Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity
Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity
复制标题
DOI：
10.1172/jci85647
复制
发表时间：
2016-11-01
影响因子：
15.9
通讯作者：
Geha, Raif S.
中科院分区：
文献类型：
--
作者：
Massaad, Michel J.;Zhou, Jia;Geha, Raif S.
免疫细胞凋亡的改变与自身免疫有关。在这里，我们已经确定了一个纯合的错义突变的基因编码的碱基切除修复酶Nei核酸内切酶VIII样3（NEIL 3），废除酶活性在3个同胞从一个血缘家庭。NEIL 3突变与这些个体的致命复发性感染、严重自身免疫、低丙种球蛋白血症和B细胞功能受损有关。同样的纯合子NEIL 3突变也在一个无症状的个体中被鉴定，该个体表现出血清自身抗体水平升高和外周B细胞耐受缺陷，但B细胞功能正常。对患者的进一步分析揭示了缺乏LPS反应性米色样锚（LRBA）蛋白表达，这是免疫缺陷的已知原因。我们接下来检查了NEIL 3对Neil 3（-/-）小鼠中自身耐受性维持的贡献。尽管Neil 3（-/-）小鼠显示正常的B细胞功能，但在用poly（I：C）处理以模拟微生物刺激后，它们表现出升高的血清自身抗体水平并发生肾炎。在Neil 3（-/-）小鼠中，脾脏T和B细胞以及来自派伊尔集合淋巴结的生发中心B细胞显示出凋亡和细胞死亡的显著增加，表明有利于自身免疫的自身抗原的潜在释放。这些发现表明NEIL 3的缺乏与淋巴细胞凋亡、自身抗体和自身免疫易感性的增加有关。
Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function. Further analysis of the patients revealed an absence of LPS-responsive beige-like anchor (LRBA) protein expression, a known cause of immunodeficiency. We next examined the contribution of NEIL3 to the maintenance of self-tolerance in Neil3(-/-) mice. Although Neil3(-/-) mice displayed normal B cell function, they exhibited elevated serum levels of autoantibodies and developed nephritis following treatment with poly(I:C) to mimic microbial stimulation. In Neil3(-/-) mice, splenic T and B cells as well as germinal center B cells from Peyer's patches showed marked increases in apoptosis and cell death, indicating the potential release of self-antigens that favor autoimmunity. These findings demonstrate that deficiency in NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies, and predisposition to autoimmunity.