Immune complexome analysis of a rich variety of serum immune complexes identifies disease-characteristic immune complex antigens in systemic sclerosis
Immune complexome analysis of a rich variety of serum immune complexes identifies disease-characteristic immune complex antigens in systemic sclerosis
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DOI：
10.1016/j.jaut.2022.102954
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发表时间：
2022-11-24
影响因子：
12.8
通讯作者：
Ohyama，Kaname
中科院分区：
文献类型：
--
作者：
Kutsuna，Yuki Jimbayashi;Iwamoto，Naoki;Ohyama，Kaname
系统性硬化症（SSc）是一种以血管内皮功能障碍和皮肤纤维化为特征的自身免疫性疾病。近年来，有关SSc患者免疫复合物（IC）的存在及其致病作用的研究报道较多。然而，这些IC中的抗原的身份是未知的。因此，我们检测了SSc患者血清中的IC，以阐明SSc的发病机制。在这项研究中，IC浓度测定血清样本SSc和系统性红斑狼疮（SLE）患者的C1q酶联免疫吸附试验，免疫复合物分析用于全面鉴定和比较纳入IC（IC抗原）的抗原。通过免疫组织化学研究了皮肤切片中SSc特异性IC抗原的表达模式。与因IC沉积而发病的SLE患者相比，SSc患者的IC抗原数量较多，IC浓度差异较小，表明SSc发病机制受IC中存在的蛋白质的影响。与此相反，IC浓度和IC抗原的数量没有显着差异，根据SSc的临床表型。我们在SSc患者中鉴定了478种IC抗原，包括先前与SSc发病机制相关的抗体靶向的多种RNAP II相关蛋白。最常检测到的RNAP II相关蛋白，RNA聚合酶II转录亚基30（MED30），在病变部位强烈表达，据报道调节内皮细胞分化。因此，病变中MED30的表达增加可能具有抗原效应，并且MED30功能可能受到IC形成的损害或抑制。RNAP II相关蛋白可能通过MED30通路等机制参与SSc的发病。
Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and skin fibrosis. Recently, the presence and pathogenic role of immune complexes (ICs) of SSc patients were reported. However, the identities of antigens in these ICs are unknown. Therefore, we examined ICs in the serum of SSc patients to elucidate SSc pathogenesis. In this study, IC concentrations in serum samples from SSc and systemic lupus erythematosus (SLE) patients were measured by C1q enzyme-linked immunosorbent assays; immune complex analysis was used for comprehensive identification and comparison of antigens incorporated into ICs (IC-antigens). The expression patterns of SSc-specific IC-antigens in skin sections were investigated by immunohistochemistry. Compared with SLE patients who developed disease because of IC deposition, SSc patients had a greater number of IC-antigens and a smaller difference in IC concentrations, suggesting that SSc pathogenesis is affected by the proteins present in ICs. In contrast, the IC concentration and number of IC-antigens did not significantly differ according to the clinical phenotype of SSc. We identified 478 IC-antigens in SSc patients, including multiple RNAP II-associated proteins that were targeted by antibodies previously associated with SSc pathogenesis. The most frequently detected RNAP II-associated protein, RNA polymerase II transcription subunit 30 (MED30), was strongly expressed at lesion sites and reportedly regulates endothelial differentiation. Therefore, increased expression of MED30 in lesions may have an antigenic effect, and MED30 function may be impaired or inhibited by IC formation. RNAP II-associated proteins may SSc pathogenesis through mechanisms such as the MED30 pathway.