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

Chantal E Hargreaves,Julian C Knight,Silvia Salatino,James E G Charlesworth,Smita Y Patel,Consuelo Anzilotti,John Broxholme,Elizabeth Bateman,Arzoo M Patel,Sarah C Sasson

doi:10.1007/s10875-021-01050-2

Abstract

PurposeCommon 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.MethodsGermline 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.ResultsTargeted 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.ConclusionThese 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.

Highlights

Common variable immunodeficiency disorders (CVID) is the most clinically prevalent cause of primary antibody failure in adults and children, with an incidence of 1:25,000 [1]
Our previously published whole genome sequencing (WGS) analysis provided evidence for the polygenic nature of sporadic CVID and a disease etiology based on the contribution of multiple interacting genes and pathways [8]
We sought to validate these data through targeted resequencing of a custom selection of 252 genes related to DNA repair pathways in a cohort of 36 sporadic CVID and 2 primary antibody deficiency (PAD) patients

Summary

Introduction

Common variable immunodeficiency disorders (CVID) is the most clinically prevalent cause of primary antibody failure in adults and children, with an incidence of 1:25,000 [1]. Characterized by recurrent infections; low serum levels of IgG, IgM, and/or IgA; and poor-specific antibody responses [2], CVID has a heterogeneous clinical course. The majority of patients have an infections-only phenotype. A subset develops a complex phenotype that can involve autoimmune cytopenia, polyclonal lymphoproliferation, enteropathy, and malignancy [3]. A complex phenotype is associated with a higher mortality rate than other patients and the general population [4]. A recent study identified NFKB1 as the predominant (4%) monogenic cause of a CVID-like phenotype [6]

Results

Discussion

Conclusion