MHC-I-opathy: A Unified Concept for the Etiology of Several Major Histocompatibility Complex-Associated Conditions...

At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting, Drs. Dennis McGonagle and Wilson Liao discussed "MHC-I-opathies," a class of immune-mediated diseases genetically associated with major histocompatibility complex class I (MHC-I) and class I peptide processing. MHC-I-opathies demonstrate epistatic interactions, genetic associations, and immunopathology that are distinct from classic B cell and autoantibody-driven autoimmune diseases. Investigations into the pathomechanisms of MHC-I-opathies have revealed a blend of tissue-specific innate immunity and CD8 T cell responses. Several functional pathomechanisms by which MHC-I molecules increase psoriasis (PsO) susceptibility were presented by McGonagle and Liao, and there were multiple associations within the HLA-C locus. Antigen presentation to T cells, HLA regulation of natural killer cells and CD8 T cells through killer immunoglobulin-like receptors, and HLA regulation of dendritic cells through leukocyte immunoglobulin-like receptors were discussed. Interestingly, MHC-I associations are not only linked to excessive inflammation in MHC-I-opathies but also to the spontaneous suppression of infection (eg, HIV-1 elite controllers). This striking prominence of MHC-I in PsO and antiviral immunity provides insight into why autoimmune alleles are maintained in the human genome and how protective antiviral pathways may be linked to aberrant activation of MHC-I-opathies. Outside of spinal inflammation in HLA-B27-positive axial psoriatic arthritis (PsA), the basis for MHC-I genetics in PsA remains less clear and is at least partly linked to greater PsA heterogeneity. Understanding the contribution of MHC-I in PsO and PsA may have important implications for therapy development.