遗传性 TNFAIP3 (A20) 失活是一种典型的体细胞淋巴瘤病变，也是 A20 (HA20) 单倍体不足的基因组特征。在 34 名 HA20 患者的队列中，我们发现杂合 TNFAIP3 缺失使免疫库偏向具有典型自身反应性抗原受体（通常在 B 和 T 细胞淋巴瘤中发现）的淋巴细胞。这种偏差是由前馈肿瘤坏死因子 (TNF)/A20/核因子 κB (NF-κB) 环介导的，该环在克隆扩展的 B（CD81、BACH2 和 NEAT1）或 T（GATA3）中形成淋巴瘤前转录组特征、TOX 和 PDCD1) 细胞。这种偏差可以通过抗 TNF 治疗逆转，但也可能进展为明显的淋巴瘤。对条件性 TNFAIP3 敲除小鼠的分析重现了 TNF/A20/NF-κB 信号轴与允许的抗原受体的连接，并表明 B 细胞和 T 细胞存在明显的调节。总之，患有 HA20 遗传性疾病的患者为了解 A20/TNF/NF-κB 介导的免疫稳态控制和临床上尚未认识到的淋巴瘤发生的早期步骤提供了一个特殊的窗口。

Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B (CD81, BACH2, and NEAT1) or T (GATA3, TOX, and PDCD1) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional TNFAIP3 knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB-mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized.