Epigenetic regulation of humoral immunity: molecular mechanisms, diseases and therapeutic targets

Humoral immunity, a fundamental branch of adaptive immunity, relies on B lymphocytes and the antibodies they produce to eliminate extracellular pathogens and neutralize toxins. The development, activation, and differentiation of B cells are tightly regulated by epigenetic mechanisms-including DNA methylation, histone modifications, chromatin dynamics, RNA modifications, and noncoding RNAs-that modulate gene expression without altering the DNA sequence, orchestrating key events such as V(D)J recombination, class switch recombination, somatic hypermutation, germinal center reactions, and the generation of memory B cells and plasma cells. In this review, we summarize how these five categories of epigenetic regulators-together with their respective writers, erasers, readers, and effectors-including DNMT3A/3B and TET enzymes, histone-modifying enzymes, SWI/SNF and INO80 remodeling complexes, N6-methyladenosine and 5-methylcytosine machineries, and microRNAs and long noncoding RNAs-collectively govern B-cell fate decisions, from early lineage commitment in the bone marrow, through germinal center dynamics, to terminal differentiation into plasma cells or memory B cells. We further examine how aberrant epigenetic programs in B cells contribute to pathogenesis across four major disease categories: B-cell malignancies, metabolic and cardiovascular diseases, autoimmune disorders, and infectious diseases. We also discuss sex-biased epigenetic mechanisms, particularly escape from X-chromosome inactivation, that may underlie the female predominance of autoimmune diseases. Finally, we discuss the therapeutic implications of targeting epigenetic regulators and assess the potential of epigenetic signatures as biomarkers.