Arjunaraja Swadhinya, Nosé Brent D, Sukumar Gauthaman, Lott Nathaniel M, Dalgard Clifton L, Snow Andrew L
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Front Immunol. 2017 Aug 2;8:913. doi: 10.3389/fimmu.2017.00913. eCollection 2017.
B cell Expansion with NF-κB and T cell Anergy (BENTA) disease is a novel B cell lymphoproliferative disorder caused by germline, gain-of-function mutations in the lymphocyte scaffolding protein CARD11, which drives constitutive NF-κB signaling. Despite dramatic polyclonal expansion of naive and immature B cells, BENTA patients also present with signs of primary immunodeficiency, including markedly reduced percentages of class-switched/memory B cells and poor humoral responses to certain vaccines. Using purified naive B cells from our BENTA patient cohort, here we show that BENTA B cells exhibit intrinsic defects in B cell differentiation. Despite a profound survival advantage relative to normal donor B cells, BENTA patient B cells were severely impaired in their ability to differentiate into short-lived IgDCD38 plasmablasts or CD138 long-lived plasma cells in response to various stimuli. These defects corresponded with diminished IgG antibody production and correlated with poor induction of specific genes required for plasma cell commitment. These findings provide important mechanistic clues that help explain both B cell lymphocytosis and humoral immunodeficiency in BENTA disease.
伴NF-κB的B细胞扩增与T细胞无能（BENTA）疾病是一种新型B细胞淋巴增殖性疾病，由淋巴细胞支架蛋白CARD11的种系功能获得性突变引起，该突变驱动组成型NF-κB信号传导。尽管幼稚和未成熟B细胞发生了显著的多克隆扩增，但BENTA患者也表现出原发性免疫缺陷的迹象，包括类别转换/记忆B细胞的百分比显著降低以及对某些疫苗的体液反应不佳。利用我们BENTA患者队列中纯化的幼稚B细胞，我们在此表明BENTA B细胞在B细胞分化中存在内在缺陷。尽管相对于正常供体B细胞具有显著的生存优势，但BENTA患者的B细胞在响应各种刺激时分化为短命的IgDCD38浆母细胞或CD138长寿浆细胞的能力严重受损。这些缺陷与IgG抗体产生减少相对应，并与浆细胞分化所需特定基因的诱导不足相关。这些发现提供了重要的机制线索，有助于解释BENTA疾病中的B细胞淋巴细胞增多和体液免疫缺陷。
