Integrated Multi-omics Analyses of NFKB1 patients B cells points towards an up regulation of NF-κB network inhibitors

Abstract

AbstractThe transcription factor NF-κB plays a pivotal role in the adaptive immune response. Pathogenic variants inNFKB1are the most common genetic etiology of common variable immunodeficiency (CVID). Patients frequently present with impaired terminal B cell differentiation, autoimmunity, and hyperinflammatory immune dysregulation. NF-κB signaling and target gene expression are expected to be dysregulated inNFKB1-mutated patients. Here, we performed a multi-omics characterization of B cells from a cohort of clinically affected and unaffectedNFKB1mutation carriers. Our analysis identified specific epigenetic dysregulation and gene expression differences on B cells fromNFKB1-mutated patients. We observed an aberrant expression of negative regulators of NF-κB signaling inNFKB1mutation carriers, which may be a key factor for the autoinflammatory phenotype of these patients. Moreover, our analysis points towards a dysregulation ofXBP1andBCL3, key players of B cell activation and proliferation at different stages of B cell differentiation. The reduced expression of negative regulators of the NF-κB network is likely to be one of several mechanisms responsible for the aberrant NF-κB signaling, which impairs the maintenance of a normal humoral immune response. In summary, our findings highlight epigenetic and gene expression changes in B cells associated withNFKB1mutations. Our data give insight into future therapeutic opportunities for patients withNFKB1(haplo)insufficiency.