Article
Clinical Neurology
Matej Skorvanek, Robert Jech, Juliane Winkelmann, Michael Zech
Summary: A male patient with immunodeficiency of unknown etiology since childhood developed a medication-refractory choreodystonic movement disorder at the age of 42. Exome-wide molecular testing revealed a pathogenic variant in the CD40LG gene, confirming the existence of a CD40LG-related condition combining compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial due to potential life-threatening immunological complications.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2022)
Article
Immunology
Parisa Amirifar, Hossein Mozdarani, Reza Yazdani, Fatemeh Kiaei, Tannaz Moeini Shad, Sepideh Shahkarami, Hassan Abolhassani, Samaneh Delavari, Mahsa Sohani, Arezou Rezaei, Gholamreza Hassanpour, Seyed Mohammad Akrami, Asghar Aghamohammadi
Summary: The study aimed to investigate class switch recombination in A-T patients, finding that patients with high IgM levels showed significantly increased rates of respiratory infections and noninfectious complications, with disruptions in their immune responses.
IMMUNOLOGICAL INVESTIGATIONS
(2021)
Article
Multidisciplinary Sciences
Rudel A. Saunders, Thomas F. Michniacki, Courtney Hames, Hilary A. Moale, Carol Wilke, Molly E. Kuo, Johnathan Nguyen, Andrea J. Hartlerode, Bethany B. Moore, JoAnn M. Sekiguchi
Summary: Ataxia-telangiectasia (A-T) is a multisystem disorder with lung complications as a major cause of mortality. This study demonstrates the significant role of ATM-deficient immune cells in causing lung pathologies in A-T, and suggests that targeted inhibition of aberrant inflammatory responses could be a viable therapeutic strategy for A-T lung disease.
SCIENTIFIC REPORTS
(2021)
Article
Pediatrics
Aleksandra Szczawinska-Poplonyk, Katarzyna Tapolska-Jozwiak, Eyal Schwartzmann, Barbara Pietrucha
Summary: This study aimed to investigate the immunodeficiency, immune dysregulation, and organ-specific immunopathology in children with A-T. The results showed that A-T patients had recurrent respiratory tract infections and obstructive airway disease, as well as impaired humoral immunity. The occurrence of autoimmune disorders was higher in patients with the HIGM phenotype, indicating a poorer prognosis.
FRONTIERS IN PEDIATRICS
(2022)
Article
Cell Biology
Majd Haj, Amit Levon, Yann Frey, Noa Hourvitz, Judith Campisi, Yehuda Tzfati, Ran Elkon, Yael Ziv, Yosef Shiloh
Summary: The genetic disorder A-T is caused by loss of the homeostatic protein kinase ATM and leads to genome instability, tissue degeneration, cancer predisposition, and premature aging. Lowering the oxygen concentration to a physiological level range significantly extends the proliferative lifespan of A-T fibroblasts, but they still undergo premature senescence and exhibit high genome instability. Senescing A-T fibroblasts show distinct transcriptional dynamics, including activation of interferon-stimulated genes and altered expression of genes associated with extracellular matrix remodeling.
Article
Clinical Neurology
Stefanie J. G. Veenhuis, Nienke J. H. van Os, Anjo J. W. M. Janssen, Marjo H. J. C. van Gerven, Karlien L. M. Coene, Udo F. H. Engelke, Ron A. Wevers, Gerjen H. Tinnevelt, Rob Ter Heine, Bart P. C. van de Warrenburg, Corry M. R. Weemaes, Nel Roeleveld, Michel A. A. P. Willemsen
Summary: Treatment with nicotinamide riboside (NR) in patients with ataxia telangiectasia (A-T) demonstrated good tolerance and was associated with improvement in ataxia and serum immunoglobulin concentrations.
MOVEMENT DISORDERS
(2021)
Review
Pharmacology & Pharmacy
Bhanu Priya, Srimadhavi Ravi, Sivapriya Kirubakaran
Summary: The DNA Damage and Response (DDR) pathway is crucial for maintaining genome integrity and preventing cancer development. The DDR pathway, particularly the ATM and ATR kinases, plays a vital role in recognizing and repairing DNA double-strand breaks (DSBs), a severe DNA damage that can lead to genomic instability. Cancer cells, with a high burden of DSBs, heavily rely on efficient DSB repair mechanisms for their survival. Therefore, targeting DSB repair pathways, such as ATM and ATR, can enhance the efficacy of DNA-damaging agents in cancer treatment. This review focuses on the roles of ATM and ATR in the DDR pathway, challenges in targeting these kinases, and current clinical trials of their inhibitors.
