Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation
Anti-PLA2R1 Antibodies Containing Sera Induce In Vitro Cytotoxicity Mediated by Complement Activation
复制标题
DOI：
10.1155/2019/1324804
复制
发表时间：
2019-12-30
影响因子：
4.1
通讯作者：
Seitz-Polski, Barbara
中科院分区：
文献类型：
--
作者：
Lateb, Mael;Ouahmi, Hajar;Seitz-Polski, Barbara
磷脂酶A2受体(PLA2R1)是特发性膜性肾病(MN)的主要自身抗原。然而，抗PLA2R1自身抗体的致病作用尚不清楚。我们的目的是评价补体介导的抗PLA2R1抗体的体外细胞毒作用。来自前瞻性队列来源的48名PLA2R1相关MN患者纳入研究。用ELISA法测定抗PLA2R1的效价、表位分布和抗PLA2R1Ig G亚类。在兔补体或补体抑制剂存在或不存在的情况下，通过免疫荧光法对高表达PLA2R1的HEK293细胞与患者或健康供者血清孵育的细胞毒性进行评估。抗PLA2 R1抗血清对高表达PLA2 R1的HEK293细胞的平均细胞毒作用为2+/-2%，加入兔补体(p=40%)后，细胞毒作用增加到24+/-6%(p=0.005)，表位扩散(通过免疫优势区以外的免疫定义)(p=0.002)和高滴度的抗PLA2 R1总Ig G(p=0.01)是肾脏预后不良的因素。含血清的抗PLA2R1抗体在体外可通过补体激活诱导细胞毒作用，且随着抗PLA2R1Ig G亚类的多样性和效价的增加，细胞毒作用增强。这些补体介导的细胞毒性水平较高的患者可以受益于补体抑制剂联合利妥昔单抗的辅助治疗，以导致更早的缓解和更少的足细胞损伤。
The phospholipase A2 receptor (PLA2R1) is the major autoantigen in idiopathic membranous nephropathy (MN). However, the pathogenic role of anti-PLA2R1 autoantibodies is unclear. Our aim was to evaluate the in vitro cytotoxicity of anti-PLA2R1 antibodies mediated by complement. Forty-eight patients with PLA2R1-related MN from the prospective cohort SOURIS were included. Anti-PLA2R1 titer, epitope profile, and anti-PLA2R1 IgG subclasses were characterized by ELISA. Cell cytotoxicity was evaluated by immunofluorescence in HEK293 cells overexpressing PLA2R1 incubated with patient or healthy donor sera in the presence or absence of rabbit complement or complement inhibitors. Mean cytotoxicity of anti-PLA2R1 sera for HEK293 cells overexpressing PLA2R1 was 2 +/- 2%, which increased to 24 +/- 6% after addition of rabbit complement (p= 40%) (p=0.005), epitope spreading (defined by immunization beyond the immunodominant CysR domain) (p=0.002), and high titer of anti-PLA2R1 total IgG (p=0.01) were factors of poor renal prognosis. Anti-PLA2R1 antibodies containing sera can induce in vitro cytotoxicity mediated by complement activation, and the level of cytotoxicity increases with the diversity and the titer of anti-PLA2R1 IgG subclasses. These patients with high level of complement-mediated cytotoxicity could benefit from adjuvant therapy using complement inhibitor associated with rituximab to induce earlier remission and less podocyte injury.