Article
Multidisciplinary Sciences
Manpreet K. Semwal, Allison K. Hester, Yangming Xiao, Chioma Udeaja, Sergio Cepeda, John S. Verschelde, Nicholas Jones, Sarah A. Wedemeyer, Simon Emtage, Kymberly Wimberly, Ann V. Griffith
Summary: This study reveals that constitutive autophagy in TSCs is regulated by low expression of catalase, which affects central T cell tolerance and may be associated with the development of autoimmune diseases.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Immunology
Manpreet K. Semwal, Nicholas E. Jones, Ann V. Griffith
Summary: The thymus is crucial for T lymphocyte development, with thymic stromal cells playing an important role. Metabolic regulation of thymic stromal cell function is an emerging area of study.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Allergy
Christopher C. Dvorak, Elie Haddad, Jennifer Heimall, Elizabeth Dunn, Rebecca H. Buckley, Donald B. Kohn, Morton J. Cowan, Sung-Yun Pai, Linda M. Griffith, Geoffrey D. E. Cuvelier, Hesham Eissa, Ami J. Shah, Richard J. O'Reilly, Michael A. Pulsipher, Nicola A. M. Wright, Roshini S. Abraham, Lisa Forbes Satter, Luigi D. Notarangelo, Jennifer M. Puck
Summary: Severe combined immunodeficiency (SCID) is an immune deficiency disorder caused by defects in the differentiation of hematopoietic stem cells into mature T lymphocytes. In 2014, the Primary Immune Deficiency Treatment Consortium published diagnostic criteria for SCID, which have now been revised. According to the updated definitions, SCID patients have low T-cell numbers, pathogenic variants in certain genes, or abnormal T-cell markers. The treatment strategy should be tailored to individual patients.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2022)
Review
Immunology
Antonella Cardinale, Carmen Dolores De Luca, Franco Locatelli, Enrico Velardi
Summary: The recognition and immune response against tumor antigens by T cells depends on the diversity of the T-cell receptor (TCR) repertoire, which can be impaired by immunological insults and aging-related decline in thymus function. Manipulating thymic function to enhance anti-tumor immunity is crucial in improving response to cancer immunotherapy, especially checkpoint blockade therapy. The limited response rate to checkpoint blockade therapy may be linked to suboptimal TCR repertoire in cancer patients prior to therapy.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Nathan Provin, Matthieu Giraud
Summary: The thymus plays a crucial role in immune tolerance, but genetic disorders can lead to thymic dysfunction and autoimmune syndromes. Recent advances in gene editing and pluripotent stem cell differentiation offer new possibilities for studying and treating genetic pathologies affecting the thymus.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Immunology
Jayashree Srinivasan, Jessica N. Lancaster, Nandini Singarapu, Laura P. Hale, Lauren I. R. Ehrlich, Ellen R. Richie
Summary: Thymic epithelial cells and hematopoietic antigen presenting cells play essential roles in central tolerance, inducing negative selection or generation of regulatory T cells. Changes in TEC and HAPC subsets across the lifespan may have potential consequences for central tolerance. Age-associated alterations in T cell and Treg function relate to changes in thymic HAPC and TEC subsets.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Alexandra Y. Kreins, Paola Bonfanti, E. Graham Davies
Summary: Inborn errors in thymic stromal cell development and function result in impaired T-cell development, leading to susceptibility to opportunistic infections and autoimmunity. Congenital athymia is a life-threatening disorder associated with complete DiGeorge syndrome and other genetic conditions, which can be treated with timely thymus transplantation. Immune reconstitution following treatment is often incomplete, emphasizing the need for advancements in thymus replacement therapy.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Ruben G. R. Pinheiro, Nuno L. Alves
Summary: TECs play an essential role in the formation of functionally diverse and self-tolerant T cells, particularly in the first weeks after birth in mice. Recent studies highlight the critical coordination between the expansion and maturation of TECs during this period and their specialized role in T cell development and selection. The impact of aging on TEC progenitors and maintenance of functional thymic epithelial microenvironments is discussed, along with how these changes affect the thymus's ability to sustain regular thymopoiesis throughout life.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Cell Biology
Jessica N. Lancaster, Damaris E. Keatinge-Clay, Jayashree Srinivasan, Yu Li, Hilary J. Selden, Seohee Nam, Ellen R. Richie, Lauren I. R. Ehrlich
Summary: Thymus involution in immune aging reduces the number of newly generated T cells and alters the thymus microenvironment. The middle-aged thymic environment does not support efficient motility of medullary thymocytes, leading to impaired central tolerance against moderate-avidity self-antigens and a decrease in Treg cells.
