The strong association of HLA-B*27 with ankylosing spondylitis (AS) was first reported nearly 50 years ago. However, the mechanistic link between HLA-B*27 and AS has remained an enigma. While 85–90% of AS patients possess HLA-B*27, majority of HLA-B*27 healthy individuals do not develop AS. This suggests that additional genes and genetic regions interplay with HLA-B*27 to cause AS. Previous genome-wide association studies (GWAS) identified key genes that are distinctively expressed in AS, including the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and ERAP2. As these gene-encoding molecules are primarily implicated in the process of peptide processing and presentation, potential pathological interaction of these molecules with HLA-B*27 may operate to cause AS by activating downstream immune responses. The aberrant peptide processing also gives rise to the accumulation of unstable protein complex in endoplasmic reticulum (ER), which drives endoplasmic reticulum–associated protein degradation (ERAD) and unfolded protein response (UPR) and activates autophagy. In this review, we describe the current hypotheses of AS pathogenesis, focusing on antigen processing and presentation operated by HLA-B*27 and associated molecules that may contribute to the disease initiation and progression of AS.

近 50 年前首次报道了 HLA-B*27 与强直性脊柱炎 (AS) 的密切关联。然而，HLA-B*27 和 AS 之间的机制联系仍然是一个谜。虽然 85-90% 的 AS 患者拥有 HLA-B*27，但大多数 HLA-B*27 健康个体不会发展为 AS。这表明其他基因和遗传区域与 HLA-B*27 相互作用导致 AS。以前的全基因组关联研究 (GWAS) 确定了在 AS 中独特表达的关键基因，包括内质网氨基肽酶 (ERAP) 1 和 ERAP2。由于这些基因编码分子主要涉及肽加工和呈递过程，因此这些分子与 HLA-B*27 的潜在病理相互作用可能通过激活下游免疫反应而导致 AS。异常的肽加工还导致内质网（ER）中不稳定蛋白质复合物的积累，从而驱动内质网相关蛋白降解（ERAD）和未折叠蛋白反应（UPR）并激活自噬。在这篇综述中，我们描述了当前关于 AS 发病机制的假设，重点关注由 HLA-B*27 操作的抗原加工和呈递以及可能有助于 AS 疾病发生和进展的相关分子。