Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.
Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.
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DOI：
10.1136/annrheumdis-2015-208094
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发表时间：
2016-04
影响因子：
27.4
通讯作者：
Svensson CI
中科院分区：
文献类型：
--
作者：
Wigerblad G;Bas DB;Fernades-Cerqueira C;Krishnamurthy A;Nandakumar KS;Rogoz K;Kato J;Sandor K;Su J;Jimenez-Andrade JM;Finn A;Bersellini Farinotti A;Amara K;Lundberg K;Holmdahl R;Jakobsson PJ;Malmström V;Catrina AI;Klareskog L;Svensson CI
自身免疫性疾病中慢性疼痛的一个有趣且迄今无法解释的特征是疼痛和炎症之间的频繁脱节。这在类风湿性关节炎（RA）中得到了很好的说明，其中关节疼痛（关节痛）可能先于关节炎症，即使在成功的抗炎治疗后也会持续存在。在目前的研究中，我们已经解决了瓜氨酸化蛋白（ACPA）的自身抗体，目前在RA，可能是直接负责的疼痛诱导，独立的炎症的可能性。将从患有RA的人类患者、健康供体和鼠源化单克隆ACPA纯化的抗体注射到小鼠中。监测疼痛样行为长达28天，并分析组织的病理学体征。 培养小鼠破骨细胞并用抗体刺激，分析上清液中因子的释放。小鼠用CXCR 1/2（白细胞介素（IL）8受体）拮抗剂瑞帕瑞辛处理。注射人或鼠源化ACPA的小鼠在没有炎症的情况下产生了持久的明显的疼痛样行为，而来自RA患者的非ACPA IgG或对照单克隆IgG没有原伤害感受效应。这种作用与ACPA介导的破骨细胞活化和伤害性趋化因子CXCL 1（人IL-8类似物）的释放相结合。ACPA诱导的疼痛样行为被瑞帕新逆转。这些数据表明，CXCL 1/IL-8，从破骨细胞释放的自身抗体依赖性的方式，通过激活感觉神经元产生疼痛。这种新的疼痛通路的鉴定可能为RA疼痛治疗以及与自身抗体产生和/或破骨细胞活化相关的其他疼痛性疾病开辟新的途径。
An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation.