Lee Eun Kyung, Joo Eun Hye, Song Kyung-A, Choi Bongkum, Kim Miyoung, Kim Seok-Hyung, Kim Sung Joo, Kang Myung-Soo
Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center and Sungkyunkwan University, Seoul 06351, Korea; Samsung Biomedical Research Institute, Seoul 06351, Korea;
Samsung Biomedical Research Institute, Seoul 06351, Korea; Department of Transplantation Surgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 06351, Korea;
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13081-6. doi: 10.1073/pnas.1407075112. Epub 2015 Oct 5.
Epstein-Barr virus (EBV) infection causes both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). The present study reveals that EBV-induced HL and NHL are intriguingly associated with a repopulated immune cell profile in humanized mice. Newborn immunodeficient NSG mice were engrafted with human cord blood CD34(+) hematopoietic stem cells (HSCs) for a 8- or 15-wk reconstitution period (denoted (8w)hN and (15w)hN, respectively), resulting in human B-cell and T-cell predominance in peripheral blood cells, respectively. Further, novel humanized mice were established via engraftment of hCD34(+) HSCs together with nonautologous fetal liver-derived mesenchymal stem cells (MSCs) or MSCs expressing an active notch ligand DLK1, resulting in mice skewed with human B or T cells, respectively. After EBV infection, whereas NHL developed more frequently in B-cell-predominant humanized mice, HL was seen in T-cell-predominant mice (P = 0.0013). Whereas human splenocytes from NHL-bearing mice were positive for EBV-associated NHL markers (hBCL2(+), hCD20(+), hKi67(+), hCD20(+)/EBNA1(+), and EBER(+)) but negative for HL markers (LMP1(-), EBNA2(-), and hCD30(-)), most HL-like tumors were characterized by the presence of malignant Hodgkin's Reed-Sternberg (HRS)-like cells, lacunar RS (hCD30(+), hCD15(+), IgJ(-), EBER(+)/hCD30(+), EBNA1(+)/hCD30(+), LMP(+)/EBNA2(-), hCD68(+), hBCL2(-), hCD20(-/weak,) Phospho STAT6(+)), and mummified RS cells. This study reveals that immune cell composition plays an important role in the development of EBV-induced B-cell lymphoma.
爱泼斯坦-巴尔病毒（EBV）感染可导致霍奇金淋巴瘤（HL）和非霍奇金淋巴瘤（NHL）。本研究表明，EBV诱导的HL和NHL与人类化小鼠中重新填充的免疫细胞谱存在有趣的关联。将新生免疫缺陷NSG小鼠用人脐血CD34(+)造血干细胞（HSCs）移植8周或15周进行重建（分别表示为(8w)hN和(15w)hN），导致外周血细胞中分别以人类B细胞和T细胞为主。此外，通过将hCD34(+) HSCs与非自体胎儿肝脏来源的间充质干细胞（MSCs）或表达活性Notch配体DLK1的MSCs一起移植，建立了新型人类化小鼠，分别导致小鼠偏向于人类B细胞或T细胞。EBV感染后，NHL在以B细胞为主的人类化小鼠中更频繁地发生，而HL则出现在以T细胞为主的小鼠中（P = 0.0013）。来自携带NHL的小鼠的人类脾细胞对EBV相关的NHL标志物呈阳性（hBCL2(+)、hCD20(+)、hKi67(+)、hCD20(+)/EBNA1(+)和EBER(+)），但对HL标志物呈阴性（LMP1(-)、EBNA2(-)和hCD30(-)），大多数HL样肿瘤的特征是存在恶性霍奇金-里德-斯腾伯格（HRS）样细胞、陷窝RS（hCD30(+)）、hCD15(+)、IgJ(-)、EBER(+)/hCD30(+)、EBNA1(+)/hCD30(+)、LMP(+)/EBNA2(-)、hCD68(+)、hBCL2(-)、hCD20(-/弱阳性)、磷酸化STAT6(+)）和木乃伊化RS细胞。本研究表明，免疫细胞组成在EBV诱导的B细胞淋巴瘤的发生发展中起重要作用。
