Composition of the intra‐erythroblastic precipitates in thalassaemia and congenital dyserythropoietic anaemia (CDA): identification of a new type of CDA with intra‐erythroblastic precipitates not reacting with monoclonal antibodies to α‐ and β‐globin chains

Abstract

Ultrathin sections of bone marrow cells from two patients with homozygous beta-thalassaemia, two patients with haemoglobin H (HbH) disease, a patient with congenital dyserythropoietic anaemia (CDA) type III and two patients with severe congenital dyserythropoietic anaemia of an unusual type were reacted with mouse monoclonal antibodies against various globin chains and the reaction visualized using a gold-labelled goat antibody against mouse IgG. The multiple rounded intra-erythroblastic inclusions found in homozygous beta-thalassaemia reacted with the monoclonal antibody against alpha-globin chains but not beta-globin chains, thus confirming that they consisted of precipitated alpha-globin chains. The branching intra-erythroblastic inclusions found in HbH disease and CDA type III reacted with the monoclonal antibody against beta-globin chains but not alpha-globin chains, indicating that they consisted of precipitated beta-globin chains. The two patients with severe CDA had been transfusion-dependent since infancy, had a normal alpha:beta globin chain synthesis ratio or parents with normal red cell indices, displayed prominent dysplastic changes in their erythroblasts, and had intra-erythroblastic inclusions resembling those seen in homozygous beta-thalassaemia. However, unlike those in beta-thalassaemia, the inclusions in these two patients did not react with the monoclonal antibody against either alpha- or beta-globin chains. The inclusions reacted with antibody against zeta-globin chains, but detailed studies in one of the patients indicated that the antigen involved was not zeta-globin. These patients have features not reported in the condition known as dominantly inherited inclusion body beta-thalassaemia and appear to suffer from a novel type of CDA in which the intra-erythroblastic inclusions may consist of some non-globin protein or structurally-abnormal alpha-globin chains.

Protein Quality Control During Erythropoiesis and Hemoglobin Synthesis

“…(110, 112, 113) Immuno-electron microscopy confirmed that the β-thalassemic inclusions contain α globin (but not β globin) and also ubiquitin, consistent with the presence of ubiquitinated α globin chains targeted for degradation by the UPS. (114, 115) Ultrastructural studies also revealed β-thalassemic α globin inclusions in autophagic vacuoles, suggesting elimination by macroautophagy. (110, 112) Similar inclusions containing both α and β globin were found in patients with dominantly-inherited β-thalassemia caused by mutations that destabilize β globin chains.…”

Quantitative proteomics of plasma vesicles identify novel biomarkers for hemoglobin E/β-thalassemic patients

“…The main pathophysiology of b-thalassemia is a reduction of b-globin chain production, which causes the unpaired a-globin chains to form an irreversible hemichrome that precipitates on the erythroid membrane. 1,2 The hemichrome or availability of free iron via the Fenton reaction results in the production of reactive oxygen species (ROS) that initiate oxidative stress and cell membrane damage. Hemoglobin E (HbE) is an abnormal hemoglobin generated due to a cryptic splice site at codon 26 of exon 1 of the HBB gene (HBB:c.79G.A [p.Glu27Lys]).…”

Dyserythropoiesis and Congenital Dyserythropoietic Anaemias

“…Two transfusion-dependent patients with this condition have been reported. Both had marked splenomegaly, a normal MCV, non-specific dysplastic changes in erythroblasts and intraerythroblastic inclusions that appear to consist of some non-globin protein (Wickramasinghe et al, 1996b). These patients must be distinguished from those with dominantly-inherited inclusion body b-thalassaemia who are not transfusion-dependent and have a low MCV, non-specific dysplastic changes in some erythroblasts and intraerythroblastic inclusions composed of both a-and b-globin chains (Thein et al, 1990;Ho et al, 1997).…”