蛋白磷酸酶镁依赖性 1A 及其抗自身抗体在强直性脊柱炎中的作用。
Role of protein phosphatase magnesium-dependent 1A and anti-protein phosphatase magnesium-dependent 1A autoantibodies in ankylosing spondylitis.
机构信息
Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.
VA Palo Alto Health Care System, Palo Alto, California, USA.
出版信息
Arthritis Rheumatol. 2014 Oct;66(10):2793-2803. doi: 10.1002/art.38763.
OBJECTIVE
Although ankylosing spondylitis (AS) is driven by immune-mediated processes, little is known about the presence and role of autoantibodies in this disease. This study was undertaken to investigate whether autoantibodies occur in and are involved in AS.
METHODS
We performed human protein microarray analysis of sera derived from patients with AS or other autoimmune disorders to identify autoantibodies associated specifically with AS, and identified autoantibody targeting of protein phosphatase magnesium-dependent 1A (PPM1A) in AS. We performed enzyme-linked immunosorbent assay (ELISA) analysis of sera from 2 independent AS cohorts to confirm autoantibody targeting of PPM1A, and to assess associations between levels of anti-PPM1A antibodies and AS disease severity or response to anti-tumor necrosis factor (anti-TNF) therapy (as measured by Bath AS Disease Activity Index [BASDAI] score). Levels of anti-PPM1A antibodies were also evaluated in sera from rats transgenic for HLA-B27 and human β2 -microglobulin. The expression of PPM1A was assessed by immunohistochemistry in synovial tissue samples from patients with AS, rheumatoid arthritis, or osteoarthritis. The role of PPM1A in osteoblast differentiation was investigated by gene knockdown and overexpression.
RESULTS
AS was associated with autoantibody targeting of PPM1A, and levels of anti-PPM1A autoantibodies were significantly higher in patients with more advanced sacroiliitis and correlated positively with BASDAI score after treatment with anti-TNF agents. The levels of anti-PPM1A autoantibodies were also higher in the sera of transgenic rats that are prone to develop spondyloarthritis than in those that are not. PPM1A was expressed in AS synovial tissue, and PPM1A overexpression promoted osteoblast differentiation, whereas PPM1A knockdown suppressed it.
CONCLUSION
Anti-PPM1A autoantibodies are present in AS, and our findings suggest that PPM1A may contribute to the pathogenic bone ankylosis characteristic of AS.
目的
虽然强直性脊柱炎（AS）是由免疫介导的过程驱动的，但对其疾病中自身抗体的存在和作用知之甚少。本研究旨在探讨自身抗体是否存在于 AS 中并参与其中。
方法
我们对来自 AS 或其他自身免疫性疾病患者的血清进行了人类蛋白质微阵列分析，以鉴定与 AS 特异性相关的自身抗体，并鉴定出 AS 中蛋白磷酸酶镁依赖性 1A（PPM1A）的自身抗体靶向性。我们对 2 个独立的 AS 队列的血清进行了酶联免疫吸附试验（ELISA）分析，以确认 PPM1A 的自身抗体靶向性，并评估抗 PPM1A 抗体水平与 AS 疾病严重程度或对肿瘤坏死因子（抗 TNF）治疗的反应（通过 Bath AS 疾病活动指数 [BASDAI] 评分衡量）之间的关联。还评估了 HLA-B27 和人 β2-微球蛋白转基因大鼠血清中的抗 PPM1A 抗体水平。通过免疫组织化学评估了 AS、类风湿关节炎或骨关节炎患者滑膜组织样本中 PPM1A 的表达。通过基因敲低和过表达研究了 PPM1A 在成骨细胞分化中的作用。
结果
AS 与 PPM1A 的自身抗体靶向性相关，并且在接受抗 TNF 药物治疗后，具有更严重的骶髂关节炎的患者的抗 PPM1A 自身抗体水平显著更高，并且与 BASDAI 评分呈正相关。易发生脊柱关节炎的转基因大鼠血清中的抗 PPM1A 自身抗体水平也高于不发生的大鼠。PPM1A 在 AS 滑膜组织中表达，PPM1A 过表达促进成骨细胞分化，而 PPM1A 敲低则抑制其分化。
结论
抗 PPM1A 自身抗体存在于 AS 中，我们的研究结果表明 PPM1A 可能有助于 AS 特征性的病理性骨强直。
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