Commensal bacteria drive B-cell lymphomagenesis in the setting of innate immunodeficiency.

IF 11.5 Q1 HEMATOLOGY
Jaeyong Jung, Sining Zhu, Almin Lalani, Judith Shakarchi, Brygida Matracz, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie
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Abstract

Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). Here we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3 /- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.

共生菌驱动先天免疫缺陷的b细胞淋巴瘤形成。
髓系细胞是先天免疫和炎症的中心角色。它们的功能由接头蛋白TRAF3调节。我们之前报道过衰老的骨髓细胞特异性traf3缺陷(M-Traf3-/-)小鼠自发地发生慢性炎症和b细胞淋巴瘤(BCL)。在这里,我们旨在确定这些小鼠中这种疾病表型的内部触发因素。我们首先在衰老的M-Traf3-/-小鼠中检测到肠道菌群失调和共生菌(CB)向肝脏的迁移。有趣的是,使用抗生素消耗CB有效地阻止了这些小鼠BCL的发展。M-Traf3 /-小鼠恶性b细胞克隆的IgH CDR3序列与常见的细菌反应性Ig克隆型具有高度的同源性。此外,M-Traf3-/- BCL小鼠表现出高血清抗体滴度。总之,我们的研究结果为先天免疫受损患者观察到的b细胞淋巴瘤发生风险增加的机制提供了见解。
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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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