Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany.
Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany.
Immunobiology. 2023 Sep;228(5):152413. doi: 10.1016/j.imbio.2023.152413. Epub 2023 Jun 20.
The complement system is an essential component of the innate immune response and plays a vital role in host defense and inflammation. Dysregulation of the complement system, particularly involving the anaphylatoxin C5a and its receptors (C5aR1 and C5aR2), has been linked to several autoimmune diseases, indicating the potential for targeted therapies. C5aR1 and C5aR2 are seven-transmembrane receptors with distinct signaling mechanisms that play both partially overlapping and opposing roles in immunity. Both receptors are expressed on a broad spectrum of immune and non-immune cells and are involved in cellular functions and physiological processes during homeostasis and inflammation. Dysregulated C5a-mediated inflammation contributes to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, epidermolysis bullosa acquisita, antiphospholipid syndrome, and others. Therefore, targeting C5a or its receptors may yield therapeutic innovations in these autoimmune diseases by reducing the recruitment and activation of immune cells that lead to tissue inflammation and injury, thereby exacerbating the autoimmune response. Clinical trials focused on the inhibition of C5 cleavage or the C5a/C5aR1-axis using small molecules or monoclonal antibodies hold promise for bringing novel treatments for autoimmune diseases into practice. However, given the heterogeneous nature of (systemic) autoimmune diseases, there are still several challenges, such as patient selection, optimal dosing, and treatment duration, that require further investigation and development to realize the full therapeutic potential of C5a receptor inhibition, ideally in the context of a personalized medicine approach. Here, we aim to provide a brief overview of the current knowledge on the function of C5a receptors, the involvement of C5a receptors in autoimmune disorders, the molecular mechanisms underlying C5a receptor-mediated autoimmunity, and the potential for targeted therapies to modulate their activity.
补体系统是先天免疫反应的重要组成部分，在宿主防御和炎症中起着至关重要的作用。补体系统的失调，特别是涉及过敏毒素 C5a 及其受体（C5aR1 和 C5aR2），与几种自身免疫性疾病有关，表明存在靶向治疗的潜力。C5aR1 和 C5aR2 是具有不同信号机制的七跨膜受体，在免疫中发挥部分重叠和相反的作用。这两个受体都在广泛的免疫和非免疫细胞上表达，并参与到稳态和炎症过程中的细胞功能和生理过程。失调的 C5a 介导的炎症导致自身免疫性疾病，如类风湿关节炎、系统性红斑狼疮、多发性硬化症、获得性大疱性表皮松解症、抗磷脂综合征等。因此，通过减少导致组织炎症和损伤的免疫细胞的募集和激活，靶向 C5a 或其受体可能为这些自身免疫性疾病带来治疗创新，从而加剧自身免疫反应。针对小分子或单克隆抗体抑制 C5 切割或 C5a/C5aR1 轴的临床试验有望为自身免疫性疾病带来新的治疗方法。然而，鉴于（系统性）自身免疫性疾病的异质性，仍然存在一些挑战，如患者选择、最佳剂量和治疗持续时间，需要进一步研究和开发，以实现 C5a 受体抑制的全部治疗潜力，理想情况下是在个性化医疗方法的背景下。在这里，我们旨在提供关于 C5a 受体功能、C5a 受体在自身免疫性疾病中的参与、C5a 受体介导的自身免疫的分子机制以及靶向治疗调节其活性的潜力的当前知识的简要概述。