Article
Biology
Noella Lopes, Nicolas Boucherit, Jeremy C. Santamaria, Nathan Provin, Jonathan Charaix, Pierre Ferrier, Matthieu Giraud, Magali Irla
Summary: Interactions between developing T cells and Aire(+) medullary thymic epithelial cells are crucial for central tolerance induction in the thymus. Self-reactive CD4(+) thymocytes control the transcriptional regulators and composition of mTEC(lo) subsets, including Aire(+) mTEC(hi) precursors, post-Aire and tuft-like mTECs. These interactions upregulate the expression of tissue-restricted self-antigens, cytokines, chemokines, and adhesion molecules important for T-cell development. Our study reveals that self-reactive CD4(+) thymocytes control multiple facets of immature mTECs, determining their heterogeneity.
Article
Immunology
Francesca Ferrua, Ileana Bortolomai, Elena Fontana, Dario Di Silvestre, Rosita Rigoni, Genni Enza Marcovecchio, Elena Draghici, Francesca Brambilla, Maria Carmina Castiello, Gloria Delfanti, Despina Moshous, Capucine Picard, Tom Taghon, Victoria Bordon, Ansgar S. Schulz, Catharina Schuetz, Silvia Giliani, Annarosa Soresina, Andrew R. Gennery, Sara Signa, Blachy J. Davila Saldana, Ottavia M. Delmonte, Luigi D. Notarangelo, Chaim M. Roifman, Pietro Luigi Poliani, Paolo Uva, Pier Luigi Mauri, Anna Villa, Marita Bosticardo
Summary: MHCII deficiency, also known as Bare Lymphocyte Syndrome, is a rare combined immunodeficiency resulting in impaired immune responses and susceptibility to infections and autoimmunity. Studies have shown abnormalities in thymic structure and function in both patients and mice with MHCII deficiency, likely due to impaired mTEC maturation and gene expression. This disease-specific TEC defects contribute to perturbation of central tolerance and pose challenges for potential benefits of hematopoietic stem cell transplantation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Esther Bernaldo-de-Quiros, Beatriz Cozar, Rocio Lopez-Esteban, Maribel Clemente, Juan Miguel Gil-Jaurena, Carlos Pardo, Ana Pita, Ramon Perez-Caballero, Manuela Camino, Nuria Gil, Maria Eugenia Fernandez-Santos, Susana Suarez, Marjorie Pion, Marta Martinez-Bonet, Rafael Correa-Rocha
Summary: Regulatory T cells (Treg) are a promising therapy for controlling inflammation. Umbilical cord blood and discarded pediatric thymus have been proposed as alternative sources of Treg. A novel manufacturing protocol has been developed to obtain high-quality and high-quantity Treg from pediatric thymus, which shows potential for cellular therapy.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biology
Matous Voboril, Jiri Brezina, Tomas Brabec, Jan Dobes, Ondrej Ballek, Martina Dobesova, Jasper Manning, Richard S. Blumberg, Dominik Filipp
Summary: mTECs and DCs in the thymus work together to present self-antigens derived from medullary thymic epithelial cells, which is essential for central tolerance. Research has shown that different subsets of thymic DCs selectively target distinct subsets of mTECs, with XCR1(+) activated DC subset being the most potent in cooperative antigen transfer.
Article
Immunology
Xue Dong, Jiayu Zhang, Qian Zhang, Zhanfeng Liang, Yanan Xu, Yong Zhao, Baojun Zhang
Summary: Thymic epithelial cells (TECs) play a critical role in the development and function of the immune system. This study demonstrates the importance of Dhx9 protein in the differentiation and function of mTECs, and its deficiency leads to decreased TEC cell numbers and the development of spontaneous autoimmune disorders.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Cell Biology
Qian Zhang, Zhanfeng Liang, Jiayu Zhang, Tong Lei, Xue Dong, Huiting Su, Yifang Chen, Zhaoqi Zhang, Liang Tan, Yong Zhao
Summary: The study reveals the crucial role of the epigenetic regulator Sirt6 in the development and differentiation of mTECs, with its deficiency leading to decreased mTEC compartment, accelerated differentiation, and autoimmune diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Biographical-Item
Immunology
Luigi D. Notarangelo, Sudhir Gupta
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Article
Allergy
Riccardo Castagnoli, Ottavia M. Delmonte, Luigi D. Notarangelo
Summary: IEI, or primary immunodeficiencies, are disorders caused by mutations in genes involved in immune host defense and immune regulation. Advances in DNA sequencing technology have led to an exponential increase in the discovery of new genes associated with IEI in the past decade.
