Vector-derived Cadherin Mimicry in Pemphigus Vulgaris: A Proposed Model Linking HLA-DRB1*04:02/14:01 Genotype with Environmental Exposure

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease caused by pathogenic autoantibodies targeting the desmosomal cadherins desmoglein 3 (DSG3) and desmoglein 1 (DSG1), essential for cell-cell adhesion. Although the role of these autoantibodies in disease pathogenesis is well established, the mechanisms initiating the autoimmune response remain unclear. A strong genetic association has been identified between PV and specific HLA class II alleles, particularly HLA-DRB1*04:02 and *14:01, which may facilitate the presentation of desmoglein-derived peptides to autoreactive CD4+ T cells. Environmental factors are also thought to contribute, with molecular mimicry being a leading hypothesis--whereby foreign antigens resembling host proteins trigger cross-reactive immune responses. In this study, we analyzed HLA-DRB1 allele frequencies in Turkish PV patients and controls, confirming strong associations with *04:02 and 14:01. Notably, we found that the heterozygous HLA-DRB104:02/14:01 genotype confers an approximately 100-fold increased risk for PV. Building on this, we propose a novel model: cadherin-like proteins from the salivary glands of mosquitoes or similar blood-feeding insects may structurally mimic DSG3/DSG1. In our model--termed vector-derived cadherin mimicry (VCM)--pattern recognition, rather than primary sequence identity (i.e., shared surface charge/topology patterns) is key to the mimicry mechanism. Repeated exposure to such antigens in genetically susceptible individuals may contribute to tolerance breakdown and disease initiation. Using HLA genotyping, peptide binding prediction, structural modeling, and molecular dynamics simulations, we provide preliminary in silico evidence supporting the VCM hypothesis as a potential trigger for PV-specific autoimmunity.