How is HLA B27 hypothesized to play a role in the pathogenesis of Axial Spondyloarthritis?
Infection with an unknown organism or exposure to an unknown antigen in a genetically susceptible individual (HLA-B27+) is hypothesized to result in the clinical expression of axSpA/AS. This is supported by the HLA-B27 transgenic rat model, which will spontaneously develop an axSpA in a normal habitat, but not when raised in a germ-free environment. There are four hypotheses:
• Arthritogenic peptide hypothesis: the arthritogenic response might involve specific microbial peptides that bind to HLA-B27 and then are presented in a unique manner to CD8+ (cytotoxic) T cells resulting in disease.
• Molecular mimicry: the induction of autoreactivity to self-antigens might develop as a result of similar structural elements shared by sequences or epitopes on the infecting organism or antigen and a portion of the HLA-B27 molecule or other self-peptides.
• Free heavy chain hypothesis: HLA-B27 heavy chains can form stable homodimers with no associated β-2 microglobulin on the cell surface. These homodimers can trigger direct activation of natural killer cells through recognition via immunoglobulin receptor-like receptors.
• Unfolded protein hypothesis: HLA-B27 has a propensity to misfold in the endoplasmic reticulum causing an unfolded protein stress response. This results in the release of inflammatory cytokines such as IL-23, which can activate proinflammatory Th-17 cells. Notably, ERAP-1 is involved in the trimming of peptides for loading in major histocompatibility complex molecules (HLA-B27) in the endoplasmic reticulum. Abnormal loading may enhance the misfolding of HLA-B27. As noted earlier, ERAP-1 and IL-23R polymorphisms both contribute to the genetic risk of developing AS.