Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation.

Abstract:

:We have previously reported on a unique patient in whom homozygosity for a mutation at IRF8 (IRF8(K108E)) causes a severe immunodeficiency. Laboratory evaluation revealed a highly unusual myeloid compartment, remarkable for the complete absence of CD141 and CD161 monocytes, absence of CD11c1 conventional dendritic cells (DCs) and CD11c1/CD1231 plasmacytoid DCs, and striking granulocytic hyperplasia. The patient initially presented with severe disseminated mycobacterial and mucocutaneous fungal infections and was ultimately cured by cord blood transplant. Sequencing RNA from the IRF8(K108E) patient's primary blood cells prior to transplant shows not only depletion of IRF8-bound and IRF8-regulated transcriptional targets, in keeping with the distorted composition of the myeloid compartment, but also a paucity of transcripts associated with activated CD41 and CD81 T lymphocytes. This suggests that T cells reared in the absence of a functional antigen-presenting compartment in IRF8(K108E) are anergic. Biochemical characterization of the IRF8(K108E) mutant in vitro shows that loss of the positively charged side chain at K108 causes loss of nuclear localization and loss of transcriptional activity, which is concomitant with decreased protein stability, increased ubiquitination, increased small ubiquitin-like modification, and enhanced proteasomal degradation. These findings provide functional insight into the molecular basis of immunodeficiency associated with loss of IRF8.

journal_name

Blood

journal_title

Blood

authors

Salem S,Langlais D,Lefebvre F,Bourque G,Bigley V,Haniffa M,Casanova JL,Burk D,Berghuis A,Butler KM,Leahy TR,Hambleton S,Gros P

doi

10.1182/blood-2014-04-570879

subject

Has Abstract

pub_date

2014-09-18 00:00:00

pages

1894-904

issue

12

eissn

0006-4971

issn

1528-0020

pii

blood-2014-04-570879

journal_volume

124

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412.

    abstract::MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expre...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-07-032714

    authors: Aichberger KJ,Mayerhofer M,Gleixner KV,Krauth MT,Gruze A,Pickl WF,Wacheck V,Selzer E,Müllauer L,Agis H,Sillaber C,Valent P

    更新日期:2007-04-01 00:00:00

  • Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation.

    abstract::Signal transducer and activator of transcription 3 (STAT3) is considered a negative regulator of inflammation, as inhibition of STAT3 signaling enhances antitumor immunity. However, STAT3 activation is a key oncogenic pathway in natural killer (NK)-lineage large granular lymphomas, and we recently reported enhanced pr...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-05-499707

    authors: Zhu S,Phatarpekar PV,Denman CJ,Senyukov VV,Somanchi SS,Nguyen-Jackson HT,Mace EM,Freeman AF,Watowich SS,Orange JS,Holland SM,Lee DA

    更新日期:2014-07-17 00:00:00

  • Modification of hemoglobin by ninhydrin.

    abstract::The Strecker degradation reaction was evaluated as a means of modifying hemoglobin in vitro, utilizing ninhydrin as a model compound. Ninhydrin led to modification of hemoglobin (when incubated with hemoglobin or red cells) at physiologic temperature and pH. Isoelectric focusing documented the formation of new hemoglo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Kokkini G,Stevens VJ,Peterson CM,Cerami A

    更新日期:1980-10-01 00:00:00

  • Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1.

    abstract::Murine IgM monoclonal antibody STRO-1 identifies a cell surface antigen expressed by stromal elements in human bone marrow (BM). STRO-1 binds to approximately 10% of BM mononuclear cells, greater than 95% of which are nucleated erythroid precursors, but does not react with committed progenitor cells (colony-forming un...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Simmons PJ,Torok-Storb B

    更新日期:1991-07-01 00:00:00

  • Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia.

    abstract::Microsatellite instability (MSI) and p53 mutations have been reported to occur in a significant proportion of patients with therapy-related acute myeloid leukemia (AML). MSH2 is one of the genes involved in DNA mismatch repair to maintain fidelity of genomic replication, and defects of MSH2 are directly involved in MS...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Zhu YM,Das-Gupta EP,Russell NH

    更新日期:1999-07-15 00:00:00

  • SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity.

