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Mastura Monif, Aamira Huq, Lynette Chee, Trevor Kilpatrick
We present a case of monocytopaenia and mycobacteria-related infection (MonoMac) syndrome in a 30-year-old man of Indian origin. The clinical diagnosis of GATA2 haploinsufficiency was suspected after an unusual neurological presentation on a background of myelodysplastic syndrome and childhood pulmonary tuberculosis. The patient had a longitudinally extensive spinal cord lesion and a lesion in the medulla. No obvious infective cause for the spinal cord MRI abnormality was found, and the lesions were presumed to be inflammatory in nature...
April 21, 2018: BMJ Case Reports
Hideyuki Yamamoto, Hikaru Hattori, Erina Takagi, Takanobu Morishita, Yuichi Ishikawa, Seitaro Terakura, Tetsuya Nishida, Yoshinori Ito, Makoto Murata, Hitoshi Kiyoi
An 18-year-old man was diagnosed with Epstein-Barr virus (EBV) -associated hemophagocytic syndrome (HPS) and treated with prednisolone (PSL) at a previous hospital. During PSL tapering, the HPS symptoms reappeared, and the patient was referred to our hospital. Increased PSL improved the symptoms, but the EBV infection remained unresolved. At age 20, he was admitted to our hospital for newly developed pneumonia and diagnosed with myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) (MDS-RCMD; normal karyotype, IPSS: Int-1) by bone marrow examination...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Marcin W Wlodarski, Matthew Collin, Marshall S Horwitz
The GATA2 gene codes for a hematopoietic transcription factor that through its two zinc fingers (ZF) can occupy GATA-DNA motifs in a countless number of genes. It is crucial for the proliferation and maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations in GATA2 were reported in several hundred patients with various phenotypes ranging from mild cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4+ cells, monocytes and dendritic cells (MonoMAC/DCML), and myeloid neoplasia...
April 2017: Seminars in Hematology
A Polat, M Dinulescu, S Fraitag, S Nimubona, F Toutain, S Jouneau, E Poullot, C Droitcourt, A Dupuy
GATA2 mutations have been identified in various diseases, such as MonoMAC syndrome, Emberger syndrome, familial myelodysplastic syndrome, acute myeloid leukaemia and dendritic cell, monocyte, B-cell and natural killer-cell deficiency. These syndromes present a wide range of clinical features, dominated by severe infections and haematological disorders such as myelodysplastic syndrome. Up to 70% of patients with GATA2 mutations have dermatological features, mainly genital or extragenital warts, panniculitis or erythema nodosum and lymphoedema...
March 2018: British Journal of Dermatology
Linda Palma, Francesca Rossetti, Sabrina Dominici, Costantina Buondelmonte, Marco B L Rocchi, Gian P Rizzardi, Giuliana Vallanti, Mauro Magnani
Contamination of pharmaceutical products and medical devices with pyrogens such as endotoxins is the most common cause of systemic inflammation and, in worst cases, of septic shock. Thus, quantification of pyrogens is crucial. The limulus amebocyte lysate (LAL)-based assays are the reference tests for in vitro endotoxin detection, in association with the in vivo rabbit pyrogen test (RPT), according to European Pharmacopoeia (EP 2.6.14), and U.S. Pharmacopoeia (USP <85>). However, several substances interfere with LAL assay, while RPT is not accurate, not quantitative, and raises ethical limits...
February 2017: Assay and Drug Development Technologies
Mark Parta, Jennifer Cuellar-Rodriguez, Alexandra F Freeman, Juan Gea-Banacloche, Steven M Holland, Dennis D Hickstein
We performed allogeneic hematopoietic stem cell transplantation in a patient with GATA2 deficiency and an Epstein-Barr virus (EBV)-related spindle cell tumor involving the liver and possibly bone. He received a matched-related donor transplant with donor peripheral blood stem cells following a myeloablative conditioning regimen. He achieved rapid and high levels of donor engraftment and had complete reversal of the clinical and immunologic phenotype of MonoMAC/GATA2 deficiency and eradication of the EBV tumors after 3 years of follow-up...
January 2017: Journal of Clinical Immunology
Sami A Anjum, Helen Lawrence, James P Holland, John A Kirby, David J Deehan, Alison J Tyson-Capper
Cobalt-containing metal-on-metal hip replacements are associated with adverse reactions to metal debris (ARMD), including inflammatory pseudotumours, osteolysis, and aseptic implant loosening. The exact cellular and molecular mechanisms leading to these responses are unknown. Cobaltions (Co2+) activate human Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to Gram negative bacterial lipopolysaccharide (LPS).We investigated the effect of Co2+-mediated TLR4 activation on human microvascular endothelial cells (HMEC-1), focusing on the secretion of key inflammatory cytokines and expression of adhesion molecules...
