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NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

2021; Springer Science+Business Media; Volume: 41; Issue: 8 Linguagem: Inglês

10.1007/s10875-021-01110-7

1573-2592

Dominic Lenz, Jens Pahl, Fabian Hauck, Seham Alameer, Meena Balasubramanian, Ivo Barić, Nikolas Boy, Joseph A. Church, Ellen Crushell, Anke Dick, Felix Distelmaier, Jidnyasa Gujar, Giuseppe Indolfi, Eberhard Lurz, Bianca Peters, Tobias Schwerd, Daniele Serranti, Stefan Kölker, Christoph Klein, Georg F. Hoffmann, Holger Prokisch, Johann Greil, Adelheid Cerwenka, Thomas Giese, Christian Staufner,

Platelet Disorders and Treatments

Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.Our study revealed reduced absolute numbers of mature CD56dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell-intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.