    abstract::Tumors have several mechanisms to escape from the immune system. One of these involves expression of intracellular anticytotoxic proteins that modulate the execution of cell death. Previously, we have shown that the serine protease inhibitor (serpin) SPI-6, which inactivates the cytotoxic protease granzyme B (GrB), is...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2004-03-0791

    authors: Bots M,Kolfschoten IG,Bres SA,Rademaker MT,de Roo GM,Krüse M,Franken KL,Hahne M,Froelich CJ,Melief CJ,Offringa R,Medema JP

    更新日期:2005-02-01 00:00:00

  • The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10.

    abstract::The inv(11)(p15q22) is a recurrent chromosomal abnormality associated with de novo and therapy-related myeloid malignancies. Here we report the molecular definition of this chromosomal aberration in four patients. Positional cloning showed the consistent rearrangement of the DDX10 gene on chromosome 11q22, which encod...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Arai Y,Hosoda F,Kobayashi H,Arai K,Hayashi Y,Kamada N,Kaneko Y,Ohki M

    更新日期:1997-06-01 00:00:00

  • Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation.

    abstract::Interleukin-25 (IL-25) is a recently described T helper 2 (T(H)2) cell-derived cytokine that belongs to the IL-17 family and induces the production of IL-4, IL-5, and IL-13 from an unidentified non-T-cell population. Here, we show that mast cells are also potent IL-25-producing cells. When bone marrow-derived mast cel...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-09-2817

    authors: Ikeda K,Nakajima H,Suzuki K,Kagami S,Hirose K,Suto A,Saito Y,Iwamoto I

    更新日期:2003-05-01 00:00:00

  • A staging system for renal outcome and early markers of renal response to chemotherapy in AL amyloidosis.

    abstract::The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response have never been validated. Newly diagnosed patients from the Pavia (n = 461, testing cohort) and Heidelberg (n = 271, val...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2014-04-570010

    authors: Palladini G,Hegenbart U,Milani P,Kimmich C,Foli A,Ho AD,Vidus Rosin M,Albertini R,Moratti R,Merlini G,Schönland S

    更新日期:2014-10-09 00:00:00

  • A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma.

    abstract::Prediagnostic serum concentration of soluble CD30 (sCD30), a marker for chronic B-cell stimulation, has been associated with increased risk of developing AIDS-related non-Hodgkin lymphoma (NHL) in a recent study of HIV(+) patients. To investigate among healthy persons whether serum sCD30 is associated with NHL risk, w...

    journal_title:Blood

    pub_type: 杂志文章,多中心研究

    doi:10.1182/blood-2009-04-217521

    authors: Purdue MP,Lan Q,Martinez-Maza O,Oken MM,Hocking W,Huang WY,Baris D,Conde B,Rothman N

    更新日期:2009-09-24 00:00:00

  • Red blood cells inhibit apoptosis of human neutrophils.

    abstract::Oxidative stress has been implicated in the triggering of apoptosis in neutrophils. Because red blood cells (RBCs) are well known to scavenge oxidants including H2O2, we tested the hypothesis that RBCs inhibit apoptosis of neutrophils by reducing intracellular oxidative stress. Apoptosis of neutrophils was evaluated b...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Aoshiba K,Nakajima Y,Yasui S,Tamaoki J,Nagai A

    更新日期:1999-06-01 00:00:00

  • Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors.

    abstract::The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a promising new antiplatelet strategy. The binding of ligands or of the ligand-mimetic peptide RGD causes a conformational change of GP IIb/IIIa from the nonactivated to the activated state. Because several blocking agents/inhibitors are ligand-mimetics, ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Peter K,Schwarz M,Ylänne J,Kohler B,Moser M,Nordt T,Salbach P,Kübler W,Bode C

    更新日期:1998-11-01 00:00:00

  • Murine malaria decreases hemopoietic stem cells.

    abstract::The causes of anemia and immunosuppression, major outcomes of malaria, are not well established. This study was undertaken to investigate whether erythropoietin (EP) production is adequate and whether the hemopoietic stem cells (CFU-S) were affected during the course of infection. Groups of female Balb/c mice infected...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Silverman PH,Schooley JC,Mahlmann LJ

    更新日期:1987-02-01 00:00:00

  • Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor.

