PDF(Pubmed)
Abstract：
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
摘要：
由常染色体隐性遗传AIRE缺乏症引起的1型自身免疫性多内分泌病综合征（APS-1）患者会产生中和I型干扰素（IFN）1,2的自身抗体，从而易患危及生命的COVID-19肺炎3。在这里，我们报道了常染色体隐性遗传性NIK或RELB缺乏的患者，或常染色体显性遗传NF-κB2缺陷的特定类型，还具有针对I型IFN的中和自身抗体，并且患危及生命的COVID-19肺炎的风险更高。在常染色体显性遗传NF-κB2缺乏症患者中，这些自身抗体仅在与由于p100加工产生p52而导致的转录（p52活性）功能丧失（LOF）和由于未加工p100的积累而导致的调节（IκBδ活性）功能获得（GOF），因此增加了IκBδ的抑制活性（下文，p52LOF/IκBδGOF)。相比之下,针对I型IFN的中和自身抗体在NFKB2变体杂合子导致p100和p52单倍体不足的个体中未发现（以下，p52LOF/IκBδLOF)或p52的功能获得(以下，p52GOF/IκBδLOF)。与APS-1患者相反，患有NIK疾病的患者，RELB或NF-κB2具有非常少的组织特异性自身抗体。然而,它们的胸腺结构异常，几乎没有表达AIRE的髓质胸腺上皮细胞。替代NF-κB途径的人类先天性错误会损害表达AIRE的髓样胸腺上皮细胞的发育，从而产生针对I型IFN的自身抗体和对病毒性疾病的易感性。