DRUG DISCOVERY TODAY
(2023)
Article
Multidisciplinary Sciences
Yijang Xu, Hang Zhou, Ginell Post, Hong Zan, Paolo Casali
Summary: The study demonstrates that Rad52 mediates IgD CSR through a microhomology-based DNA repair pathway, leading to the expression of IgD in B cells.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Ilaria Callegari, Mika Schneider, Giuliano Berloffa, Tobias Muhlethaler, Sebastian Holdermann, Edoardo Galli, Tim Roloff, Renate Boss, Laura Infanti, Nina Khanna, Adrian Egli, Andreas Buser, Gert Zimmer, Tobias Derfuss, Nicholas S. R. Sanderson
Summary: In this study, we isolated spike-protein-specific B cells and produced recombinant antibodies of IgM, IgG, and IgA classes. Two IgM antibodies demonstrated potent virus neutralization at picomolar concentrations, but this potency was lost when switched to IgG. Decreased avidity alone cannot explain the loss of potency.
Article
Immunology
Oksana Boyarchuk, Halyna Makukh, Larysa Kostyuchenko, Nataliya Yarema, Ivanna Haiboniuk, Volodymyr Kravets, Oleksandra Shulhai, Bohdan Tretyak
Summary: The study aimed to determine TREC/KREC levels in patients with AT for early diagnosis. It found that TREC and KREC levels were significantly lower in AT patients, with a positive correlation between TREC levels and CD4 absolute values. This suggests that measuring TREC/KREC levels could facilitate early detection of AT and improve patient outcomes.
IMMUNOLOGIC RESEARCH
(2021)
Article
Immunology
Chloe Oudinet, Xuefei Zhang, Nadine Puget, Nia Kyritsis, Claire Leduc, Fatima-Zohra Braikia, Audrey Dauba, Frederick W. Alt, Ahmed Amine Khamlichi
Summary: Immunoglobulin class switch recombination plays a crucial role in humoral immune responses by altering the effector functions of antibodies. The A-NHEJ pathway in CSR shows a preference for longer junctional micro-homologies, and the molecular basis of S mu specificity remains unclear. Introducing the E mu enhancer into the S gamma 3 region confers the recombinational features of S mu to S gamma 3, indicating a bias for longer MH.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biology
Hongchang Zhao, Stella R. Hartono, Kirtney Mae Flores de Vera, Zheyuan Yu, Krishni Satchi, Tracy Zhao, Roger Sciammas, Lionel Sanz, Frederic Chedin, Jacqueline Barlow, Michela Di Virgilio
Summary: Class switch recombination is a crucial process for generating distinct antibody isotypes, and defects in this process are associated with autoimmune disorders and lymphoma genesis. In this study, we found that cells lacking two enzymes involved in removing R loops exhibited increased R loop formation and genome instability at the immunoglobulin heavy chain locus. However, this did not affect transcriptional activity, AID recruitment, or class switch recombination efficiency. Our findings suggest that senataxin and RNase H2 act together in removing R loops, promoting efficient repair and suppressing AID-dependent genome instability and insertional mutagenesis.
Article
Biochemistry & Molecular Biology
Er-yi Wang, Hao Chen, Bao-qing Sun, Hui Wang, Hui-Qi Qu, Yichuan Liu, Xi-zhuo Sun, Jingchun Qu, Zhang-fu Fang, Lifeng Tian, Yi-feng Zeng, Shau-Ku Huang, Hakon Hakonarson, Zhi-gang Liu
Summary: The study found that serum levels of TGF-beta 1 significantly increased in the early and middle stages of COVID-19 and were correlated with the levels of SARS-CoV-2-specific IgA and the APACHE II score in patients with severe disease. The findings suggest TGF-beta 1 may play a key role in COVID-19, based on the genetic association of the TGF-beta 1 activator THBS3 with severe COVID-19 identified by the COVID-19 Host Genetics Initiative.
Article
Immunology
Parisa Amirifar, Mahya Mehrmohamadi, Mohammad Reza Ranjouri, Seyed Mohammad Akrami, Nima Rezaei, Ali Saberi, Reza Yazdani, Hassan Abolhassani, Asghar Aghamohammadi
Summary: The study identified variants associated with the antigen processing and presentation pathway, as well as variants in four genes involved in DNA double-strand breaks repair signaling in a group of A-T patients. These additional genetic influences may explain the heterogeneity in the CSR defect phenotype among A-T patients.
JOURNAL OF CLINICAL IMMUNOLOGY
(2022)
Article
Immunology
Shlomo Elias, Rahul Sharma, Michael Schizas, Izabella Valdez, Sham Rampersaud, Sun-Mi Park, Paula Gonzalez-Figueroa, Quan-Zhen Li, Beatrice Hoyos, Alexander Y. Rudensky
Summary: Regulatory T cells control autoreactive B cells in the bone marrow in a CXCR4-dependent manner, affecting their ability to produce antibodies.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