PEDIATRIC ALLERGY AND IMMUNOLOGY
(2022)
Article
Clinical Neurology
Francesco Doglietto, Linda Daffini, Elena Fazzari, Manuela Cominelli, Francesca Pagani, Pietro Luigi Poliani
Summary: This article reports a rare case of sellar metastasis from clear cell sarcoma. The patient had undergone surgery for sarcoma 9 years ago and presented with symptoms of headache and diabetes insipidus. After MRI examination, the patient underwent endoscopic surgery and showed no evidence of local recurrence in the sella. Instead, a brain metastasis and other deposits were discovered in the paravertebral and pelvic muscles during the 2-year follow-up.
CLINICAL NEUROPATHOLOGY
(2022)
Review
Neurosciences
Edoardo Agosti, Simona Serioli, Kanwaljeet Garg, Alberto Pietrantoni, Pietro Luigi Poliani, Marco Maria Fontanella
Summary: This study reported a rare case of multiple vertebral metastases from anal squamous cell carcinoma (SCC) and aimed to define a treatment strategy. Through case presentation and literature review, it was found that there is currently no universally accepted treatment strategy for vertebral metastases from anal SCC. Prompt and aggressive, local and systemic, and multimodal treatment of the vertebral lesions may be crucial for improving patient outcomes.
INTERNATIONAL JOURNAL OF NEUROSCIENCE
(2023)
Article
Radiology, Nuclear Medicine & Medical Imaging
Francesca Branzoli, Dinesh K. Deelchand, Roberto Liserre, Pietro Luigi Poliani, Lucia Nichelli, Marc Sanson, Stephane Lehericy, Malgorzata Marjanska
Summary: The ability of the PRESS sequence to detect cystathionine in gliomas was evaluated, and the effect of omitting cystathionine on the quantification of the neurochemical profile was assessed. Cystathionine was detectable in gliomas but not in normal tissue, and its omission led to biases in the quantification of other key neurochemicals involved in cancer metabolism.
MAGNETIC RESONANCE IN MEDICINE
(2022)
Article
Medicine, Research & Experimental
Fabio Russo, Eliana Ruggiero, Rosalia Curto, Laura Passeri, Francesca Sanvito, Ileana Bortolomai, Anna Villa, Silvia Gregori, Andrea Annoni
Summary: The study developed a gene transfer approach to modify the T cell repertoire in thymic epithelial cells, correcting the autoimmune response in type 1 diabetes. The strategy involved intrathymic injection of a lentiviral vector to achieve stable transgene expression in thymic epithelial cells, leading to successful correction of the disease in mice models.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2022)
Article
Clinical Neurology
Alberto Pietrantoni, Simona Serioli, Manuela Cominelli, Giovanni Lodoli, Roberto Stefini, Vincenzo Villanacci, Pietro Luigi Poliani
Summary: This article reports a rare case in which a patient was diagnosed with granulomatous hypophysitis, PitNET, and Crohn's disease, providing new evidence for the association between these diseases.
Review
Allergy
Francesca Pala, Luigi D. Notarangelo, Marita Bosticardo
Summary: In this review, the authors provide a summary of inborn errors of immunity characterized by T-cell lymphopenia due to defects in thymic stroma or hematopoietic-intrinsic defects of T-cell development. They also discuss recent advances in diagnostic tools and potential therapeutic approaches to correct thymic defects.
PEDIATRIC ALLERGY AND IMMUNOLOGY
(2022)
Article
Oncology
Valentina Pieri, Alberto L. Gallotti, Denise Drago, Manuela Cominelli, Ilaria Pagano, Valentina Conti, Silvia Valtorta, Angela Coliva, Sara Lago, Daniela Michelatti, Luca Massimino, Federica Ungaro, Laura Perani, Antonello Spinelli, Antonella Castellano, Andrea Falini, Alessio Zippo, Pietro L. Poliani, Rosa Maria Moresco, Annapaola Andolfo, Rossella Galli
Summary: Glioblastoma (GBM), a deadly brain tumor, has dysregulated metabolism that can be targeted for precise therapeutic strategies. Studying GBM sphere-forming cells, researchers identified the L-fucose pathway as a vulnerability specific to mesenchymal GBM, offering a potential precision medicine approach for targeting cancer metabolism.
