Department of Rheumatology and Clinical Immunology, Medical Centre-University of Freiburg, Faculty of Medicine, 79106 Freiburg, Baden-Wuerttemberg, Germany.
Department of Nephropathology, Friedrich-Alexander University (FAU) of Erlangen-Nuremberg, 91054 Erlangen, Bavaria, Germany.
Int J Mol Sci. 2019 Jul 1;20(13):3234. doi: 10.3390/ijms20133234.
It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE-/- animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE-/- mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE-/- animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.
自身抗原如何成为体液免疫介导的自身免疫性疾病中抗体的靶标，目前尚不完全清楚。在这种情况下，警报素被认为是一个重要的调节层次。警报素被多种受体识别，如晚期糖基化终产物受体 (RAGE)。由于 RAGE 在炎症条件下上调，强烈结合核酸，并在警报素识别后介导促炎反应，我们的目的是研究其对免疫复合物介导的自身免疫性疾病的贡献。为了实现这一目标，我们在烷化剂诱导狼疮、胶原诱导和血清转移关节炎的小鼠模型中使用了 RAGE-/-动物。通过酶联免疫吸附试验评估自身抗体，通过蛋白尿定量和组织学评估肾脏疾病，通过关节炎评分评估关节炎。通过流式细胞术确定相关的免疫状态。在这两种疾病实体中，我们在 RAGE-/-小鼠中检测到自身抗体水平有下降的趋势，但临床结果没有差异。与自身抗体水平一致，RAGE-/-动物的亚组表现出浆细胞、生发中心 B 细胞减少，滤泡 B 细胞增加。根据我们的结果，我们认为 RAGE 缺乏本身并不会显著影响抗体介导的自身免疫。RAGE 可能与其他受体一起发挥作用，将环境因素与自身反应性免疫反应联系起来。
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