法国人类传染病遗传学实验室Anne Puel，Jean-Laurent Casanova和Tom Le Voyer共同合作，近期取得重要工作进展。他们研究发现，替代性NF-κB通路缺乏症患者体内有I型IFN自身抗体。相关研究成果2023年11月8日在线发表于《自然》杂志上。

据介绍，由常染色体隐性AIRE缺乏引起的1型自身免疫性多内皮病变综合征（APS-1）患者产生中和I型干扰素（IFN）的自身抗体，从而导致危及生命的新冠肺炎肺炎。

研究人员报告了常染色体隐性NIK或RELB缺乏症患者，或一种特定类型的自染色体显性NF-κB2缺乏症患者也具有针对I型IFN的中和自身抗体，并且患危及生命的新冠肺炎肺炎风险更高。在常染色体显性遗传的NF-κB2缺乏症患者中，这些自身抗体仅在与p100加工受损导致的转录（p52活性）功能丧失（LOF），和未加工的p100积累导致的调节（IκBδ活性）功能获得（GOF）相关的变体杂合的个体中发现，因此增加了IκBδ（以下称为p52^LOF/IκBδ^GOF）的抑制活性。相反，在导致p100和p52单倍性不足（以下简称p52^LOF/IκBδ^LOF）或p52功能获得（以下简称p52^GOF/I NF-κBδ^LOF）的NFKB2变异体杂合的个体中未发现针对I型IFN的中和自身抗体。与APS-1患者相比，NIK、RELB或NF-κB2疾病患者的组织特异性自身抗体很少。

然而，它们的胸腺结构异常，很少有表达AIRE的髓质胸腺上皮细胞。人类先天性的替代性NF-κB通路错误损害了表达AIRE的髓质胸腺上皮细胞的发育，从而导致产生针对I型IFN的自身抗体和对病毒性疾病的易感性。

附：英文原文

Title: Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency

Author: Le Voyer, Tom, Parent, Audrey V., Liu, Xian, Cederholm, Axel, Gervais, Adrian, Rosain, Jrmie, Nguyen, Tina, Perez Lorenzo, Malena, Rackaityte, Elze, Rinchai, Darawan, Zhang, Peng, Bizien, Lucy, Hancioglu, Gonca, Ghillani-Dalbin, Pascale, Charuel, Jean-Luc, Philippot, Quentin, Gueye, Mame Sokhna, Maglorius Renkilaraj, Majistor Raj Luxman, Ogishi, Masato, Soude, Camille, Migaud, Mlanie, Rozenberg, Flore, Momenilandi, Mana, Riller, Quentin, Imberti, Luisa, Delmonte, Ottavia M., Mller, Gabriele, Keller, Baerbel, Orrego, Julio, Franco Gallego, William Alexander, Rubin, Tamar, Emiroglu, Melike, Parvaneh, Nima, Eriksson, Daniel, Aranda-Guillen, Maribel, Berrios, David I., Vong, Linda, Katelaris, Constance H., Mustillo, Peter, Raedler, Johannes, Bohlen, Jonathan, Bengi Celik, Jale, Astudillo, Camila, Winter, Sarah, McLean, Catriona, Guffroy, Aurlien, DeRisi, Joseph L., Yu, David, Miller, Corey, Feng, Yi, Guichard, Audrey, Bziat, Vivien, Bustamante, Jacinta, Pan-Hammarstrm, Qiang, Zhang, Yu, Rosen, Lindsey B., Holland, Steve M., Bosticardo, Marita, Kenney, Heather, Castagnoli, Riccardo, Slade, Charlotte A.

Issue&Volume: 2023-11-08

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. Inborn errors of the alternative NF-κB pathway in humans 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

DOI: 10.1038/s41586-023-06717-x

Source: https://www.nature.com/articles/s41586-023-06717-x