Review
Immunology
Maria Carmina Castiello, Chiara Brandas, Valentina Capo, Anna Villa
Summary: Increased IgE levels and eosinophilia are commonly observed in Omenn syndrome, which is caused by decreased V(D)J recombination and leads to restricted T and B cell receptor repertoire. RAG proteins play a crucial role in initiating V(D)J recombination, and their absence results in a block in lymphocyte differentiation, leading to T-B severe combined immunodeficiency. Hypomorphic mutations of RAG genes can generate a limited number of T and B cells, resulting in various immunological phenotypes, including immunodeficiency, inflammation, immune dysregulation, and autoimmunity. This study highlights the importance of RAG genes in lymphocyte differentiation and the maintenance of immune tolerance.
CURRENT OPINION IN IMMUNOLOGY
(2023)
Article
Genetics & Heredity
Mara Giacche, Alessandra Panarotto, Luigi Mori, Pietro Luigi Poliani, Roberto Lanzi, Marco Schiavo Lena, Maurizio Castellano
Summary: ARMC5 gene genetic screening in 10 patients with PBMAH identified four germline variants, including one known variant and two novel variants. Somatic analysis further supported the pathogenic effect of the germline variants. This study highlights the importance of genetic testing in sporadic PBMAH patients and expands the spectrum of molecular variants involved in PBMAH syndrome.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Review
Immunology
Maria Carmina Castiello, Samuele Ferrari, Anna Villa
Summary: Allogeneic hematopoietic stem cell transplantation is an effective treatment for inborn errors of immunity, but autologous hematopoietic stem/progenitor cell therapy based on gene addition has demonstrated to be an innovative and safe therapeutic strategy. The recent advent of targeted gene editing offers a cure to inherited immune defects not approachable by conventional gene addition. This review analyzes the current state-of-the-art of conventional gene therapy and innovative protocols of genome editing in primary immunodeficiencies, highlighting potential advantages and limits of gene correction.
SEMINARS IN IMMUNOLOGY
(2023)
Article
Neurosciences
Roberto Liserre, Francesca Branzoli, Francesca Pagani, Magdalena Gryzik, Manuela Cominelli, Evelina Miele, Malgorzata Marjanska, Francesco Doglietto, Pietro Luigi Poliani
Summary: Medulloblastoma (MB) is a common malignant brain tumor in children and rarely found in adults. MB can be classified into four major molecular groups based on transcriptome profile. DNA methylation profiling has identified additional subgroups within these groups. This case report presents a rare occurrence of an adult MB with both non-canonical somatic IDH1(p.R132C) mutation and a GNAS mutation. Further genetic characterization of MB and the use of advanced medical imaging are important for understanding their biology and improving patient management. The findings raise the need for further investigations on therapeutic implications and prognostic relevance.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Health Care Sciences & Services
Francesca Pagani, Magdalena Gryzik, Elena Somenza, Manuela Cominelli, Piera Balzarini, Alberto Schreiber, Davide Mattavelli, Piero Nicolai, Francesco Doglietto, Pietro Luigi Poliani
Summary: Chordomas are rare primary malignant tumors arising from the notochord, with a propensity for the skull base and sacrococcygeal region. Different histotypes and molecular alterations, including PTEN deficiency, contribute to the aggressiveness of chordomas. PTEN loss leads to hyperactivation of the Akt/mTOR pathway, which promotes cell proliferation and invasiveness. In this study, a new human PTEN-deleted chordoma cell line was established and characterized, exhibiting molecular features similar to the parent tumor. These cells were sensitive to treatment with mTOR inhibitors, suggesting their potential therapeutic value for PTEN-deleted chordoma patients.
JOURNAL OF PERSONALIZED MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Serena Calamaio, Marialaura Serzanti, Jennifer Boniotti, Annamaria Fra, Emirena Garrafa, Manuela Cominelli, Rosanna Verardi, Pietro Luigi Poliani, Silvia Dotti, Riccardo Villa, Giovanna Mazzoleni, Patrizia Dell'Era, Nathalie Steimberg
Summary: The process of developing a new drug is time-consuming and expensive, and hepatotoxicity is a major concern. Animal models have limitations due to interspecies differences, but human induced pluripotent stem cells (hiPSCs) offer new possibilities for drug testing. We miniaturized the process of generating hepatic organoids using hiPSC-derived mesenchymal stem cells, hepatocytes, and endothelial cells. These organoids were cultivated in vitro using static and dynamic cultures, and could be maintained for up to 1 week. This hiPSC-derived liver organoid model could potentially replace animal testing in pharmacological and toxicological studies.