Abstract
HLA-B27 is recognized as the major genetic factor responsible for the development of SpA. Nevertheless, its pathogenic role remains largely unexplained despite 40 years of investigations. The primary influence of HLA-B27 peptide binding properties on its pathogenic character remains a valid hypothesis, albeit it could bear consequences distinct from the activation of an harmful CD8+ T cell, as initially proposed according to the classical “arthritigenic” peptide hypothesis. A misfolding of HLA-B27 molecules occurring during their synthesis could potentially trigger an endoplasmic reticulum stress response and thereby cause inflammation. The production of non-canonical HLA-B27 dimers could induce a Th17 immunological response by interacting with natural killer receptors. The pathogenic immune response observed in patients as well as in animal models of SpA seems to be dominated by an activation of the IL-23-dependent Th17 pathway. Dysfunction of antigen-presenting cells (dendritic cells, monocytes/macrophages), as was first evidenced in the HLA-B27 transgenic rat model of SpA, could potentially account for a shift of the T cell response towards pathogenic Th17 expansion.
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