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Endotoxin Tolerance
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
F. Ulrich Schade, Regina Flach, Sascha Flohé, Matthias Majetschak, Ernst Kreuzfelder, Emilio Domínguez-Fernández, Jochen Börgermann, Martin Reuter, Udo Obertacke
In summary, the data presented in this section show that there is good evidence to conclude that macrophages have a key role in the development of endotoxin tolerance. As shown in Table 1, the tolerance-inducing/desensitizing effects of endotoxin have been studied using different experimental approaches, including macrophages of tolerant hosts and in vitro LPS-desensitized cells. Although there are some properties in common between the different systems, e.g., a decreased capacity to form TNF, other parameters differ considerably. For example, desensitization of monomac 6 cells increases IL-10 synthesis, while it is blocked in desensitized human monocytes and monocytes or macrophages from endotoxin-tolerant humans or mice. Such differences are equally seen for NO synthesis: in macrophages from endotoxin-tolerant rats NO synthesis is increased, while desensitized monocytes show decreased NO production. Of interest, there may be organ differences, since in lungs of endotoxin-tolerant mice, NO synthesis was found to be decreased, while it was increased in the serum of tolerant rats challenged with LPS. Care should, therefore, be taken in extrapolating properties determined in isolated cells or cell lines to endotoxin tolerance in general.
GATA2 Deficiency
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
GATA2 deficiency displays high (>90%) penetrance and variable expressivity. Despite their shared genetic background (all with inactivating GATA2 mutations), diseases grouped under GATA2 deficiency (i.e., MonoMAC syndrome, Emberger syndrome, familial MDS/AML, DCML, NK cell deficiency, CMML, aplastic anemia, and chronic neutropenia) each shows a specific constellation of signs and symptoms. In addition, individuals with identical GATA2 gene mutations may exhibit vastly different presentations.
Germ line predisposition to myeloid malignancies appearing in adulthood
Published in Expert Review of Hematology, 2018
Martina Crysandt, Kira Brings, Fabian Beier, Christian Thiede, Tim H Brümmendorf, Edgar Jost
GATA-binding protein 2 (GATA2) is a zinc finger protein acting as a transcription factor for hematopoiesis and lymphatic vessel genesis. In addition to predisposition for MDS and AML, germ line mutations in GATA2 are associated with MonoMAC and Emberger syndrome [47,48]. Patients with the same mutation can display significant interindividual variability in the clinical phenotype and the association between a specific GATA2 mutation and the individual clinical phenotype is not well understood. In patients with a MonoMAc syndrome, mutations are most often detected in the zinc finger-2 domain [49]. The development of MDS and rapid transformation in AML in families with a GATA2 mutation occurs at high penetrance and typically at young age and is often associated with acquired additional sex combs like 1 (ASXL1) mutations, monosomy 7 and a hypocellular, fibrotic bone marrow [50]. Patients with a MonoMAC syndrome suffer from severe monocytopenia, NK- and B-cell deficiency and a decrease in dendritic cells [49]. As a consequence, they often present with opportunistic viral and mycobacterial infections, pulmonary alveolar proteinosis as well as the development of MDS, chronic myelomonocytic leukemia and AML (Table 5). Myeloid disorders arise in early adulthood and the patient’s bone marrow shows a hypocellular and fibrotic aspect associated with multilineage dysplasia, monosomy 7, trisomy 8, or trisomy 1q at chromosomal analysis.