University of Oxford Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK.
Curr Opin Immunol. 2013 Feb;25(1):97-102. doi: 10.1016/j.coi.2012.11.002.
The strong genetic association of ERAP1 (endoplasmic reticulum aminopeptidase 1) with ankylosing spondylitis (AS), which is restricted to HLA-B27 positive cases, has profound pathogenetic implications. ERAP1 is involved in trimming peptides to optimal length for binding to HLA class 1 molecules, thereby not only affecting the stability and processing of HLA-B27 but also influencing the peptide repertoire presented to the immune system. This could have secondary effects on specific adaptive or autoimmune responses in AS. However, it appears increasingly likely that the pathogenic effect of ERAP1 may be mediated through effects on innate immunity, such as altering the interaction between HLA-B27 and immune receptors such as the killer immunoglobulin-like receptors (KIR) found on a range of innate immune cells or via the endoplasmic reticulum unfolded protein response. ERAP1 variants associated with reduced endopeptidase activity appear to be protective against AS, raising the possibility that ERAP1 inhibition could represent a future treatment strategy.
ERAP1（内质网氨肽酶 1）与强直性脊柱炎（AS）的强烈遗传关联，这种关联仅限于 HLA-B27 阳性病例，具有深远的发病机制意义。ERAP1 参与将肽修剪至与 HLA 类 1 分子结合的最佳长度，从而不仅影响 HLA-B27 的稳定性和加工，还影响递呈给免疫系统的肽库。这可能对 AS 中的特定适应性或自身免疫反应产生次要影响。然而，ERAP1 的致病作用似乎越来越可能通过对先天免疫的影响来介导，例如改变 HLA-B27 与免疫受体（如杀伤免疫球蛋白样受体（KIR））之间的相互作用，这些受体存在于一系列先天免疫细胞上，或通过内质网未折叠蛋白反应。与内切肽酶活性降低相关的 ERAP1 变体似乎对 AS 具有保护作用，这增加了 ERAP1 抑制可能代表未来治疗策略的可能性。