    abstract::The malignant Reed-Sternberg cell of Hodgkin disease is an aberrant B cell that persists in an immunolgically mediated inflammatory infiltrate. Despite its nonproductive immunoglobulin genes, the Reed-Sternberg cell avoids the usual apoptotic fate of defective immune cells through an unknown mechanism. A likely candid...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Annunziata CM,Safiran YJ,Irving SG,Kasid UN,Cossman J

    更新日期:2000-10-15 00:00:00

  • CD34+CD38- hematopoietic precursors derived from human embryonic stem cells exhibit an embryonic gene expression pattern.

    abstract::Gene expression patterns of CD34(+)CD38(-) cells derived from human embryonic stem cells (ESCs) were compared with those of cells isolated from adult human bone marrow (BM) using microarrays; 1692 and 1494 genes were expressed at levels at least 3-fold above background in cells from BM and ESCs, respectively. Of these...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-10-3575

    authors: Lu SJ,Li F,Vida L,Honig GR

    更新日期:2004-06-01 00:00:00

  • Transfusion-related sepsis: a silent epidemic.

    abstract::In this issue of Blood, Hong et al advocate for use of additional US Food and Drug Administration (FDA)–approved safety measures for transfusion. Most patients transfused with contaminated platelets do not show immediate clinical signs. Active surveillance suggests patient risk 10- to 40-fold higher than passive hemov...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2015-12-685198

    authors: Benjamin RJ

    更新日期:2016-01-28 00:00:00

  • Extracellular histones induce erythrocyte fragility and anemia.

    abstract::Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2017-06-790519

    authors: Kordbacheh F,O'Meara CH,Coupland LA,Lelliott PM,Parish CR

    更新日期:2017-12-28 00:00:00

  • New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia.

    abstract::The MLLT10 gene, located at 10p13, is a known partner of MLL and PICALM in specific leukemic fusions generated from recurrent 11q23 and 11q14 chromosome translocations. Deep sequencing recently identified NAP1L1/12q21 as another MLLT10 partner in T-cell acute lymphoblastic leukemia (T-ALL). In pediatric T-ALL, we have...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2013-02-487256

    authors: Brandimarte L,Pierini V,Di Giacomo D,Borga C,Nozza F,Gorello P,Giordan M,Cazzaniga G,Te Kronnie G,La Starza R,Mecucci C

    更新日期:2013-06-20 00:00:00

  • Downstream effectors of oncogenic ras in multiple myeloma cells.

    abstract::Ectopic expression of mutated K-ras or N-ras in the interleukin 6 (IL-6)-dependent ANBL6 multiple myeloma cell line induces cytokine-independent growth. To investigate the signaling pathways activated by oncogenic ras that may stimulate IL-6-independent growth, we compared ANBL6 cells stably transfected with mutated K...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-08-2640

    authors: Hu L,Shi Y,Hsu JH,Gera J,Van Ness B,Lichtenstein A

    更新日期:2003-04-15 00:00:00

  • Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production.

    abstract::We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-01-0012

    authors: Kim MR,Manoukian R,Yeh R,Silbiger SM,Danilenko DM,Scully S,Sun J,DeRose ML,Stolina M,Chang D,Van GY,Clarkin K,Nguyen HQ,Yu YB,Jing S,Senaldi G,Elliott G,Medlock ES

    更新日期:2002-10-01 00:00:00

  • EZH2 mutational status predicts poor survival in myelofibrosis.

    abstract::We genotyped 370 subjects with primary myelofibrosis (PMF) and 148 with postpolycythemia vera/postessential thrombocythemia (PPV/PET) MF for mutations of EZH2. Mutational status at diagnosis was correlated with hematologic parameters, clinical manifestations, and outcome. A total of 25 different EZH2 mutations were de...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2011-06-363424

    authors: Guglielmelli P,Biamonte F,Score J,Hidalgo-Curtis C,Cervantes F,Maffioli M,Fanelli T,Ernst T,Winkelman N,Jones AV,Zoi K,Reiter A,Duncombe A,Villani L,Bosi A,Barosi G,Cross NC,Vannucchi AM

    更新日期:2011-11-10 00:00:00

  • CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy.

    abstract::Gemtuzumab ozogamicin (GO) contains an anti-CD33 antibody to facilitate uptake of a toxic calicheamicin-gamma(1) derivative. While recent in vitro data demonstrated a quantitative relationship between CD33 expression and GO cytotoxicity, previous correlative studies failed to identify a significant association between...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-09-047399

    authors: Walter RB,Gooley TA,van der Velden VH,Loken MR,van Dongen JJ,Flowers DA,Bernstein ID,Appelbaum FR

