CD55在免疫介导的再生障碍性贫血小鼠模型中促进造血干细胞和祖细胞存活

摘要(中文译文)

特发性再生障碍性贫血（AA）是一种危及生命的自身免疫性骨髓衰竭综合征，以骨髓细胞减少和外周全血细胞减少为特征。虽然补体系统失调已被认为与多种自身免疫性疾病（包括类风湿关节炎和系统性红斑狼疮）的发病机制有关，但其在AA中的作用仍知之甚少。值得注意的是，AA患者中常可检测到自身抗体，且这些抗体具有激活补体级联反应的潜力。利用免疫介导的AA小鼠模型，我们发现同种异体脾细胞移植可诱导骨髓衰竭，并伴随补体系统的激活，表现为血浆补体成分C3和C5水平升高。为了从功能上解析直接细胞毒性T细胞效应与补体激活等间接机制各自的贡献，我们将与供体脾细胞同基因的造血干/祖细胞（HSPCs）共移植入同种异体受体小鼠。在此背景下，缺乏补体抑制因子Cd55的HSPCs被负向选择，表明其在体内对补体介导的攻击易感性增加。重要的是，药物性抑制补体级联反应可挽救AA小鼠中Cd55缺陷型HSPCs的选择劣势，证明在该模型中补体激活对HSPCs施加了负向选择压力。总之，这些发现支持补体通路在免疫介导的AA发病机制中发挥功能性作用。有必要进一步研究评估补体抑制联合标准免疫抑制治疗对AA患者的治疗潜力。

Abstract

Idiopathic aplastic anaemia (AA) is a life-threatening autoimmune bone marrow (BM) failure syndrome characterized by a hypocellular BM and peripheral pancytopenia. While dysregulation of the complement system has been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, its role in AA remains poorly understood. Notably, autoantibodies are frequently detected in AA patients and have the potential to activate the complement cascade. Using an immune-mediated murine model of AA, we found that allogeneic transplantation of splenocytes induced BM failure accompanied by activation of the complement system, as evidenced by elevated plasma levels of complement components C3 and C5. To functionally dissect the contributions of direct cytotoxic T-cell effects versus indirect mechanisms such as complement activation, we co-transplanted hematopoietic stem and progenitor cells (HSPCs) congenic to the donor splenocytes into allogeneic recipient mice. In this context, HSPCs deficient in the complement inhibitor Cd55 were negatively selected, indicating increased susceptibility to complement-mediated attack in vivo. Importantly, pharmacological inhibition of the complement cascade rescued the selective disadvantage of Cd55-deficient HSPCs in AA mice, demonstrating that complement activation imposes a negative selective pressure on HSPCs in this model. Together, these findings support a functional role for the complement pathway in the pathogenesis of immune-mediated AA. Further studies are warranted to evaluate the therapeutic potential of combining complement inhibition with standard immunosuppressive therapy in patients with AA.

如何引用

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