Genome-wide analyses and functional profiling of human NK cell lines.

Natural killer (NK) cell lines, including YTS, NK92, NK3.3, and NKL, represent excellent models for the study of human natural killer cells. While phenotypic and functional differences between these cell lines have been reported, a multi-parametric study, encompassing genomic, phenotypic, and functional assays, has not been performed.

Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder.

Background: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint.

Objective: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders.

Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-κB activation and autoinflammatory disease.

Receptor-induced NF-κB activation is controlled by NEMO, the NF-κB essential modulator. Hypomorphic NEMO mutations result in X-linked ectodermal dysplasia with anhidrosis and immunodeficiency, also referred to as NEMO syndrome. Here we describe a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations.

Practical NK cell phenotyping and variability in healthy adults.

Human natural killer (NK) cells display a wide array of surface and intracellular markers that indicate various states of differentiation and/or levels of effector function. These NK cell subsets exist simultaneously in peripheral blood and may vary among individuals. We examined variety among selected NK cell receptors expressed by NK cells from normal donors, as well as the distribution of select NK cell subsets and NK cell receptor expression over time in several individual donors.

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency.

Background: Dedicator of cytokinesis 8 (DOCK8) mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, increased IgE levels, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse.

Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset.

Mutations in the transcription factor GATA2 underlie the syndrome of monocytopenia and B- and natural killer (NK)-cell lymphopenia associated with opportunistic infections and cancers. In addition, patients have recurrent and severe viral infections. NK cells play a critical role in mediating antiviral immunity.

Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity.

The Fc receptor on NK cells, FcγRIIIA (CD16), has been extensively studied for its role in mediating antibody-dependent cellular cytotoxicity (ADCC). A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients. Here, we identified a new patient with this CD16 mutation and compared the patient's NK cells to those of the originally reported patient.

Bilateral adrenal EBV-associated smooth muscle tumors in a child with a natural killer cell deficiency.

EBV-associated smooth muscle tumors are found in immunocompromised patients, most commonly HIV/AIDS. We present a 12-year-old girl with the first documented case of EBV-related smooth muscle tumors in the presence of a rare classic NK cell deficiency. This sheds light on the role of NK cells in controlling EBV-related smooth muscle tumors.

Novel mutation in STXBP2 prevents IL-2-induced natural killer cell cytotoxicity.

We have identified dizygotic twins with a novel syntaxin-binding protein 2 (STXBP2) mutation, where cytotoxicity cannot be restored with IL-2. This defines STXBP2 as an absolute requirement for NK cell cytotoxic function.

CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia.

Background: CD27 is a lymphocyte costimulatory molecule that regulates T-cell, natural killer (NK) cell, B-cell, and plasma cell function, survival, and differentiation. On the basis of its function and expression pattern, we considered CD27 a candidate gene in patients with hypogammaglobulinemia.

Objective: We sought to describe the clinical and immunologic phenotypes of patients with genetic CD27 deficiency.

IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo.

Substance P inhibits natural killer cell cytotoxicity through the neurokinin-1 receptor.

SP is a potent neuroimmunomodulator that functions through ligating members of the neurokinin receptor family, one of which, NK1R, is widely expressed in immune cells. As in humans, circulating SP levels are increased in pathologic states associated with impairment of NK cell functions, such as depression and HIV infection, we hypothesized that SP has a direct, inhibitory effect upon NK cells. We have studied a clonal human NK cell line (YTS) as well as ex vivo human NK cells and have determined that truncated and full-length NK1R isoforms are expressed in and SP bound by ex vivo NK cells and the YTS NK cell line.

Comèl-Netherton syndrome defined as primary immunodeficiency.

Background: Mutations in serine protease inhibitor Kazal-type 5 (SPINK5), encoding the serine protease inhibitor lympho-epithelial Kazal-type 5 related inhibitor (LEKTI), cause Comèl-Netherton syndrome, an autosomal-recessive disease characterized by congenital ichthyosis, bamboo hair, and atopic diathesis. Despite increased frequency of infections, the immunocompetence of patients with Comèl-Netherton syndrome has not been extensively investigated.

Objective: To define Comèl-Netherton syndrome as a primary immunodeficiency disorder and to explore the benefit of intravenous immunoglobulin replacement therapy.

Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity.

Background: Human hypomorphic nuclear factor-kappaB essential modulator (NEMO) mutations cause diverse clinical and immunologic phenotypes, but understanding of their scope and mechanistic links to immune function and genotype is incomplete.

Objective: We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.

Methods: Phenotypes of 72 individuals with NEMO mutations were compiled.

Cdc42-interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse.

An essential function of the immunological synapse (IS) is directed secretion. NK cells are especially adept at this activity, as they direct lytic granules to the synapse for secretion, which enables cytotoxicity and facilitates host defense. This initially requires rearrangement of the actin cytoskeleton and, subsequently, microtubule-dependent trafficking of the lytic granules.