November 22, 2016: Oncotarget
L-W Ding, T Ikezoe, K-T Tan, M Mori, A Mayakonda, W Chien, D-C Lin, Y-Y Jiang, M Lill, H Yang, Q-Y Sun, H P Koeffler
No abstract text is available yet for this article.
January 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marieke E Hoonakker, Lisa M Verhagen, Elder Pupo, Alex de Haan, Bernard Metz, Coenraad F M Hendriksen, Wanda G H Han, Arjen Sloots
The potency of whole-cell pertussis (wP) vaccines is still determined by an intracerebral mouse protection test. To allow development of suitable in vitro alternatives to this test, insight into relevant parameters to monitor the consistency of vaccine quality is essential. To this end, a panel of experimental wP vaccines of varying quality was prepared by sulfate-mediated suppression of the BvgASR master virulence regulatory system of Bordetella pertussis during cultivation. This system regulates the transcription of a range of virulence proteins, many of which are considered important for the induction of effective host immunity...
2016: PloS One
Ana Lukic, Jie Ji, Helena Idborg, Bengt Samuelsson, Lena Palmberg, Susanne Gabrielsson, Olof Rådmark
Leukotrienes (LTs) play major roles in lung immune responses, and LTD4 is the most potent agonist for cysteinyl LT1, leading to bronchoconstriction and tissue remodeling. Here, we studied LT crosstalk between myeloid cells and pulmonary epithelial cells. Monocytic cells (Mono Mac 6 cell line, primary dendritic cells) and eosinophils produced primarily LTC4 In coincubations of these myeloid cells and epithelial cells, LTD4 became a prominent product. LTC4 released from the myeloid cells was further transformed by the epithelial cells in a transcellular manner...
September 2016: Journal of Lipid Research
Alexandre Paradis, Stéphane Bernier, Nancy Dumais
In this study, we examined whether bacterial pathogen-associated molecular patterns recognized by toll-like receptors (TLRs) can modify the CCR7-dependent migration of human monocytes. MonoMac-1 (MM-1) cells and freshly isolated human monocytes were cultivated in the presence of agonists for TLR4 (which senses lipopolysaccharides from gram-negative bacteria), TLR1/2 (which senses peptidoglycan from gram-positive bacteria), and TLR9 (which recognizes bacterial DNA rich in unmethylated CpG DNA). CCR7 mRNA transcription was measured using quantitative reverse transcription polymerase chain reaction and protein expression was examined using flow cytometry...
June 15, 2016: Journal of Neuroimmunology
Ashley K Koegel, Inga Hofmann, Kristin Moffitt, Barbara Degar, Christine Duncan, Venée N Tubman
Patients with GATA2 haploinsufficiency have a significant predisposition to developing cytopenias, unique infectious manifestations, and myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). We report a unique case of a patient who presented with B-cell acute lymphoblastic leukemia (B-ALL) and was subsequently diagnosed with monocytopenia and mycobacterium avium complex (MonoMAC) syndrome/GATA2 haploinsufficiency. The development of MDS/AML in patients with GATA2 haploinsufficiency is well described, however, the development of ALL has not been reported in the literature...
October 2016: Pediatric Blood & Cancer
Patrick Ebner, Janina Rinker, Minh Thu Nguyen, Peter Popella, Mulugeta Nega, Arif Luqman, Birgit Schittek, Moreno Di Marco, Stefan Stevanovic, Friedrich Götz
Excretion of cytoplasmic proteins in pro- and eukaryotes, also referred to as "nonclassical protein export," is a well-known phenomenon. However, comparatively little is known about the role of the excreted proteins in relation to pathogenicity. Here, the impact of two excreted glycolytic enzymes, aldolase (FbaA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on pathogenicity was investigated in Staphylococcus aureus Both enzymes bound to certain host matrix proteins and enhanced adherence of the bacterial cells to host cells but caused a decrease in host cell invasion...
June 2016: Infection and Immunity
Polynikis Kaimakis, Emma de Pater, Christina Eich, Parham Solaimani Kartalaei, Mari-Liis Kauts, Chris S Vink, Reinier van der Linden, Martine Jaegle, Tomomasa Yokomizo, Dies Meijer, Elaine Dzierzak
The Gata2 transcription factor is a pivotal regulator of hematopoietic cell development and maintenance, highlighted by the fact that Gata2 haploinsufficiency has been identified as the cause of some familial cases of acute myelogenous leukemia/myelodysplastic syndrome and in MonoMac syndrome. Genetic deletion in mice has shown that Gata2 is pivotal to the embryonic generation of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). It functions in the embryo during endothelial cell to hematopoietic cell transition to affect hematopoietic cluster, HPC, and HSC formation...
