Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo–differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV⁺ peripheral blood–derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV⁺ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.

中文翻译：

---

接受人类 B 细胞的免疫缺陷小鼠的移植后淋巴增殖性疾病需要 BCR 信号传导

移植后淋巴增殖性疾病（PTLD）是一个重大的治疗挑战，由于缺乏合适的机制表征模型，很难使用人体细胞进行研究。在这里，我们证明，从健康供体亚群中分离的离体分化 B 细胞在转移到免疫缺陷小鼠体内时，可以引发类似于 PTLD 的病理学。 PTLD 样病理的主要驱动因素是产生 IgM 的浆母细胞，其携带 Epstein-Barr 病毒 (EBV) 基因组，表达通常与 EBV 潜伏期相关的基因。我们发现，一小部分 EBV ⁺外周血来源的 B 细胞表达自身反应性非突变 B 细胞受体 (BCR)，在没有 BCR 刺激的情况下，在培养物中迅速扩增。此外，我们发现 EBV ⁺浆母细胞的体外和体内扩增需要 BCR 信号传导。最后，用 BCR 通路抑制剂依鲁替尼治疗免疫缺陷小鼠可延迟体内 PTLD 样病理的发生。这些数据对于有发生 PTLD 风险的移植受者的诊断和护理具有重要意义。