Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

中文翻译：

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TRAF3 突变人类的免疫缺陷、自身免疫和 B 细胞恶性肿瘤风险增加


肿瘤坏死因子受体相关因子 3 (TRAF3) 是免疫的核心调节因子。 TRAF3 在 B 细胞恶性肿瘤中经常发生体细胞突变，但其在人类免疫中的作用尚不清楚。在这里，我们在五个不相关的家族中描述了一种免疫失调综合征，包括反复细菌感染、自身免疫、全身炎症、B 细胞淋巴增殖和高丙种球蛋白血症。受影响的个体均具有 TRAF3 的单等位基因突变，从而降低了 TRAF3 的表达。免疫表型分析显示，患者的 B 细胞失调，核因子-κB 2 激活增加，线粒体呼吸增强，炎症反应加剧。患者出现轻度 CD4 + T 细胞淋巴细胞减少症，幼稚 T 细胞比例减少，但调节性 T 细胞和循环滤泡辅助 T 细胞增加。在这种临床表型的指导下，有针对性的分析表明，常见的遗传变异也会降低 TRAF3 的表达，与更广泛人群中 B 细胞恶性肿瘤、系统性红斑狼疮、较高的免疫球蛋白水平和细菌感染的风险增加相关。 TRAF3 减少会通过多种细胞内促炎途径的内在激活和线粒体呼吸增加而驱动 B 细胞过度活跃，从而带来疾病风险，这可能是来自失调的 T 细胞的帮助。因此，我们定义了单基因 TRAF3 单倍体不足综合征，并证明了常见的 TRAF3 变异如何影响一系列人类疾病。