COVID-19 is associated with epigenetic dysregulation in regulatory B cells linked to recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) affects 1-2% of reproductive-aged women, often with unexplained immune etiology. Regulatory B cells (Bregs) maintain maternal-fetal tolerance via interleukin-10 (IL-10) and are dysfunctional in RPL, but environmental triggers remain unknown. We aimed to determine whether SARS-CoV-2 infection is associated with persistent Breg dysfunction in RPL patients through epigenetic mechanisms and evaluate therapeutic rescue strategies. In this study, we analyzed peripheral blood from RPL patients (n = 30) and fertile controls (n = 30) with confirmed COVID-19 (2020-2022). Breg frequency (CD19⁺CD24hiCD38hi), IL-10 production, and epigenetic states (ATAC-seq, ChIP-qPCR, bisulfite sequencing) were assessed. RNA-seq defined transcriptional programs. Functional rescue was tested using HDACi/DNMTi in vitro and in a CBA/J × DBA/2J murine RPL model. The results showed that unlike fertile controls who recovered normal IL-10⁺ Breg function after COVID-19, RPL patients showed persistent IL-10 suppression associated with repressive chromatin, increased H3K27me3, decreased H3K27ac, and IL10 promoter hypermethylation. Non-infected RPL patients already had lower IL-10⁺ Breg frequencies; COVID-19 was associated with exacerbated IL-10 downregulation (ΔIL-10: 42.3% vs. 18.7%, p = 0.006). Epigenetic inhibition reversed this defect in vitro, and epigenetically reprogrammed Bregs improved pregnancy outcomes in mice (40% reduction in fetal resorption, p < 0.01). In conclusion, SARS-CoV-2 infection is associated with epigenetic silencing of IL10 in Bregs from RPL patients, linked to a durable tolerance defect. COVID-19 may represent a contributory environmental factor associated with RPL, and epigenetic modulation is a potential therapeutic avenue.