Self DNA from Lymphocytes That Have Undergone Activation-Induced Cell Death Enhances Murine B Cell Proliferation and Antibody Production

Systemic lupus erythematosus (SLE) is characterized by prominent autoinflammatory tissue damage associated with impaired removal of dying cells and DNA. Self DNA-containing immune complexes are able to activate both innate and adaptive immune responses and play an important role in the maintenance and exacerbation of autoimmunity in SLE. In this study, we used DNA from lymphocytes that have undergone activation-induced cell death (ALD-DNA) and analyzed its role on the activation and differentiation of B cells from normal BALB/c mice as well as lupus-prone MRL+/+ and MRL/lpr mice. We found that ALD-DNA directly increased the expression of costimulatory molecules and the survival of naïve B cells in vitro. Although ALD-DNA alone had little effect on the proliferation of naïve B cells, it enhanced LPS-activated B cell proliferation in vitro and in vivo. In addition, ALD-DNA increased plasma cell numbers and IgG production in LPS-stimulated cultures of naïve B cells, in part via enhancing IL-6 production. Importantly, B cells from lupus mice were hyperresponsive to ALD-DNA and/or LPS relative to normal control B cells in terminal plasma cell differentiation, as evidenced by increases in CD138+ cell numbers, IgM production, and mRNA levels of B lymphocyte-induced maturation protein-1 (Blimp-1) and the X-box binding protein 1 (XBP1). Furthermore, ALD-DNA enhanced CD40-activated naïve B cell proliferation. Collectively, these data indicate that self DNA can serve as a DAMP (damage-associated molecular pattern) that cooperates with signals from both innate and adaptive immunity to promote polyclonal B cell activation, a common characteristic of autoimmune diseases.

系统性红斑狼疮（SLE）以显著的自身炎症性组织损伤为核心特征，该类损伤与死亡细胞及DNA的清除功能受损密切相关。含有自身DNA的免疫复合物可同时激活固有免疫与适应性免疫应答，并在SLE自身免疫的维持与病情加重过程中发挥关键作用。本研究采用经历激活诱导细胞死亡的淋巴细胞来源DNA（ALD-DNA），分析其对正常BALB/c小鼠、狼疮易感小鼠MRL+/+及MRL/lpr的B细胞活化与分化的调控作用。研究结果显示，ALD-DNA可在体外直接上调共刺激分子的表达，并提升初始B细胞的存活率。尽管ALD-DNA单独作用对初始B细胞的增殖几乎无影响，但可在体内外增强脂多糖（LPS）激活的B细胞增殖。此外，ALD-DNA可在脂多糖刺激的初始B细胞培养体系中增加浆细胞数量与免疫球蛋白G（IgG）的产生，该效应部分通过增强白细胞介素-6（IL-6）的分泌实现。尤为关键的是，与正常对照B细胞相比，狼疮小鼠的B细胞在终末浆细胞分化阶段对ALD-DNA和/或脂多糖呈现高反应性，具体表现为CD138阳性细胞数量、免疫球蛋白M（IgM）的产生水平，以及B淋巴细胞诱导成熟蛋白-1（Blimp-1）与X盒结合蛋白1（XBP1）的mRNA表达量均显著升高。进一步研究发现，ALD-DNA可增强CD40激活的初始B细胞增殖。综上，本研究数据表明，自身DNA可作为损伤相关分子模式（DAMP），通过协同固有免疫与适应性免疫的信号通路，促进多克隆B细胞活化——而这正是自身免疫性疾病的共同病理特征之一。