From the Division of Immunology and Children's Research Center (V.N., M.G., J.T.), University Children's Hospital Zurich, University of Zurich; Neuroimmunology and MS Research Section (J.R., I.J., R.M.), Department of Neurology, University Hospital Zurich, University of Zurich; and Department of Medical Oncology and Hematology (A.M.M., U.S.), University Hospital Zurich.
Neurol Neuroimmunol Neuroinflamm. 2022 Oct 13;9(6). doi: 10.1212/NXI.0000000000200027. Print 2022 Nov.
Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.
Using longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.
Total B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.
Our detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.
自体造血干细胞移植（aHSCT）越来越多地用于治疗多发性硬化症（MS）的侵袭性形式。人们认为，该过程可导致免疫重置和自身耐受免疫系统的恢复。人们已经对 T 细胞的免疫重建进行了广泛的研究，但对 B 细胞的研究仅在有限的程度上进行。由于越来越多的证据表明 B 细胞在 MS 发病机制中起重要作用，因此我们在此试图更好地了解 MS 患者接受 aHSCT 后的 B 细胞系统的重建和更新程度。
我们使用纵向多维流式细胞术和免疫球蛋白重链（IgH）受体序列分析，在使用 BCNU +依托泊苷+Ara-C+马法兰抗胸腺细胞球蛋白进行 aHSCT 后，在特定的时间间隔内分析了 20 例 MS 患者的 B 细胞区室，并将这些发现与健康对照者的数据进行了比较。
总 B 细胞数量在 3 个月内恢复，并在移植后 1 年内增加至正常水平以上，依次从主要的过渡状态转变为幼稚免疫表型。记忆亚群恢复缓慢，并且在移植后 1 年内仍低于正常水平，其多样性减少。同种型亚类分析显示，IgG1 表达细胞的比例增加，IgG2 细胞减少。IgH 序列的突变分析表明，高突变的记忆 B 细胞和浆细胞可能在预处理过程中短暂存活，而对序列簇重叠、可变（IGHV）和连接（IGHJ）基因使用以及多样性的分析表明，移植后晚期的 repertoire 得到了更新。在早期巨细胞病毒再激活的患者中，幼稚和记忆 B 细胞的重建延迟。
我们对 MS 患者 aHSCT 后 B 细胞重建的详细描述表明，移植后 1 年内记忆 B 细胞的再激活潜力降低，这可能使患者易受感染，但也可能是其作用机制的重要方面。
