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在类风湿关节炎中,IgE 抗瓜氨酸化蛋白抗体具有功能作用的证据。

Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis.

机构信息

Department of Rheumatology and Pathology, and Central Medical Immunology Laboratory, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.

出版信息

Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2586-91. doi: 10.1073/pnas.0913054107. Epub 2010 Jan 25.

DOI:10.1073/pnas.0913054107
PMID:20133791
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2823893/
Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease involving inflammation of the joints. Among the autoantibodies described in RA, anticitrullinated protein antibodies (ACPAs) are highly specific and predictive for RA. In addition, ACPAs have been implicated in the pathogenesis of RA. However, a direct functional response of immune cells from ACPA(+) RA patients toward citrullinated proteins has not been demonstrated. In this study, we show that exposure to citrullinated antigens leads to activation of basophils from ACPA(+) RA patients within 20 minutes. This was not observed after exposure of basophils to noncitrullinated control antigens or after stimulation of basophils from ACPA(-) RA patients and healthy controls. Basophil activation was correlated with the binding of citrullinated proteins to basophils. Furthermore, serum from ACPA(+) RA patients in contrast to that from ACPA(-) RA patients could specifically sensitize human FcepsilonRI expressing rat basophil cells (RBL), enabling activation by citrullinated proteins. Mast cell degranulation products such as histamine levels were enhanced in synovial fluid of ACPA(+) RA patients as compared with ACPA(-) RA and osteoarthritis patients. In addition, histamine levels in synovial fluid from ACPA(+) RA patients correlated with IgE levels, suggesting degranulation of mast cells by cross-linking IgE. Immunohistochemistry on synovial biopsies demonstrated an increased number of degranulated CD117(+) mast cells in ACPA(+) RA patients; IgE and FcepsilonRI expression in synovial mast cells from ACPA(+) RA patients was increased. In conclusion, our results show an immunological response of immune cells from ACPA(+) RA patients in a citrulline-specific manner. Moreover, these data indicate a role for IgE-ACPAs and FcepsilonRI-positive cells in the pathogenesis of RA.

摘要

类风湿关节炎(RA)是一种系统性自身免疫性疾病,涉及关节炎症。在 RA 中描述的自身抗体中,抗瓜氨酸蛋白抗体(ACPAs)对 RA 具有高度特异性和预测性。此外,ACPAs 与 RA 的发病机制有关。然而,尚未证明 ACPA(+)RA 患者的免疫细胞对瓜氨酸化蛋白有直接的功能反应。在这项研究中,我们表明,暴露于瓜氨酸化抗原会在 20 分钟内激活 ACPA(+)RA 患者的嗜碱性粒细胞。在暴露于非瓜氨酸化对照抗原后或在刺激 ACPA(-)RA 患者和健康对照者的嗜碱性粒细胞后,未观察到这种情况。嗜碱性粒细胞的激活与瓜氨酸化蛋白与嗜碱性粒细胞的结合有关。此外,与 ACPA(-)RA 患者和健康对照者的血清相比,来自 ACPA(+)RA 患者的血清可以特异性地致敏表达人 FcepsilonRI 的大鼠嗜碱性粒细胞(RBL),从而使嗜碱性粒细胞通过瓜氨酸化蛋白激活。与 ACPA(-)RA 和骨关节炎患者相比,来自 ACPA(+)RA 患者的滑液中的肥大细胞脱颗粒产物(如组胺水平)增强。此外,来自 ACPA(+)RA 患者的滑液中的组胺水平与 IgE 水平相关,表明 IgE 交联可导致肥大细胞脱颗粒。滑膜活检的免疫组织化学显示 ACPA(+)RA 患者中脱颗粒的 CD117(+)肥大细胞数量增加;来自 ACPA(+)RA 患者的滑膜肥大细胞中 IgE 和 FcepsilonRI 的表达增加。总之,我们的结果显示 ACPA(+)RA 患者的免疫细胞以瓜氨酸特异性方式产生免疫反应。此外,这些数据表明 IgE-ACPAs 和 FcepsilonRI 阳性细胞在 RA 的发病机制中起作用。

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