Ataxia-Telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic diseases with similar cellular phenotypes that are caused by mutations in the recently described ATM (encoding ATM) and NBS1 (encoding p95) genes, respectively. Both disorders are accompanied by immunodeficiency in a majority of patients, but the mechanism involved has as yet not been established. We demonstrate that in cells from A-T patients, the switch (S) recombination junctions are aberrant and characterized by a strong dependence on short sequence homologies and devoid of normally occurring mutations around the breakpoint. A low number of S fragments were generated in cells from NBS patients and showed only limited dependence on sequence identity and mutation frequencies were similar to those observed in normal controls. We propose that ATM and p95 are both involved in the final step(s) in class switch recombination with related, but disparate, functional roles. Thus, the general pathway involved in DNA repair also has a major influence on the immunoglobulin isotype switching process.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/1521-4141(200205)32:5<1300::AID-IMMU1300>3.0.CO;2-L | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
ATM Expression and Activation in Ataxia Telangiectasia Patients with and without Class Switch Recombination Defects.
J Clin Immunol
January 2025
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children´s Medical Center, Tehran University of Medical Sciences, 62 Qarib St., Keshavarz Blvd, Tehran, 14194, Iran.
Background: Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.
View Article and Find Full Text PDFIntraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report.
BMC Ophthalmol
January 2025
Department of Ophthalmology, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo, 162-8666, Japan.
Background: To report a case of intraocular inflammation (IOI) after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration.
Case Presentation: An 80-year-old man with diabetes mellitus had neovascular age-related macular degeneration refractory to treatment with aflibercept 2 mg. Despite ten injections of faricimab, the exudation remained, and we switched to brolucizumab, which resulted in a mild IOI.
The LIM-domain-only protein LMO2 and its binding partner LDB1 are differentially required for class switch recombination.
Proc Natl Acad Sci U S A
January 2025
Department of Immunology and Microbiology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
The LIM-domain-only protein LMO2 interacts with LDB1 in context-dependent multiprotein complexes and plays key roles in erythropoiesis and T cell leukemogenesis, but whether they have any roles in B cells is unclear. Through a CRISPR/Cas9-based loss-of-function screening, we identified LMO2 and LDB1 as factors for class switch recombination (CSR) in murine B cells. LMO2 contributes to CSR at least in part by promoting end joining of DNA double-strand breaks (DSBs) and inhibiting end resection.
View Article and Find Full Text PDFIgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility.
Antiviral Res
January 2025
School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education; Shenzhen Key Laboratory of Pathogenic Microbes and Biosafety. Electronic address:
IgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer.
View Article and Find Full Text PDFRIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses.
Nat Commun
January 2025
Laboratory of Genome Diversification & Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125, Berlin, Germany.
The establishment of protective immune responses relies on the ability of terminally differentiated B cells to secrete a broad variety of antigen-specific antibodies with different effector functions. RIF1 is a multifunctional protein that promotes antibody isotype diversification via its DNA end protection activity during class switch recombination. In this study, we showed that RIF1 ablation resulted in increased plasmablast formation ex vivo and enhanced terminal differentiation into plasma cells upon immunization.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!