
Summary: This review discusses the risk factors, pathophysiology, and defect pathways of type 1 diabetes (T1D) as well as different intervention strategies based on patient characteristics. It highlights the potential benefits of depleting T cells or targeting B lymphocytes in early-onset T1D and the need for more sophisticated, precise, and specific disease-modifying therapies for slow-progressing T1D in adults. The use of genetic editing and immune profiling may aid in determining the specific T1D endotypes patients suffer from. Stratification of endotypes in clinical trials seems essential for precision medicines and clinical decision making.
FRONTIERS IN MEDICINE
(2022)
Article
Hematology
Astrid G. S. van Halteren, Jessica S. Suwandi, Sander Tuit, Jelske Borst, Sandra Laban, Roula Tsonaka, Ada Struijk, Anna-Sophia Wiekmeijer, Melissa van Pel, Bart O. Roep, Jaap Jan Zwaginga, Arjan C. Lankester, Koen Schepers, Maarten J. D. van Tol, Willem E. Fibbe
Summary: Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of stem cell transplantation. This study used mass cytometry to analyze the immune cells in children with severe aGVHD and compared the results with control groups. The onset of aGVHD was associated with the appearance of specific myeloid and lymphoid cells in the blood and affected organs such as the skin and gastrointestinal tract. The findings highlight the importance of immune cell profiling for evaluating clinical response and managing severe aGVHD.
Article
Multidisciplinary Sciences
Rene O. van Tienhoven, Anh Nguyet Vu, John Kaddis, Bart Roep
Summary: Type 1 diabetes patients carrying a protective insulin gene variant have reduced risk of proliferative diabetic retinopathy (PDR) and diabetic kidney disease (DKD) as long-term complications. The presence of this variant is associated with superior glycemic control and improved beta cell function. Intensive insulin therapy combined with this protective variant further decreases the risk of these complications.
Article
Immunology
Bart O. Roep
Summary: The current standard of care for type 1 diabetes patients focuses on managing symptoms rather than addressing the underlying cause. Understanding the immunological aspects of the disease is crucial in order to develop effective treatments and personalize patient care. Immune monitoring provides valuable insights into disease progression, patient heterogeneity, and therapeutic responses, despite the associated challenges and costs. This perspective highlights the importance of immune monitoring in future trials and patient selection.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Endocrinology & Metabolism
Sarah C. Shuck, Peter Achenbach, Bart O. Roep, John S. Termini, Carlos Hernandez-Castillo, Christiane Winkler, Andreas Weiss, Anette-Gabriele Ziegler
Summary: The study found that serum levels of MG-AGEs were associated with the rate of progression to stage 3 type 1 diabetes, with lower levels increasing the risk of progression. This provides a potential new clinical biomarker for determining the rate of disease progression and points to contributing metabolic pathways.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Endocrinology & Metabolism
Neslihan Erdem, Kuan-Tsen Chen, Meirigeng Qi, Yuqi Zhao, Xiwei Wu, Isaac Garcia, Hsun Teresa Ku, Enrique Montero, Ismail H. Al-Abdullah, Fouad Kandeel, Bart O. Roep, Jeffrey S. Isenberg
Summary: TSP1 is a secreted protein that is increased in disease and age. It binds to the cell receptor CD47 and creates a checkpoint for immune activation. Human islets express CD47 and secrete TSP1, but lack SIRPa. These findings are important for the use of CD47 and SIRPa blocking molecules in cancer patients.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2023)
Article
Endocrinology & Metabolism
Rene van Tienhoven, Maria J. L. Kracht, Arno R. van der Slik, Sofia Thomaidou, Anouk H. G. Wolters, Ben N. G. Giepmans, Juan Pablo Romero Riojas, Michael S. Nelson, Francoise Carlotti, Eelco J. P. de Koning, Rob C. Hoeben, Arnaud Zaldumbide, Bart O. Roep
Summary: Transcriptome analysis identified insulin-gene-derived transcripts in non-beta endocrine islet cells. Researchers studied alternative splicing of human INS mRNA in pancreatic islets and found an alternatively spliced INS product that is expressed in delta cells but not in beta cells. This variant encodes the complete insulin signal peptide and B chain, and its presence in delta cells may play a role in islet autoimmunity and pathology.
Article
Medicine, General & Internal
Tomi Suomi, Inna Starskaia, Ubaid Ullah Kalim, Omid Rasool, Maria K. Jaakkola, Toni Gronroos, Tommi Valikangas, Caroline Brorsson, Gianluca Mazzoni, Sylvaine Bruggraber, Lut Overbergh, David Dunger, Mark Peakman, Piotr Chmura, Seren Brunak, Anke M. Schulte, Chantal Mathieu, Mikael Knip, Riitta Lahesmaa, Laura L. Elo
Summary: This study aimed to identify transcriptional changes associated with disease progression in patients with recent-onset type 1 diabetes. They found that genes and pathways related to innate immunity were downregulated during the first year after diagnosis. Associations between gene expression changes and ZnT8A autoantibody positivity were also observed. Additionally, changes in the expression of 16 genes were found to predict the decline in C-peptide at 24 months, and increased B cell levels and decreased neutrophil levels were associated with rapid progression, consistent with previous reports.
Article
Medicine, General & Internal
Janet M. Wenzlau, Yong Gu, Aaron Michels, Marian Rewers, Kathryn Haskins, Liping Yu
Summary: Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing β cells of the pancreatic islets. Our laboratory has recently discovered novel β cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides. These peptides can activate T cells in T1D patients and diabetic mouse models, and antibodies to these peptides may serve as valuable early biomarkers of the disease.