中和抗白细胞介素 1 受体拮抗剂自身抗体可诱导 IgG4 相关疾病中的炎症和纤维化介质。
Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.
机构信息
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif.
Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif.
出版信息
J Allergy Clin Immunol. 2022 Jan;149(1):358-368. doi: 10.1016/j.jaci.2021.05.002. Epub 2021 May 8.
BACKGROUND
IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined.
OBJECTIVE
Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD.
METHODS
We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays.
RESULTS
We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls.
CONCLUSION
A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
背景
IgG4 相关疾病（IgG4-RD）是一种纤维炎症性疾病，涉及 B 细胞耐受丧失和自身抗体产生。然而，这些异常体液免疫反应的相关靶标和作用尚不清楚。
目的
我们旨在确定促进 IgG4-RD 发病机制的新型自身抗体和自身抗原靶标。
方法
我们对 IgG4-RD 患者的浆母细胞抗体库进行了测序。通过使用细胞因子微阵列表达代表性 mAb，并对其特异性进行了表征。通过体外实验研究了抗白细胞介素 1 受体拮抗剂（IL-1RA）自身抗体的作用。
结果
我们从 IgG4-RD 患者的克隆扩增浆母细胞衍生的 mAb 中鉴定出对人 IL-1RA 的强烈反应。与对照组相比，IgG4-RD 患者的血浆对 IL-1RA 的反应性升高，并中和了 IL-1RA 活性，导致体外炎症和纤维化介质的产生。在 IgG4-RD 患者的病变组织中检测到 IL-1RA。具有 IgG4 亚类抗 IL-1RA 自身抗体的患者比没有抗 IL-1RA 自身抗体的患者受影响的器官更多。肽分析鉴定出位于 IL-1RA/IL-1R 界面附近的抗 IL-1RA 抗体的 IL-1RA 表位。与对照组相比，系统性红斑狼疮（SLE）和类风湿关节炎（RA）患者的血清中也存在升高的抗 IL-1RA 自身抗体。
结论
一小部分 IgG4-RD 患者具有抗 IL-1RA 自身抗体，通过中和 IL-1RA 促进促炎和促纤维化介质的产生。这些发现支持 IgG4-RD 发病机制的新免疫机制。SLE 和 RA 患者中也存在抗 IL-1RA 自身抗体，表明多种自身免疫性疾病中存在潜在的共同途径。
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