Elevated microRNA-130b levels disrupt B cell tolerance specifically in females by downregulating estrogen receptor alpha (ERα) and PTEN, allowing autoreactive immune cells to escape normal elimination checkpoints. Genetic deletion of ERα in female mice compromised immune tolerance, while males showed reduced B cell numbers but maintained tolerance mechanisms. In multiple sclerosis patients, higher circulating miR-130b levels correlated with increased brain lesions and cognitive decline. This discovery reveals a fundamental sex difference in immune system regulation that could explain why autoimmune diseases like lupus and multiple sclerosis disproportionately affect women. The research identifies a previously unknown role for estrogen signaling in immune tolerance, suggesting that hormonal fluctuations throughout a woman's life may influence autoimmune disease risk. The miR-130b-ERα axis represents a potential therapeutic target, as modulating this pathway might restore proper immune tolerance in females. However, this bioRxiv preprint awaits peer review, and the clinical translation of these mouse model findings to human autoimmune prevention or treatment remains speculative. The work appears paradigm-shifting in connecting sex hormones to fundamental immune tolerance mechanisms.