null genotype underpins recurrence of meningiomas.

Introduction: Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited.

Objective: To identify gene expression signatures of 1p22qNF2 meningioma recurrence, with concurrent biallelic inactivation of and loss of chr1p that are heterogenous but enriched for recurrent meningiomas.

Spontaneous mutation in 2310061I04Rik results in reduced expression of mitochondrial genes and impaired brain myelination.

Here, we describe a spontaneous mouse mutant with a deletion in a predicted gene 2310061I04Rik (Rik) of unknown function located on chromosome 17. A 59 base pair long deletion occurred in the first intron of the Rik gene and disrupted its expression. Riknull mice were born healthy and appeared anatomically normal up to two weeks of age.

TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.

Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similar to , or -deficient mice, -deficient embryos died around midgestation due to impaired endothelium integrity. They displayed significantly lower expression of transcription factor , an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway.

COMMD10 Is Essential for Neural Plate Development during Embryogenesis.

The COMMD (copper metabolism MURR1 domain containing) family includes ten structurally conserved proteins (COMMD1 to COMMD10) in eukaryotic multicellular organisms that are involved in a diverse array of cellular and physiological processes, including endosomal trafficking, copper homeostasis, and cholesterol metabolism, among others. To understand the role of COMMD10 in embryonic development, we used /J mice, where the transgene is integrated into an intron of the gene, creating a functional knockout of in homozygous mice. Breeding heterozygous mice produced no COMMD10-deficient offspring, suggesting that COMMD10 is required for embryogenesis.

Specific gene expression signatures of low grade meningiomas.

Introduction: Meningiomas are the most common primary central nervous system (CNS) tumors in adults, representing approximately one-third of all primary adult CNS tumors. Although several recent publications have proposed alternative grading systems of meningiomas that incorporate genomic and/or epigenomic data to better predict meningioma recurrence and progression-free survival, our understanding of driving forces of meningioma development is still limited.

Objective: To define gene expression signatures of the most common subtypes of meningiomas to better understand cellular processes and signaling pathways specific for each tumor genotype.

Mutated KLF4(K409Q) in meningioma binds STRs and activates gene expression.

Krüppel-like factor 4 (KLF4) is a transcription factor that has been proven necessary for both induction and maintenance of pluripotency and self-renewal. Whole-genome sequencing defined a unique mutation in KLF4 (KLF4) in human meningiomas. However, the molecular mechanism of this tumor-specific KLF4 mutation is unknown.

Acetaminophen Inhibits the Neutrophil Oxidative Burst: Implications for Diagnostic Testing.

Background: Chronic granulomatous disease is a primary immunodeficiency characterized by recurrent bacterial and fungal infections, granuloma formation, and inflammatory disease. Impaired neutrophil oxidative function is an essential diagnostic criterion. In vitro exposure of neutrophils to acetaminophen, a commonly used over-the-counter medication, has been associated with reduced neutrophil oxidative function.

Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals.

Purpose: DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay.

Methods: We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations.

Broad spectrum of autoantibodies in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

Using a protein microarray, a broad spectrum of autoantibodies were demonstrated in patients with either Wiskott-Aldrich syndrome (WAS) or with X-linked thrombocytopenia (XLT), indicating that immune dysregulation is an integral component of both diseases.

Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia.

Inherited, complete deficiency of human HOIL-1, a component of the linear ubiquitination chain assembly complex (LUBAC), underlies autoinflammation, infections, and amylopectinosis. We report the clinical description and molecular analysis of a novel inherited disorder of the human LUBAC complex. A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC.

TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB.

Objective: To investigate the impact of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) upon immunological recovery and the T-cell compartment after initiation of TB and antiretroviral therapy (ART).

Design And Methods: We prospectively evaluated T-cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n = 154) of highly immunosuppressed HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretrovirals randomized clinical trial. We compared findings from patients who developed TB-IRIS with findings from patients who did not develop TB-IRIS.

Next generation sequencing reveals skewing of the T and B cell receptor repertoires in patients with wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is due to mutations of the WAS gene encoding for the cytoskeletal WAS protein, leading to abnormal downstream signaling from the T cell and B cell antigen receptors (TCR and BCR). We hypothesized that the impaired signaling through the TCR and BCR in WAS would subsequently lead to aberrations in the immune repertoire of WAS patients. Using next generation sequencing (NGS), the T cell receptor β and B cell immunoglobulin heavy chain (IGH) repertoires of eight patients with WAS and six controls were sequenced.

Flow cytometry biomarkers distinguish DOCK8 deficiency from severe atopic dermatitis.

DOCK8 deficiency is a primary immunodeficiency characterized by recurrent sinopulmonary infections, dermatitis with cutaneous infections, elevated serum IgE levels, eosinophilia, and a high incidence of food allergy. Given the seriousness of DOCK8 deficiency, it is important to recognize it early and initiate appropriate therapy. Diagnosis relies on examining DOCK8 protein expression and sequencing of the 48 exons in the DOCK8 gene, but these assays are not always readily available.

