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

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

doi:10.1007/s10875-021-01110-7

Abstract

PurposeBiallelic 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.MethodsClinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.ResultsOur 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.ConclusionIn summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

Highlights

NBAS-associated disease is a rare autosomal recessive disorder with a broad spectrum of clinical symptoms, mainly involving liver, growth, skeletal system, nervous system, integument, immune system, and musculature
We investigated whether the remaining natural killer (NK) cells in NBAS-deficient patients retained responsiveness to the prototypical target cell line K562 by measuring CD107a upregulation on NK cells as a functional marker for cytolytic granule release (Fig. 3A–B)
NBAS-associated disease is a complex disorder with a heterogeneous clinical spectrum involving multiple organ systems that can be categorized into three different clinical subgroups “β-propeller,” “Sec39,” and “C-terminal” [3]

Summary

Introduction

NBAS-associated disease is a rare autosomal recessive disorder with a broad spectrum of clinical symptoms, mainly involving liver, growth, skeletal system, nervous system, integument, immune system, and musculature. In 2015, NBAS variants were linked to fever-related recurrent acute liver failure [infantile liver failure syndrome 2 (ILFS2), MIM 616483] [2]. NBAS-associated disease has been documented in at least 110 patients from 97 families and NBAS variants can be classified into three subgroups according to the affected part of the protein: “Sec39,” with a predominant hepatic phenotype (ILFS2), “C-terminal” with the multisystemic SOPH phenotype, and “β-propeller” with a combined phenotype (ILFS2-SOPH) [3]. Immunological symptoms and laboratory alterations such as frequent infections, hypogammaglobulinemia, low natural killer (NK) cell numbers, and neutropenia have been observed in more than 60% of patients with NBASassociated disease throughout all defined subgroups [3].

Methods

Results

Conclusion