An integrated immunogenetic network architecture linking antigen processing and innate immune activation in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a polygenic inflammatory disease in which antigen presentation and innate immune activation converge. While HLA-B27 is the strongest genetic determinant, other loci, such as ERAP1, DEFB1, MICA, and NLRP3, also contribute to disease susceptibility through coordinated mechanisms. However, the higher-order interaction structure integrating these pathways is not well understood. A case-control study analyzed nine variants in the DEFB1, HLA-B, ERAP1, MICA, and NLRP3 genes. Linkage disequilibrium (LD) was evaluated using D' and r2 statistics to identify structured haplotypic blocks. Epistatic interactions were assessed using multifactor dimensionality reduction (MDR), and interaction information metrics were used to quantify synergistic effects. Structured LD blocks were observed within ERAP1 variants, whereas cross-locus LD was limited. MDR analysis revealed that the strongest synergistic interaction was between DEFB1 rs11362 and NLRP3 rs3806268 (21.9% of the total positive epistatic information), followed by DEFB1 rs1800972 and ERAP1 rs27044 (11.0%), suggesting the presence of coordinated barrier-inflammasome and barrier-antigen processing axes. These findings indicate that AS is characterized by a multilayered immunogenetic network in which epithelial defense, antigen processing, cytotoxic activation, and inflammasome signaling interact synergistically to shape immune dysregulation.