Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Arthritis Res Ther. 2011;13(6):R191. doi: 10.1186/ar3520. Epub 2011 Nov 22.
Anti-citrullinated protein/peptide antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA) patients and are thought to have a close relationship with the pathogenesis of arthritis. Several proteins, including fibrinogen, vimentin, and alpha-enolase, were reported as ACPA-target antigens, and their importance in RA pathogenesis was widely proposed. We identified citrullinated immunoglobulin binding protein (citBiP) as another ACPA target in RA patients and examined its pro-inflammatory role in arthritis.
We measured the levels of anti-citBiP, anti-BiP, and anti-cyclic citrullinated peptide (CCP) antibodies in the serum of RA patients (n = 100), systemic lupus erythematosus (SLE) patients (n = 60), and healthy controls (n = 30) using ELISA and immunoblotting. Epitope mapping was performed using 27 citBiP-derived peptides. In the mouse study, after DBA/1J mice were immunized with BiP or citBiP, serum titers of ACPAs were measured by ELISA and immunohistochemistry. The development of collagen-induced arthritis (CIA) was observed in BiP- or citBiP-pre-immunized mice.
The serum levels of anti-BiP and anti-citBiP antibodies were significantly increased in RA patients, although only anti-BiP antibodies were slightly increased in SLE patients. Interestingly, anti-citBiP antibody levels were higher than anti-BiP antibody levels in 72% of RA patients, whereas no significant increase in anti-citBiP antibody levels was detected in SLE patients and healthy controls. The serum levels of anti-CCP antibodies were correlated with those of anti-citBiP antibodies in RA patients (R2 = 0.41). Several citrulline residues of citBiP were determined to be major epitopes of anti-citBiP antibodies, one of which showed cross-reactivity with CCP. Immunization of DBA/1J mice with citBiP induced several kinds of ACPAs, including anti-CCP and anti-citrullinated fibrinogen antibodies. Pre-immunization with citBiP exacerbated CIA, and anti-CCP antibody levels were increased in citBiP-pre-immunized CIA mice.
CitBiP is a newly described ACPA target that may play a pro-inflammatory role in arthritis.
抗瓜氨酸化蛋白/肽抗体（ACPAs）对类风湿关节炎（RA）患者具有高度特异性，并且被认为与关节炎的发病机制密切相关。一些蛋白质，包括纤维蛋白原、波形蛋白和α-烯醇化酶，被报道为 ACPA 靶抗原，它们在 RA 发病机制中的重要性被广泛提出。我们鉴定出瓜氨酸化免疫球蛋白结合蛋白（citBiP）为 RA 患者的另一个 ACPA 靶标，并研究了其在关节炎中的促炎作用。
我们使用 ELISA 和免疫印迹法测量了 100 例 RA 患者、60 例系统性红斑狼疮（SLE）患者和 30 例健康对照者血清中的抗 citBiP、抗 BiP 和抗环瓜氨酸肽（CCP）抗体水平。使用 27 个 citBiP 衍生肽进行表位作图。在小鼠研究中，在 DBA/1J 小鼠用 BiP 或 citBiP 免疫后，通过 ELISA 和免疫组织化学测量 ACPA 的血清滴度。观察到 BiP 或 citBiP 预免疫小鼠胶原诱导性关节炎（CIA）的发展。
虽然 SLE 患者中仅抗 BiP 抗体略有增加，但 RA 患者血清中抗 BiP 和抗 citBiP 抗体的水平显著升高。有趣的是，在 72%的 RA 患者中，抗 citBiP 抗体水平高于抗 BiP 抗体水平，而在 SLE 患者和健康对照者中未检测到抗 citBiP 抗体水平的显著增加。RA 患者血清中抗 CCP 抗体水平与抗 citBiP 抗体水平相关（R2 = 0.41）。确定 citBiP 的几个瓜氨酸残基为抗 citBiP 抗体的主要表位，其中一个与 CCP 有交叉反应性。用 citBiP 免疫 DBA/1J 小鼠诱导多种 ACPA，包括抗 CCP 和抗瓜氨酸化纤维蛋白原抗体。用 citBiP 预免疫加重 CIA，并且 citBiP 预免疫 CIA 小鼠的抗 CCP 抗体水平增加。
CitBiP 是一种新描述的 ACPA 靶标，可能在关节炎中发挥促炎作用。
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