Endogenous retroviral elements (ERVs) are a class of retrotransposons derived from ancient retroviral infections that have integrated into the host genome. Due to their ability to transpose across the genome and potentially leading to genomic instability, ERV activity is normally repressed by host defense mechanisms, including DNA methylation and histone modifications. However, a progressive, genome-wide loss of DNA methylation is observed during B cell maturation, potentially increasing ERV susceptibility to activation. The specific contribution of DNA methylation to ERV regulation in human B cells remains largely unknown. This research aims to define the downstream consequences of ERV transcriptional activation, including the ability of ERV-derived products to engage innate immune sensors and the potential for ERVs to function as cis-regulatory elements for nearby genes. Given that aberrant ERV reactivation has been implicated in autoimmune disease, these findings may provide new insight into the mechanisms of immune dysregulation and identify novel pathways driving chronic inflammation and autoantibody production.