    更新日期:2007-05-15 00:00:00

  • Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities.

    abstract::The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-09-307264

    authors: Perrot A,Luquet I,Pigneux A,Mugneret F,Delaunay J,Harousseau JL,Barin C,Cahn JY,Guardiola P,Himberlin C,Recher C,Vey N,Lioure B,Ojeda-Uribe M,Fegueux N,Berthou C,Randriamalala E,Béné MC,Ifrah N,Witz F,Groupe Ouest

    更新日期:2011-07-21 00:00:00

  • Hereditary abnormality of platelet aggregation attributable to nucleotide storage pool deficiency.

    abstract::An abnormality of platelet aggregation has been detected in six family members with mild bleeding tendencies. In citrated platelet-rich plasma, primary aggregation induced by ADP or epinephrine and agglutination in response to ristocetin were present but second wave aggregation and aggregation in response to collagen ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Ingerman CM,Smith JB,Shapiro S,Sedar A,Silver MJ

    更新日期:1978-08-01 00:00:00

  • Induction of monocytic differentiation and tumorigenicity by v-Ha-ras in differentiation arrested hematopoietic cells.

    abstract::Activated ras genes are often associated with human myeloid leukemias with a monocytic differentiated phenotype. To investigate the role of the activated ras gene in leukemogenesis, a myeloid nontumorigenic cell line (FDC-P1) was infected with a selectable retroviral vector carrying the v-Ha-ras gene (H1neo). Infected...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hibi S,Löhler J,Friel J,Stocking C,Ostertag W

    更新日期:1993-04-01 00:00:00

  • Chronic lymphocytic leukemia and the Warburg effect.

    abstract::In this issue of Blood, Jitschin et al demonstrate a microenvironmental glycolytic shift in chronic lymphocytic leukemia (CLL) cells mediated by Notch-c-Myc signaling. Interfering in the Notch-c-Myc pathway and reprogramming glycolytic metabolism could contribute to overcoming drug resistance in CLL. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2015-04-636332

    authors: Moreno C

    更新日期:2015-05-28 00:00:00

  • Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia.

    abstract::Deregulation of signal transduction pathways (STPs) may promote leukemogenesis by conferring cell proliferation and survival advantages in acute myelogenous leukemia (AML). Several agents targeting STPs are under development; however, redundancy and cross-talk between STPs could activate multiple downstream effectors ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-02-003475

    authors: Kornblau SM,Womble M,Qiu YH,Jackson CE,Chen W,Konopleva M,Estey EH,Andreeff M

    更新日期:2006-10-01 00:00:00

  • Circulating forms of intercellular adhesion molecule (ICAM)-1 in mice lacking membranous ICAM-1.

    abstract::Mice deficient in intercellular adhesion molecule-1 (ICAM-1), lacking membranous ICAM-1, show a normal development but abnormalities of inflammatory and immune functions. Although the membrane-bound form of ICAM-1 is not detectable in the mutant strain, circulating ICAM-1 (cICAM) is present in serum from ICAM-1-defici...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: van Den Engel NK,Heidenthal E,Vinke A,Kolb H,Martin S

    更新日期:2000-02-15 00:00:00

  • Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia.

    abstract::Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q11.2), which results in the PML-RARA fusion gene. In previous studies, we demonstrated that expression of a human PML-RARA complementary DNA in murine granulocyte precursor cells initiated the development of leukemia. However, leukemogenesis by P...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v99.8.2985

    authors: Le Beau MM,Bitts S,Davis EM,Kogan SC

    更新日期:2002-04-15 00:00:00

  • Defective adhesion of blood platelets to vascular microfibrils in the Bernard-Soulier syndrome.

    abstract::Bernard-Soulier syndrome (BSS) platelets, which lack the membrane glycoprotein complex Ib-IX, do not adhere to subendothelium. The adhesion of platelets from two patients with BSS to subendothelial microfibrils (MFs) and type I collagen was compared in an in vitro assay adapted to patients with low platelet count. Wit...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Fauvel-Lafève F,Tabaka V,Caen JP,Legrand YJ

    更新日期:1993-10-01 00:00:00