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

Abstract

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.