The MHC-I-opathy architecture: immunogenetic and biomechanical determinants of disease expression

Major histocompatibility complex class I molecule (MHC-I)-opathies were originally proposed to unify clinically heterogenous diseases such as spondyloarthritis, psoriasis and Behcet's disease, in which MHC class I genetics, endoplasmic reticulum aminopeptidase (ERAP)-dependent peptide processing, barrier dysfunction, mechanical stress and CD8 T‑cell responses intersect. In this review, we argue that this concept has become increasingly defined and should now be considered as a graded pathogenic framework. Within this model, type 17 MHC-I-opathies, including psoriasis and spondyloarthritis, are largely coupled to interleukin (IL)-23/IL-17-driven neutrophilic inflammation, whereas Takayasu arteritis may represent a type 1 MHC-I-opathy in which human leucocyte antigen B*52 (HLA-B*52)-associated antigen presentation converges with IL-12B, interferon gamma (IFNγ), tumour necrosis factor (TNF) and macrophage-driven granulomatous vascular inflammation. Disease expression is shaped not by MHC‑I carriage alone, but by the extent to which multiple genetic, environmental and tissue-specific layers align the HLA/ERAP-mediated peptide repertoire, barrier perturbation, microbiota- or tissue-derived antigenic pressure, biomechanical stress and adaptive CD8 T‑cell effector programmes. The more completely these layers converge, the more likely a disease or patient is to display the characteristic behaviour of an MHC-I-opathy, including earlier onset, recurrent tissue-localised inflammation, broader anatomical involvement and greater severity. This framework moves the field beyond susceptibility odds ratios toward phenotype stratification, prognostic prediction and rational selection of targeted therapies, including cytokine blockade, modulation of antigen presentation and approaches directed at pathogenic CD8 T‑cell repertoires.