José Carreras Center for Immuno-and Gene Therapy and Internal Medicine I, Saarland University Medical School, Homburg/Saar.
Institute of Medical Microbiology and Hygiene, Saarland University, Homburg.
Haematologica. 2023 Dec 1;108(12):3347-3358. doi: 10.3324/haematol.2023.282698.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB104 or HLADRB1 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.
结节性淋巴细胞为主型霍奇金淋巴瘤（NLPHL）是一种表达功能性 B 细胞受体（BCR）的霍奇金淋巴瘤。最近，我们描述了莫拉氏菌抗原 RpoC 及其超抗原 MID/hag 对 IgD+淋巴细胞为主细胞的双重刺激模型，与超长 CDR3 和 HLA-DRB104 或 HLA-DRB107 单倍型相关。本研究的目的是将抗原筛选扩展到其他细菌和病毒。分析了 7 例新病例和 15 例先前报道病例的片段抗体结合（Fab）区域。在 22 例（22.7%）病例中观察到非莫拉氏菌反应性 Fab 区域对罗特氏菌裂解物的反应性。通过二维凝胶中的比较银染和免疫染色鉴定罗特氏菌的半乳糖呋喃糖基转移酶（Gltf）和 2,3-丁二醇脱氢酶（Bdh），随后通过质谱和western blot 以及酶联免疫吸附试验进行验证。罗特氏菌 Gltf 和 Bdh 均可诱导体外 BCR 途径激活和增殖。表达重组罗特氏菌反应性 BCR 的 DEV 细胞中，重组 Gltf/ETA'-免疫毒素缀合物诱导细胞凋亡。在 7 个新表达的 BCR 中确认了对 M. catarrhalis RpoC 的反应性（总共 10/22 对莫拉氏菌反应），导致 15/22（68.2%）个病例对定义的细菌抗原具有 BCR 反应性。这些发现加强了细菌触发导致 NLPHL 亚群的假设。
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