Decreased ATM Function Causes Delayed DNA Repair and Apoptosis in Common Variable Immunodeficiency Disorders

Abstract

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.

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors

“…With respect to the identified variants, the majority have been identified in genes involved in DNA repair, especially DSR. The latter is in accordance with the previously reported high frequency of genetic variation in DNA repair genes in CVID ( 57 , 58 ). A genetic background affecting DNA repair would be in line with studies demonstrating chromosomal radiosensitivity ( 59 , 60 ) and DSR defects in CVID ( 58 ) as well as with the identified higher prevalence of NMSC, whose key risk factor is the ultraviolet radiation through its DNA damage-inducing potential ( 61 ).…”

“…The increasing availability of NGS technologies has led to the increasing identification of the genetic background of CVID and to a growing proportion of monogenic disorders, which manifest as CVID. According to recent reports, the proportion of monogenic forms has increased, exceeding 20% of cases ( 56 – 58 ). In the present work, most sequenced patients were sporadic cases.…”

“…This together with the fact that not all studied patients were subjected to WES may account for the relatively low percentage of patients detected with pathogenic variants. However, in a recent study evaluating the genetic background of immunodeficiency through whole-genome sequencing (WGS) in a large patient cohort mainly consisting of sporadic PID, only approximately 10% of tested patients were identified to harbor pathogenic or likely pathogenic genetic variants ( 58 ). Germline mutations in CTLA4 or NFKB1 can cause CVID and at the same time associate with an increased risk of malignancy ( 12 , 56 ).…”

Hallmarks of Cancers: Primary Antibody Deficiency Versus Other Inborn Errors of Immunity

“…The same phenomenon can be present in other entities of PAD with low IgA levels including congenital agammaglobulinemia and IgA deficiency (62,(66)(67)(68). Of note, a minority of CVID patients can present chromosomal radiosensitivity due to disruption of DNA repair machinery and must be considered for tumorigenesis due to genome instability and regular screening for cancer and avoidance of malignancy triggers must be added to their routine management (69,70).…”

Effects of subchronic exposure of nonylphenol on the expression of immune-related factors and estrogen receptors in the spleen of rats

“…The cells were washed twice with Stain Buffer, 1 ml/tube/time, centrifuged at 300×g for 5 min. Finally the cells were resuspended with 0.5 ml Stain Buffer and tested on a flow cytometer (BD FACS Calibur, USA) [75,76].…”