Koren E, Koscec M, Wolfson-Reichlin M, Ebling F M, Tsao B, Hahn B H, Reichlin M
Arthritis/Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
J Immunol. 1995 May 1;154(9):4857-64.
Murine monoclonal and human affinity-purified Abs to native DNA (anti-nDNA) that cross-react with the A and D SnRNP polypeptides were analyzed for direct injurious effects against cultured pig kidney (PK15) cells under ordinary cell-culture conditions. Of the two murine nephritogenic Abs derived from NZB/NZW F1 mice (BWds1 and BWds3), BWds1 initially bound to the cell surface and subsequently penetrated into cells localizing in nuclei and cytoplasm. BWds3 was consistently and abundantly associated with the surface of live cells without penetration. In the presence of rabbit C, BWds3 caused massive cell lysis (85% dead cells) whereas BWds1 had only a modest lytic effect (24% dead cells). One of the nonpathogenic murine anti-nDNA Abs (5GD5) that did not cross-react with the A and D polypeptides showed no interaction with PK-15 cells and had no injurious effects. Affinity-purified autoantibodies to nDNA isolated from two SLE patients with high anti-nDNA titers and clinically active lupus nephritis showed properties similar to the murine mAbs. They both strongly cross-reacted with the A and D SnRNP polypeptides and interacted with live PK-15 cells. One of them (Cr) penetrated into live cells and localized within cytoplasm and nuclei whereas the other (Pe) bound mostly to the cell surface and caused significant cell lysis in the presence of C. Results of this study suggest that the nephritogenic murine anti-nDNA as well as subpopulations of human anti-nDNA Abs could exert their injurious influence through direct interactions with kidney cells using two different pathogenic mechanisms (i.e., C-mediated cytotoxicity and potential cell cycle dysfunctions. Interestingly, cross-reactivity of anti-nDNA Abs with the A and D SnRNP polypeptides appears to be a prerequisite for their direct pathogenicity.
分析了与A和D Sm核蛋白多肽发生交叉反应的针对天然DNA的鼠单克隆抗体和人亲和纯化抗体（抗天然DNA抗体）在普通细胞培养条件下对培养的猪肾（PK15）细胞的直接损伤作用。在源自NZB/NZW F1小鼠的两种致肾炎性鼠抗体（BWds1和BWds3）中，BWds1最初结合到细胞表面，随后穿透进入细胞并定位于细胞核和细胞质中。BWds3持续且大量地与活细胞表面结合而不穿透。在兔补体存在的情况下，BWds3导致大量细胞裂解（85%死亡细胞），而BWds1只有适度的裂解作用（24%死亡细胞）。一种与A和D多肽不发生交叉反应的非致病性鼠抗天然DNA抗体（5GD5）与PK-15细胞无相互作用，也无损伤作用。从两名抗天然DNA滴度高且临床上有活动性狼疮性肾炎的系统性红斑狼疮患者中分离得到的亲和纯化的抗天然DNA自身抗体表现出与鼠单克隆抗体相似的特性。它们都与A和D Sm核蛋白多肽强烈交叉反应，并与活的PK-15细胞相互作用。其中一种（Cr）穿透进入活细胞并定位于细胞质和细胞核内，而另一种（Pe）大多结合到细胞表面，并在补体存在的情况下导致显著的细胞裂解。本研究结果表明，致肾炎性鼠抗天然DNA抗体以及人抗天然DNA抗体亚群可通过两种不同的致病机制（即补体介导的细胞毒性和潜在的细胞周期功能障碍）与肾细胞直接相互作用来发挥其损伤作用。有趣的是，抗天然DNA抗体与A和D Sm核蛋白多肽的交叉反应似乎是其直接致病性的先决条件。