March 17, 2016: Blood
Anna Lübking, Sebastian Vosberg, Nikola P Konstandin, Annika Dufour, Alexander Graf, Stefan Krebs, Helmut Blum, Axel Weber, Stig Lenhoff, Mats Ehinger, Karsten Spiekermann, Philipp A Greif, Jörg Cammenga
Heterozygous mutations in GATA2 underlie different syndromes, previously described as monocytopenia and mycobacterial avium complex infection (MonoMAC); dendritic cell, monocytes, B- and NK lymphocytes deficiency (DCML); lymphedema, deafness and myelodysplasia (Emberger syndrome) and familiar myelodysplastic syndrome/acute myeloid leukemia (MDS / AML). Onset and severity of clinical symptoms vary and preceding cytopenias are not always present. We describe a case of symptomatic DCML deficiency and rather discrete bone marrow findings due to GATA2 mutation...
2015: Leukemia Research Reports
Anna Maciejewski-Duval, Floriane Meuris, Alexandre Bignon, Marie-Laure Aknin, Karl Balabanian, Laurence Faivre, Marlène Pasquet, Vincent Barlogis, Claire Fieschi, Christine Bellanné-Chantelot, Jean Donadieu, Géraldine Schlecht-Louf, Viviana Marin-Esteban, Françoise Bachelerie
GATA2 deficiency-formerly described as MonoMAC syndrome; dendritic cells, monocytes, B cells, and natural killer cell deficiency; familial myelodysplastic syndrome/acute myeloid leukemia; or Emberger syndrome-encompasses a range of hematologic and nonhematologic anomalies, mainly characterized by monocytopenia, B lymphopenia, natural killer cell cytopenia, neutropenia, immunodeficiency, and a high risk of developing acute myeloid leukemia. Herein, we present 7 patients with GATA2 deficiency recruited into the French Severe Chronic Neutropenia Registry, which enrolls patients with all kinds of congenital neutropenia...
June 2016: Journal of Leukocyte Biology
Maaike R Scheenstra, Vishal Salunkhe, Iris M De Cuyper, Mark Hoogenboezem, Eveline Li, Taco W Kuijpers, Timo K van den Berg, Laura Gutiérrez
Dendritic cells (DCs) are key initiators and regulators of the immune response. The development of the DC lineage and their subsets requires an orchestrated regulation of their transcriptional program. Gata1, a transcription factor expressed in several hematopoietic cell lineages, has been recently reported to be required for mouse DC development and function. In humans, GATA1 is involved in the lineage separation between monocyte-derived DCs and Langerhans cells (LC) and loss of GATA1 results in differentiation arrest at the monocyte stage...
December 2015: Blood Cells, Molecules & Diseases
Yanbao Xiong, Michael Murphy, Tissa T Manavalan, Goutham Pattabiraman, Fu Qiu, Hui-Hsin Chang, I-Cheng Ho, Andrei E Medvedev
Endotoxin tolerance protects the host by limiting excessive 'cytokine storm' during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating the expression of proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that the induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4, but increased total protein phosphatase (PP) activity and the expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP nonreceptor type (PTPN) 22 and mitogen-activated protein kinase phosphatase (MKP)-1...
2016: Journal of Innate Immunity
Yo Saito, Tohru Fujiwara, Keiichi Ohashi, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Kenichi Ishizawa, Hideo Harigae
Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in both hematopoietic stem and progenitor cells and is essential for cell proliferation, survival, and differentiation. Recently, evidence from studies of aplastic anemia, MonoMAC syndrome, and lung cancer has demonstrated a mechanistic link between GATA-2 and human pathophysiology. GATA-2-dependent disease processes have been extensively analyzed; however, the transcriptional mechanisms upstream of GATA-2 remain less understood...
2015: PloS One
Michael B Murphy, Yanbao Xiong, Goutham Pattabiraman, Tissa T Manavalan, Fu Qiu, Andrei E Medvedev
Development of endotoxin tolerance in macrophages during sepsis reprograms Toll-like receptor 4 signaling to inhibit proinflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators and protects the host from excessive inflammation and tissue damage. However, endotoxin tolerance renders septic patients immunocompromised and unable to control secondary infections. Although previous studies have revealed the importance of several negative regulators of Toll-like receptor signaling in endotoxin tolerance, the role of Pellino proteins has not been addressed...
December 2015: Journal of Leukocyte Biology
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