Department of Pathology, Academic Medical Center, University of Amsterdam, 1012 ZA Amsterdam, The Netherlands.
J Exp Med. 2013 Jan 14;210(1):59-70. doi: 10.1084/jem.20121801. Epub 2013 Jan 7.
B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for β-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. β-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for β-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to β-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.
B 细胞慢性淋巴细胞白血病（CLL）是成人中最常见的白血病，是 CD5(+)CD19(+)B 淋巴细胞的克隆性扩张。CLL 分为两类，一类是携带未突变或体细胞突变免疫球蛋白（Igs）的，分别与不利和有利的预后相关。超过 30%的 CLL 可以根据其定型 B 细胞受体（BCR）的表达进行分组，这强烈表明独特的抗原参与了 CLL 的发展。携带 Ig 重链可变（IGHV）基因处于种系构型的未突变 CLL 表达低亲和力、多和自身反应性 BCR。然而，突变 IGHV 基因（M-CLL）的 CLL 的抗原特异性仍然难以捉摸。在这项研究中，我们描述了 M-CLL 的一个新亚群，该亚群表达高度特异性针对β-(1,6)-葡聚糖的定型 BCR，β-(1,6)-葡聚糖是酵母和丝状真菌的主要抗原决定簇。β-(1,6)-葡聚糖结合依赖于定型的 Ig 重链和轻链，以及 IGHV-CDR3 中的一个独特氨基酸。IGHV 突变回复到种系构型会降低对β-(1,6)-葡聚糖的亲和力，表明这些 BCR 确实是针对其同源抗原进行亲和力选择的。此外，表达这些定型受体的 CLL 细胞会对β-(1,6)-葡聚糖增殖。这项研究确立了一类常见病原体作为体细胞突变人类 B 细胞淋巴瘤亚群的功能配体。
