The rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33) is a major stimulator of autoimmunity in rats with pristane-induced arthritis
The rheumatoid arthritis-associated autoantigen hnRNP-A2 (RA33) is a major stimulator of autoimmunity in rats with pristane-induced arthritis
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DOI：
10.4049/jimmunol.179.11.7568
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Steiner, Guenter
中科院分区：
文献类型：
--
作者：
Hoffmann, Markus H.;Tuncel, Jonatan;Steiner, Guenter
在易受影响的 DA.1F 大鼠中单次皮内注射矿物油降植烷可诱发与类风湿性关节炎 (RA) 非常相似的糜烂性关节炎。降植烷诱发的关节炎 (PIA) 是由自身反应性 T 细胞驱动的，但迄今为止尚未鉴定出自身抗原。因此，我们分析了 B 和 T 细胞对可能参与 RA 发病机制的自身抗原的反应，包括 IgG、瓜氨酸蛋白、应激蛋白、葡萄糖 6-磷酸异构酶和异质核核糖核蛋白 (hnRNP)-A2 (RA33)。发病前 1 周，在降植烷引发的 DA.1F 大鼠血清中可检测到 hnRNP-A2 的 IgG 和 lgM 自身抗体，在急性期达到最高水平，并与关节炎严重程度相关。除类风湿因子外，未观察到针对其他抗原的自身抗体。注射降植烷10天后分离出的CD4(+)淋巴结细胞响应hnRNP-A2的刺激产生IFN-γ但不产生IL-4，而其他候选Ag均不引起细胞因子分泌。令人惊讶的是，hnRNP-A2 还刺激幼稚动物的淋巴结细胞以 MyD88 依赖性方式产生炎性细胞因子。此外，hnRNP-A2 在注射降植烷的大鼠关节中高度过表达。过度表达与抗 RA33 抗体的出现同时发生，并且比 PIA 临床症状出现早几天。综上所述，这些数据表明 hnRNP-A2 是 PIA 自身免疫的主要诱导剂之一。因此，该Ag可能在PIA以及人类RA的发病机制中发挥关键作用。
A single intradermal injection of the mineral oil pristane in susceptible DA.1F rats induces erosive arthritis closely mimicking rheumatoid arthritis (RA). Pristane-induced arthritis (PIA) is driven by autoreactive T cells but no autoantigen has been identified to date. We therefore analyzed B and T cell responses to autoantigens potentially involved in the pathogenesis of RA, including IgG, citrullinated proteins, stress proteins, glucose-6-phosphate isomerase, and heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (RA33). IgG and lgM autoantibodies to hnRNP-A2 were detectable in sera of pristane-primed DA.1F rats already 1 wk before disease onset, reached maximum levels during the acute phase, and correlated with arthritis severity. Apart from rheumatoid factor, autoantibodies to other Ags were not observed. CD4(+) lymph node cells isolated 10 days after pristane injection produced IFN-gamma but not IL-4 in response to stimulation with hnRNP-A2, whereas none of the other candidate Ags elicited cytokine secretion. Surprisingly, hnRNP-A2 also stimulated lymph node cells of naive animals to produce inflammatory cytokines in a MyD88-dependent manner. Furthermore, hnRNP-A2 was highly overexpressed in the joints of rats injected with pristane. Overexpression coincided with the appearance of anti-RA33 Abs and preceded the onset of clinical symptoms of PIA by several days. Taken together, these data suggest hnRNP-A2 to be among the primary inducers of autoimmunity in PIA. Therefore, this Ag might play a pivotal role in the pathogenesis of PIA and possibly also human RA.