Abstract
Pemphigus vulgaris (PV) is a rare but potentially life-threatening autoimmune blistering disorder characterized by circulating IgG autoantibodies that target the desmosomal cadherins desmoglein-3 (Dsg3) and desmoglein-1 (Dsg1). These autoantibodies impair keratinocyte adhesion, leading to loss of cell–cell cohesion (acantholysis) and the formation of painful mucocutaneous erosions. While early models emphasized steric hindrance of desmosomal adhesion as the primary pathogenic mechanism, contemporary research has revealed that PV is a multifactorial disorder involving complex interactions between humoral immunity, T-cell dysregulation, genetic susceptibility and keratinocyte signalling pathways. Autoantibody binding not only blocks adhesion but also activates intracellular signalling cascades, triggers desmoglein internalization and promotes cytoskeletal remodelling, collectively contributing to desmosome destabilization. Advances in immunology have identified key roles for B-cell subsets, follicular helper T cells, regulatory T-cell dysfunction and HLA class II alleles in promoting autoantibody production and loss of tolerance. These mechanistic insights have led to transformative changes in the therapeutic landscape. Rituximab, an anti-CD20 monoclonal antibody, has become a standard first-line therapy, offering superior remission rates compared with conventional immunosuppression. More recent innovations, including neonatal Fc receptor (FcRn) inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors and antigen-specific approaches such as chimeric autoantibody receptor T (CAAR-T) cells, aim to provide targeted, durable disease control with reduced systemic toxicity. This review synthesizes current knowledge on the immunopathology of PV and highlights how mechanistic advances have driven the development of next-generation therapies, ultimately moving the field toward precision and potentially antigen-specific treatment strategies.
Keywords: Acantholysis Mechanisms, Autoimmune Blistering Diseases, B-Cell Targeted Therapy, CAR-T Cell Therapy, Desmoglein Autoantibodies, FcRn Inhibition.