Wermeling Fredrik, Chen Yunying, Pikkarainen Timo, Scheynius Annika, Winqvist Ola, Izui Shozo, Ravetch Jeffrey V, Tryggvason Karl, Karlsson Mikael C I
Department of Medicine, Karolinska Institutet, Stockholm 171 76, Sweden.
J Exp Med. 2007 Oct 1;204(10):2259-65. doi: 10.1084/jem.20070600. Epub 2007 Sep 24.
Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.
凋亡细胞被认为是自身免疫性疾病（如系统性红斑狼疮，SLE）中自身抗原的主要来源。与此一致的是，凋亡细胞清除缺陷已被证明会增加疾病易感性。然而，关于凋亡细胞衍生的自身抗原如何激活自身反应性B细胞以及这一过程发生的位置，我们仍知之甚少。在本研究中，我们发现凋亡细胞被脾脏边缘区巨噬细胞上表达的特定清道夫受体摄取，并且缺乏这些受体的小鼠对自身抗体反应的阈值较低。此外，在易患SLE的小鼠出现临床症状之前就发现了针对清道夫受体的抗体，并且在已确诊的SLE患者中也发现了这些抗体。我们的研究结果描述了一种新机制，即针对清道夫受体的自身抗体可改变对凋亡细胞的反应，影响耐受性，从而促进疾病进展。由于这些自身抗体在小鼠疾病发作前就能被检测到，它们可能作为SLE的早期指标具有预测价值。
