HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8⁺ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4⁺ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.

HLA-B*27 具有患脊柱关节炎 （SpA） 的高风险，包括伴有或不伴有外周关节炎的中轴型 SpA、附着点炎、急性前葡萄膜炎和胃肠道炎症。尽管尚未建立明确的机制来解释这种 HLA I 类蛋白在 SpA 发病机制中的作用，但已经出现了三个主要假设。首先是 HLA-B27 显示的自身肽类似于微生物衍生的肽，导致引发疾病的自身反应性 CD8⁺ T 细胞的扩增。第二种和第三种假说侧重于 HLA-B27 的异常特性，包括其形成细胞表面二聚体的趋势，这些二聚体可以激活 CD4⁺ 辅助性 T 细胞上的先天杀伤免疫球蛋白样受体，从而触发致病性细胞因子的产生。HLA-B27 还在内质网中错误折叠，这可以激活未折叠的蛋白质反应，增加 IL-23 表达，从而促进 17 型细胞因子的产生。间充质干细胞中的 HLA-B27 错误折叠也与间充质干细胞衍生的成骨细胞增强骨形成有关，这可能导致轴向 SpA 的结构损伤。在本综述中，我们总结了关于 HLA-B27 在 SpA 中的作用的普遍观点，讨论了最新进展以及当前知识的差距，并为未来的研究提供了解决这些未满足需求的建议。