Could vector-derived cadherin mimicry contribute to pemphigus vulgaris? An immunogenetic and in silico study involving HLA-DRB104:02 and 14:01

Abstract

Introduction: Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune blistering disease characterized by autoantibodies directed against the desmosomal cadherins desmoglein 3 (DSG3) and desmoglein 1 (DSG1), which are essential for keratinocyte adhesion. While the pathogenic role of these autoantibodies is well established, the upstream events leading to loss of immune tolerance against desmogleins remain incompletely understood. Genetic susceptibility conferred by HLA class II alleles and environmental exposures are thought to interact during disease initiation. In this study, we investigated HLA-DRB1 allele and genotype associations in Turkish PV patients and explored a hypothesis-generating framework linking genetic susceptibility with environmental exposure. Specifically, we examined whether vector-derived cadherin-like proteins could represent potential molecular mimics of desmogleins in genetically predisposed individuals. Methods: HLA-DRB1 allele frequencies were analyzed in 86 PV patients and 200 healthy controls using PCR-SSOP and Luminex-based genotyping. In silico analyses included MHC class II peptide-binding prediction (IEDB), structural modeling using AlphaFold, and molecular dynamics simulations performed with GROMACS. These computational approaches were applied to evaluate structural similarity and relative binding compatibility between cadherin-like peptides derived from hematophagous vectors and disease-associated HLA-DRB1 alleles, including *04:02 and *14:01. Results: HLA-DRB1*04:02 and HLA-DRB1*14:01 alleles were significantly enriched in PV patients compared with controls, and the heterozygous HLA-DRB1*04:02/14:01 genotype was overrepresented in the patient cohort. Structural and energetic analyses indicated that selected vector-derived cadherin-like peptides can adopt stable conformations when bound to these HLA variants and display conformational features compatible with DSG3 ectodomain–derived peptides. Discussion: These findings highlight strong immunogenetic associations in PV and introduce a structurally and immunogenetically informed, hypothesis-generating Vector-derived Cadherin Mimicry (VCM) framework. By integrating genetic association data with computational modeling, this conceptual model suggests that repeated exposure to vector-derived cadherin-like proteins may represent a plausible environmental component contributing to PV susceptibility in genetically predisposed individuals. Experimental validation will be required to further evaluate this framework and its relevance to PV pathogenesis.