Epigenetic regulation of B cell tolerance and dysfunction in autoimmune disease

Epigenetic regulation orchestrates B cell development, lineage commitment, subset differentiation and activation, and is equally central to the maintenance of B cell self-tolerance. Disruption of epigenetic homeostasis at successive tolerance checkpoints - from central tolerance in the bone marrow to peripheral tolerance at germinal centre and extrafollicular stages - can lead to the emergence of autoreactive B cells and the production of autoantibodies in systemic autoimmune diseases. In this Review, we describe the molecular mechanisms by which multiple epigenetic layers - encompassing DNA methylation, histone modification, chromatin remodelling, non-coding RNA regulation and RNA modification - collectively regulate normal B cell function and, when dysregulated, contribute to autoimmune pathogenesis. We examine how specific epigenetic axes, including microRNA-PI3K signalling, DNA demethylation-histone deacetylation balance and chromosome-linked innate immune receptor control, underpin tolerance checkpoint failure and B cell dysfunction in autoimmune disease. Finally, we discuss emerging epigenetic-targeted therapeutic strategies and highlight future research directions aimed at modulating disease-relevant B cell programmes in systemic autoimmunity.