1) Arthritogenic/spondylogenic peptide hypothesis: This hypothesis is based on the canonical function of HLA-B27 as an MHC class I molecule presenting antigenic peptides to CD8+ T cells. Disease is thought to be the result of a T cell-mediated anti-self-immune response against particular HLA-B27–peptide combinations.27 The peptide hypothesis has an advantage in that it can explain the organ specificity of AS by assuming that expression of the arthritogenic/spondylogenic peptides is restricted to the affected tissues. The model implies breakdown of tolerance toward self-peptides, which may occur in the context of an infection and may involve cross-reactivity with microbial peptides. However, no specific arthritogenic/spondylogenic peptides have been identified so far, and there is no convincing evidence for a critical role for CD8+ T cells in AS pathogenesis.
2) Misfolding hypothesis: Shortly after the demonstration that MHC class I HCs require the interaction with b2m for proper folding in the ER, it was found that HLA-B27 is special in that HLA-B27 HCs have an increased propensity to misfold, even in the presence of b2m.28,29 The accumulation of misfolded proteins in the ER is known to trigger a cellular stress response called unfolded protein response (UPR). The UPR involves multiple pathways all directed at resolving the accumulation of misfolded proteins in the ER. However, in certain situations, UPR activation can induce an inflammatory response.30 This has been demonstrated in cells from HLA-B27 transgenic rats, thereby offering a plausible explanation for the development of disease in these animals without a requirement for CD8+ T cells.31,32 However, there is little supportive evidence for aberrant activation of the UPR in HLA-B27+ humans with AS. (Editor’s note: For more on this hypothesis, see “Conformational Flexibility” on p. 20 in this issue.)
3) Homodimer/NK cell receptor hypothesis: Around the same time that misfolding of HLA-B27 HCs was described, another special molecular feature of HLA-B27 was discovered. HLA-B27 HCs may form disulfide-linked HC homodimers, which do not require b2m for cell surface expression. It was subsequently shown that the inhibitory NK cell receptor KIR3DL2 interacts more strongly with HLA-B27 HC homodimers than with conventional MHC class I complexes.33 Despite their name, the expression of many NK cell receptors, including KIR3DL2, is not limited to NK cells, and there are data demonstrating that HLA-B27 homodimers may result in inappropriate activation of KIR3DL2 expressing CD4+ T cells.34 Why ligation of an inhibitory NK cell receptor would drive CD4+ T cell activation and how such non-antigen-specific T cell activation would lead to a distinctly organ-specific disease are some of the questions that remain to be answered.
