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Abstract：
Primary vitreoretinal lymphoma (PVRL) is a rare subtype of DLBCL and can progress into primary central nervous system lymphoma (PCNSL). To investigate the role of chronic antigenic stimulation in PVRL, we cloned and expressed B-cell receptors (BCR) from PVRL patients and tested for binding against human auto-antigens. SEL1L3, a protein with multiple glycosylation sites, was identified as the BCR target in 3/20 PVRL cases. SEL1L3 induces proliferation and BCR pathway activation in aggressive lymphoma cell lines. Moreover, SEL1L3 conjugated to a toxin killed exclusively lymphoma cells with respective BCR-reactivity. Western Blot analysis indicates the occurrence of hyper-N-glycosylation of SEL1L3 at aa 527 in PVRL patients with SEL1L3-reactive BCRs. The BCR of a PVRL patient with serum antibodies against SEL1L3 was cloned from a vitreous body biopsy at diagnosis and of a systemic manifestation at relapse. VH4-04*07 was used in both lymphoma manifestations with highly conserved CDR3 regions. Both BCRs showed binding to SEL1L3, suggesting continued dependence of lymphoma cells on antigen stimulation. These results indicate an important role of antigenic stimulation by post-translationally modified auto-antigens in the genesis of PVRL. They also provide the basis for a new treatment approach targeting unique lymphoma BCRs with ultimate specificity.
摘要：
原发性玻璃体视网膜淋巴瘤(PVRL)是一种少见的DLBCL亚型,可进展为原发性中枢神经系统淋巴瘤(PCNSL)。探讨慢性抗原刺激在PVRL中的作用,我们从PVRL患者中克隆并表达了B细胞受体(BCR),并检测了其与人自身抗原的结合情况.SEL1L3，一种具有多个糖基化位点的蛋白质，在3/20例PVRL病例中被确定为BCR目标。SEL1L3在侵袭性淋巴瘤细胞系中诱导增殖和BCR途径激活。此外，与毒素缀合的SEL1L3仅杀死具有各自BCR反应性的淋巴瘤细胞。Western印迹分析表明，在患有SEL1L3反应性BCR的PVRL患者中，SEL1L3在aa527处发生了高N糖基化。在诊断时从玻璃体活检中克隆出具有针对SEL1L3的血清抗体的PVRL患者的BCR，并在复发时出现全身表现。VH4-04*07用于具有高度保守的CDR3区域的两种淋巴瘤表现。两种BCR均显示与SEL1L3结合，表明淋巴瘤细胞对抗原刺激的持续依赖性。这些结果表明翻译后修饰的自身抗原刺激在PVRL的发生中的重要作用。它们还为靶向具有最终特异性的独特淋巴瘤BCR的新治疗方法提供了基础。
