José Carreras Center for Immuno- and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar, Germany.
Institute for Medical Informatics, Statistics, and Epidemiology, Universität Leipzig, Leipzig, Germany.
Blood. 2018 Dec 27;132(26):2744-2753. doi: 10.1182/blood-2018-03-836932. Epub 2018 Sep 24.
To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper--glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
为了探讨慢性抗原刺激在原发性中枢神经系统淋巴瘤（PCNSL）中的作用，我们寻找了自身抗原，并从 8/12 例 PCNSL 中鉴定出了无菌α基序域包含蛋白 14（SAMD14）和神经组织特异性 F-肌动蛋白结合蛋白 I（neurabin-I），它们是 B 细胞受体（BCR）的自身抗原靶标。在各自的病例中，SAMD14 和 neurabin-I 被异常高糖基化（SAMD14 在 ASN339，neurabin-I 在 ASN1277），解释了它们的自身免疫原性。SAMD14 和 neurabin-I 诱导了 BCR 途径的激活和转染了 SAMD14 和 neurabin-I 反应性 BCR 的侵袭性淋巴瘤细胞系的增殖。此外，与表达各自 BCR 的截短外毒素杀伤淋巴瘤细胞偶联的 neurabin-I 的 BCR 结合表位。这些结果支持了中枢神经系统（CNS）驱动自身抗原经翻译后修饰后持续抗原刺激在 PCNSL 发病机制中的作用，为其 CNS 嗜性提供了解释，并为一种新的特异性治疗方法奠定了基础。
