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The Inducible Defense System: The Induction and Development of the Inducible Defence
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael A. Hickey, Diane Wallace Taylor
The antigen-specific receptor on T cells is called the T cell receptor (TcR) and is similar in structure to the receptor on B cells (Figure 8.2). It consists of the 40–50 kDa alpha chain which is joined to the 40–45 kDa beta chain. These two glycosylated protein chains are linked by a disulfide bond. Most T cells express alpha/beta TcR, which is highly specific for antigen. T cell receptors, however, cannot bind directly to intact antigen. They only bind to protein antigens, and these proteins must first be internalized by another cell, which digests the protein into peptides, and then presents the peptides on its cell surface. The process is known as antigen processing and presentation and the cells involved in this process are known as antigen presenting cells (APC.
Haematological disorders
Published in Judy Bothamley, Maureen Boyle, Medical Conditions Affecting Pregnancy and Childbirth, 2020
Alpha thalassaemia relates to the number of α (alpha) globin chains that are deleted. Normal haemoglobin A has two alpha globin chains. The production of the alpha globin chains is controlled by four genes, two genes inherited from each parent. The alpha chain is essential, as it is present in all types of haemoglobin and the more alpha chains missing, the greater the defect. See Table 6.1 for possible combinations, their clinical significance and implications for pregnancy.
Haematological disorders
Published in Judy Bothamley, Maureen Boyle, Medical Conditions Affecting Pregnancy and Childbirth, 2020
The alpha chain is essential, as it is present in all types of haemoglobin and if this chain is omitted the condition known as alpha thalassaemia major is incompatible with life, with fetal demise occurring due to severe anaemia and hydrops, unless – rarely – intrauterine blood transfusion is carried out. There are normally two pairs (i.e., four) of alpha globin genes and if one or two of these genes are missing the result is the alpha thalassaemia trait. A chronic haemolytic anaemia with normal life expectancy called haemoglobin H, or alpha thalassaemia intermedia, is where there is deletion of three alpha globin chains. Antenatal screening includes detecting those with carrier status for a number of alpha thalassaemia traits.
An expert review of voxelotor for the treatment of hemolytic anemia in patients with sickle cell disease: ‘bridging the gap between laboratory data and patient related outcomes’
Published in Expert Review of Hematology, 2023
Baba P. D. Inusa, Khuthala Mnika, Samah Babiker
Voxelotor acts by increasing oxygen affinity directly, reduces the polymerization of HbS and reduces RBC hemolysis leading to an increase in Hb values [9]. It increases the oxygen affinity by reversibly binding to the alpha-chain of HbS in a dose-dependent manner and reduces hemolysis [2,10]. This increase in hemoglobin is offset by the reduced oxygen delivery to the tissues due to increased oxygen affinity. Voxelotor offers a new mechanism of action for treating SCD by modulating hemoglobin oxygen affinity; it forms a reversible covalent bond with the N-terminal of the alpha chain. This results in allosteric modification of Hb by increasing oxygen affinity and decreasing the level of deoxygenation, thus reducing the level of RBC polymerization. Voxelotor is orally absorbed with a bioavailability of about 36 hours and the percentage reversible RBC–voxelotor binding is 20–30% [11]. The combination of hemolysis and anemia is responsible for a wide variety of complications in SCD, from acute hypoxia to end organ damage such as pulmonary hypertension, renal disorder, and stroke [12,13]. The potential benefit from a direct reduction in HbS polymerization and hemolysis is the improvement in anemia and RBC health [4,8,9]
A deep dive into future therapies for microcytic anemias and clinical considerations
Published in Expert Review of Hematology, 2023
François Rodrigues, Tereza Coman, Guillemette Fouquet, Francine Côté, Geneviève Courtois, Thiago Trovati Maciel, Olivier Hermine
Advances in the understanding of IE during beta-thalassemia relied on the discovery of the pivotal role of caspases during erythropoiesis. Caspases were initially thought to play an exclusively negative role in erythropoiesis, since it had been shown that EPO deprivation triggers erythroid precursors apoptosis via caspase 3 and 9 activations [148–150]. In addition, local production of Fas in the bone marrow tampers the erythrocytes production through caspase-8 dependent extrinsic apoptosis [149,150]. However, caspases 3, 9, and 2 are also activated during normal erythropoiesis, albeit in a transitory fashion [150]. Inhibiting caspase activation in vitro prevents erythroblasts maturation [151]. Interestingly, classical targets of caspase-3, such as Acinus or lamin B, are cleaved during erythropoiesis, while others such as the erythroid differentiation factor GATA-1 are not [151]. The role of Hsp70, a protein chaperone which translocates in the nucleus during erythropoiesis to protect GATA-1 from caspase-3 mediated cleavage, explains these observations [152]. This mechanism is disrupted in beta-thalassemia, in which confocal microscopy studies have shown that free alpha-chain aggregates segregate Hsp70 in the cytoplasm and preclude its nuclear translocation [153]. Unprotected GATA-1 is then cleaved by caspase-3. GATA-1 action being necessary for erythroid survival during differentiation, thalassemic erythroblasts undergo apoptosis, explaining ineffective erythropoiesis [153,154].
Homeobox A5 and A9 expression and beta-thalassemia
Published in British Journal of Biomedical Science, 2021
EAE Badr, IE-T El-Sayed, MKR Alasadi
β-thalassemia is a spectrum of hereditary blood disorders characterized by defects in the synthesis of the β chains of haemoglobin resulting in a range of phenotypes from severe anaemia to clinically asymptomatic individuals [1,2]. The severity of symptoms is related to the extent of absent production of β-globin chain. The genotypic variability of β-globin synthesis is designated as β(+) for decreased production and β(0) for absent production. The phenotypic variability is designated as either minor, intermediate, or major. β-thalassemia minor is heterozygosity with one unaffected beta-globin gene and one affected, either β(+) or β(0). Homozygosity or compound heterozygosity with β(+) or β(0) causes intermediate and major. These are distinguished clinically by the severity of anaemia and not by genotype [3]. The molecular defects in β-thalassemia result in absent or reduced β-chain production. Alpha chain synthesis is unaffected, and hence there is an imbalanced globin chain production leading to an excess of α chains. In the absence of their partners, they are unstable, and they precipitate in the red cell precursors, giving a rise to large intracellular inclusions, which interferes with red cell maturation [4]. Hence, the pathogenesis of β-thalassemia has been attributed to ineffective erythropoiesis due to intramedullary apoptosis and delayed maturation of erythroid progenitor cells [5].