Genetic and Molecular Determinants of Pemphigus Vulgaris and their Therapeutic Implications

Pemphigus vulgaris (PV) is a rare, potentially life-threatening autoimmune blistering disease driven by pathogenic IgG autoantibodies targeting desmosomal cadherins (primarily desmoglein-3 and desmoglein-1), leading to loss of keratinocyte adhesion (acantholysis). Beyond antibody-mediated mechanisms, convergent evidence supports a strong genetic contribution to disease susceptibility, phenotype, and therapeutic response. This expanded narrative review synthesizes classical and emerging genetic determinants of PV, including HLA class II associations, non-HLA immune modifiers, desmosomal/epithelial susceptibility genes, genome-wide association study (GWAS) loci, epigenetic and transcriptomic signals, and integrates contemporary therapeutic advances (rituximab, FcRn inhibitors, BTK inhibition, and antigen-specific cell therapies). We highlight genotype-phenotype relationships, ethnic differences in risk alleles, translational biomarkers, and future directions for precision medicine in PV.