Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
Spondylitis Program, University Health Network, Toronto, Ontario, Canada.
Semin Immunopathol. 2021 Apr;43(2):245-253. doi: 10.1007/s00281-020-00833-w. Epub 2021 Feb 2.
The strong association of HLA-B27 with ankylosing spondylitis (AS) was first reported nearly 50 years ago. However, the mechanistic link between HLA-B27 and AS has remained an enigma. While 85-90% of AS patients possess HLA-B27, majority of HLA-B27 healthy individuals do not develop AS. This suggests that additional genes and genetic regions interplay with HLA-B27 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-B27 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.
HLA-B27 与强直性脊柱炎（AS）的强关联最早在近 50 年前被报道。然而，HLA-B27 与 AS 之间的机制联系仍然是个谜。虽然 85-90%的 AS 患者携带 HLA-B27，但大多数 HLA-B27 健康个体不会发展为 AS。这表明其他基因和遗传区域与 HLA-B27 相互作用导致 AS。先前的全基因组关联研究（GWAS）确定了在 AS 中具有独特表达的关键基因，包括内质网氨肽酶（ERAP）1 和 ERAP2。由于这些编码分子主要参与肽加工和呈递过程，这些分子与 HLA-B27 的潜在病理性相互作用可能通过激活下游免疫反应导致 AS。异常的肽加工还导致内质网（ER）中不稳定蛋白复合物的积累，这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 AS 发病机制的当前假说，重点介绍了 HLA-B*27 及其相关分子介导的抗原加工和呈递，这些可能有助于 AS 的发病和进展。