Hypomorphic Janus kinase 3 mutations result in a spectrum of immune defects, including partial maternal T-cell engraftment.

Background: Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells. Maternal T-cell engraftment is a common finding in infants with severe combined immunodeficiency but is not typically observed in patients with residual T-cell development.

Objective: We sought to study in detail the molecular, cellular, and humoral immune phenotype and function of 3 patients with hypomorphic JAK3 mutations.

Tumor necrosis factor receptor-associated factor 1 (TRAF1) deficiency attenuates atherosclerosis in mice by impairing monocyte recruitment to the vessel wall.

Background: Members of the tumor necrosis factor superfamily, such as tumor necrosis factor-alpha, potently promote atherogenesis in mice and humans. Tumor necrosis factor receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines.

Methods And Results: This study tested the hypothesis that TRAF1 modulates atherogenesis in vivo.

ERK-dependent Bim modulation downstream of the 4-1BB-TRAF1 signaling axis is a critical mediator of CD8 T cell survival in vivo.

During an acute immune response, CD8 T cells undergo rapid expansion followed by a contraction phase during which the majority of activated T cells die, leaving a few survivors to persist as memory cells. The regulation of T cell survival is critical at each stage of this response. 4-1BB, a TNFR family member, has been implicated in prolonging the survival of activated and memory CD8 T cells; however, the precise mechanisms by which 4-1BB sustains T cell survival are incompletely understood.

TNF receptor-associated factor 1 expressed in resident lung cells is required for the development of allergic lung inflammation.

TNF is a major therapeutic target in a range of chronic inflammatory disorders, including asthma. TNFR-associated factor (TRAF)1 is an intracellular adaptor molecule important for signaling by TNFR. In this study, we investigated the role of TRAF1 in an adoptive transfer model of allergic lung inflammation.

NF-kappaB2 mutation targets TRAF1 to induce lymphomagenesis.

The NF-kappaB2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-kappaB2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies.

TRAF-1, -2, -3, -5, and -6 are induced in atherosclerotic plaques and differentially mediate proinflammatory functions of CD40L in endothelial cells.

Objective: Several lines of evidence implicate CD40 ligand (CD40L, CD154) as a mediator and marker of atherosclerosis. This study investigated the involvement of tumor necrosis factor receptor-associated factors (TRAFs) in CD40 signaling in endothelial cells (ECs) and their expression in atheromata and cells involved in atherogenesis.

Methods And Results: CD40L enhanced the basal expression of TRAF-1, -2, -3, and 6, but not TRAF-5 in ECs.

TRAF1 regulates recruitment of lymphocytes and, to a lesser extent, neutrophils, myeloid dendritic cells and monocytes to the lung airways following lipopolysaccharide inhalation.

Inhaled lipopolysaccharide (LPS) induces an inflammatory response that may contribute to the pathogenesis of asthma and other airway diseases. Here we investigate the role of tumour necrosis factor (TNF) receptor-associated factor 1 (TRAF1) in leucocyte recruitment using a model of LPS-induced lung inflammation in mice. TRAF1(-/-) mice are completely deficient in the recruitment of lymphocytes to the lower respiratory tract after inhalation of LPS.

A critical role for TNF receptor-associated factor 1 and Bim down-regulation in CD8 memory T cell survival.

The mechanisms that allow the maintenance of immunological memory remain incompletely defined. Here we report that tumor necrosis factor receptor (TNFR)-associated factor (TRAF) 1, a protein recruited in response to several costimulatory TNFR family members, is required for maximal CD8 T cell responses to influenza virus in mice. Decreased recovery of CD8 T cells in vivo occurred under conditions where cell division was unimpaired.

TRAF1 regulates Th2 differentiation, allergic inflammation and nuclear localization of the Th2 transcription factor, NIP45.

We have previously reported that tumor necrosis factor receptor-associated factor 1 (TRAF1), an intracellular protein, which binds to a range of molecules, including tumor necrosis factor (TNF) receptor family members, regulates TNF-induced NF-kappaB and AP-1 signaling as well as TCR-triggered proliferative responses in T cells. In order to define the role of TRAF1 in Th cell differentiation, we analyzed the responses of TRAF1-/- T cells following TCR activation. Stimulation of TRAF1-/- T cells by antigen resulted in significantly increased expression of the Th2 cytokines (IL-4, IL-5 and IL-13) compared with wild-type (WT) controls.

Acute tumor necrosis factor-alpha-induced liver injury in the absence of tumor necrosis factor receptor-associated factor 1 gene expression.

Pulmonary and serum levels of tumor necrosis factor-alpha (TNF-alpha), are elevated in many lung diseases, causing local inflammation, fever, and multiorgan, including hepatic, dysfunction. Cellular responses to TNF-alpha are determined by recruitment of specific proteins to intracellular receptor signaling complexes. One of these proteins, TNF receptor-associated factor 1 (TRAF1), is highly regulated in pulmonary cells.