Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Department of Pediatric Immunology, Rheumatology and Infectious diseases, Meibergdreef 9, Amsterdam, The Netherlands; Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Meibergdreef 9, Amsterdam, The Netherlands.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
Clin Immunol. 2019 Jun;203:23-27. doi: 10.1016/j.clim.2019.03.010. Epub 2019 Apr 3.
Genetic studies are identifying an increasing number of monogenic causes of Common Variable Immunodeficiency (CVID). Pathogenic variants in the C-terminus of NFKB2 have been identified in the subset of CVID patients whose immunodeficiency is associated with ectodermal dysplasia and central adrenal insufficiency. We describe 2 unrelated CVID pedigrees with 4 cases of pathogenic stop gain variants (c.1903C > T) in the ankyrin repeat domain (ARD) of NF-κB2, leading to a premature truncation of the protein at p.Arg635Term (R635X). By immunophenotyping and functional ex vivo B- and T-cell experiments we characterized the variant by reduced class-switched memory B-cell counts and immature plasmablasts, unable to produce IgG and IgA. Features of a poor proliferative T-cell response and reduced expansion of CD4CXCR5 T cells was only observed in the two clinically affected index cases without any clear clinical correlate. In conclusion, pathogenic stop variants in the ARD of NFKB2 can cause 'infection-only' CVID with an abnormal B-cell phenotype and a variable clinical penetrance.
遗传研究正在确定越来越多的常见可变免疫缺陷（CVID）的单基因病因。在免疫缺陷与外胚层发育不良和中枢肾上腺功能不全相关的 CVID 患者亚组中，已经鉴定出 NFKB2 C 末端的致病性变异体。我们描述了 2 个无关的 CVID 家系，其中有 4 例致病性终止增益变异体（c.1903C>T）位于 NF-κB2 的锚蛋白重复域（ARD）中，导致蛋白在 p.Arg635Term（R635X）处过早截断。通过免疫表型和体外 B 细胞和 T 细胞功能实验，我们通过减少的类别转换记忆 B 细胞计数和未成熟浆母细胞来表征该变体，这些细胞无法产生 IgG 和 IgA。仅在两个临床上受影响的指数病例中观察到增殖性 T 细胞反应和 CD4CXCR5 T 细胞扩增减少的特征，并且没有任何明确的临床相关性。总之，NFKB2 的 ARD 中的致病性终止变异体可导致具有异常 B 细胞表型和可变临床外显率的“仅感染”CVID。
