Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders
| Autor: | E. Bateman, Chantal E. Hargreaves, Arzoo M Patel, Smita Y. Patel, Consuelo Anzilotti, James E G Charlesworth, John Broxholme, Silvia Salatino, Sarah C. Sasson, Julian C. Knight |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine DNA Repair DNA repair DNA damage Immunology Gene Expression Apoptosis Ataxia Telangiectasia Mutated Proteins Germline Young Adult 03 medical and health sciences 0302 clinical medicine Gene expression medicine Humans Immunology and Allergy Gene Aged Aged 80 and over biology business.industry Common variable immunodeficiency CVID DNA damage and repair Cancer Middle Aged medicine.disease common variable immunodeficiency disorders 3. Good health Common Variable Immunodeficiency Phenotype 030104 developmental biology Case-Control Studies 030220 oncology & carcinogenesis biology.protein Female Original Article primary antibody deficiency Antibody business DNA Damage |
| Zdroj: | Journal of Clinical Immunology |
| ISSN: | 1573-2592 0271-9142 |
| DOI: | 10.1007/s10875-021-01050-2 |
| Popis: | Purpose Common variable immunodeficiency disorders (CVID) is characterized by low/absent serum immunoglobulins and susceptibility to bacterial infection. Patients can develop an infections-only phenotype or a complex disease course with inflammatory, autoimmune, and/or malignant complications. We hypothesized that deficient DNA repair mechanisms may be responsible for the antibody deficiency and susceptibility to inflammation and cancer in some patients. Methods Germline variants were identified following targeted sequencing of n = 252 genes related to DNA repair in n = 38 patients. NanoString nCounter PlexSet assay measured gene expression in n = 20 CVID patients and n = 7 controls. DNA damage and apoptosis were assessed by flow cytometry in n = 34 CVID patients and n = 11 controls. Results Targeted sequencing supported enrichment of rare genetic variants in genes related to DNA repair pathways with novel and rare likely pathogenic variants identified and an altered gene expression signature that distinguished patients from controls and complex patients from those with an infections-only phenotype. Consistent with this, flow cytometric analyses of lymphocytes following DNA damage revealed a subset of CVID patients whose immune cells have downregulated ATM, impairing the recruitment of other repair factors, delaying repair and promoting apoptosis. Conclusion These data suggest that germline genetics and altered gene expression predispose a subset of CVID patients to increased sensitivity to DNA damage and reduced DNA repair capacity. |
| Databáze: | OpenAIRE |
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