There have been no reports of severe haemolytic disease of the newborn (HDN) due to Gerbich (Ge) antibodies. Two babies with HDN due to anti-Ge3, both born to the same mother, are described. The anti-Ge appeared in the first pregnancy and was not detectable in the first trimester, the babies' reticulocyte and bilirubin values were not greatly elevated (similar to HDN due to Kell antibodies), and the anaemia in both cases was either not apparent or not severe until 2 to 4 weeks after birth. Ge antigens are found on glycophorins (GPs) C and D; GPC, like Kell, has been shown to be expressed early on erythroid progenitor cells. The maternal anti-Ge3 was shown to promote phagocytosis of Ge+ early erythroid progenitors by monocytes (similar to what has been reported with anti-K and K+ progenitor cells). Thus, anti-Ge3 may cause immune destruction of erythroid progenitors and possibly suppression of erythropoiesis (which would explain the reticulocyte and bilirubin values seen in both cases). Anti-Ge3 appears to be capable of causing severe HDN. We suggest that babies born to mothers with anti-Ge should have their haemoglobin concentrations monitored for signs of anaemia for several weeks after birth. Functional assays may prove useful.
The monoclonal antibody-specific immobilization of erythrocyte antigens (MAIEA) technique is an immunoassay devised primarily for locating blood group antigens on specific red-cell membrane proteins. The assay involves the incubation of intact red cells with two antibodies, one human alloantibody, the other a nonhuman antibody, usually a rodent monoclonal antibody, but polyclonal antibodies of rabbit origin have been utilized. For a positive result, both antibodies must bind to the same membrane protein. The red cells are lysed, the membrane solubilized and the trimolecular complex of two antibodies and membrane protein is captured in a well coated with goat antirodent (or rabbit) immunoglobulin. The immobilized complex is then detected by the use of peroxidase-conjugated goat antihuman (or rodent) immunoglobulin. Negative results, due to mutual blocking between the human and animal antibodies when their epitopes are close together on the same molecule, have permitted a degree of localization of epitopes on some proteins. This has been most effective in the mapping of Cromer blood group system antigens on the complement control protein domains of decay-accelerating factor (DAF, CD55), but has also proved informative in the clustering of antigens on the Lutheran and Kell glycoproteins. MAIEA is an effective tool for the identification of antibodies to Knops-system antigens on complement receptor 1 (CR1, CD35) in immunohaematology reference laboratories. These antibodies are clinically unimportant, but must be identified before they can be ignored for transfusion purposes.
A distinction between CDAII and HS can be made using the EMA Binding test and anti-CD44 binding. Confirmation of CDAII can subsequently be made based on clinical presentation together with either bone marrow examination or DNA sequencing of SEC23B. © 2016 International Clinical Cytometry Society.
Kna, McCa, Sla and Yka are red cell antigens of relatively high frequency, located on complement receptor 1 (CR1, CD35). Antibodies to these Knops system antigens are not uncommon. They are not haemolytic and do not reduce the survival of transfused incompatible red cells, but they are a nuisance in transfusion laboratories as they can cause an incompatible crossmatch and must be identified before they can be dismissed as clinically insignificant. Human red cell alloantibodies can be shown to be Knops system antibodies by the monoclonal-antibody-specific immobilization of erythrocyte antigens (MAIEA) test, using murine monoclonal anti-CR1. In addition to confirming that Kna, McCa, Sla and Yka are located on CR1, the MAIEA test was used to confirm that Csa is not on CR1. Red cells of the Helgeson phenotype, the null phenotype of the Knops system by conventional serological methods, have levels of Kna, McCa, Sla and Yka intermediate between those of alpha-chymotrypsin-treated cells (which lack Knops system antigens) and those of positive control cells. Level of expression of Knops system antigens is very variable and intensity of staining of immunoblots probed with monoclonal anti-CR1 correlated with strength of Knops system antigens, as determined by the MAIEA test. In individuals heterozygous for alleles producing different allotypes, separate bands representing each allotype on an immunoblot showed identical intensity of staining, suggesting that the quantity of CR1 on red cells is controlled, at least in part, by a locus independent of CR1. An analysis of CR1 on red cells of individuals who have made Knops system antibodies suggested that the Knops system antigens and the antibodies that detect them are complex and heterogeneous.
The novel tyrosine kinase inhibitor nilotinib is equipotent with imatinib and does not induce apoptosis in CML stem cells Chronic myeloid leukaemia (CML) is a myeloproliferative disorder of stem cell origin characterised by a shortened 'Philadelphia' (Ph + ) chromosome 22. A novel oncoprotein BcrAbl is translated from the fusion oncogene, bcrabl, that arises from the t 9;22 reciprocal translocation. BcrAbl is a constitutively active tyrosine kinase that upregulates diverse intracellular signal transduction pathways resulting in multiple adverse effects on cell processes including proliferation, differentiation and adhesion. The rationally designed tyrosine kinase inhibitor, imatinib mesylate (IM; GlivecÒ, Novartis Pharma, Switzerland) has proven highly effective in the treatment of CML with the majority of early chronic phase patients achieving complete cytogenetic remisssion and in some cases molecular remission. However, many advanced phase patients have developed clinical resistance. Previous in vitro studies by our group have highlighted a population of quiescent Ph + stem cells that persist and accumulate following IM exposure demonstrating the anti-proliferative effects of this drug. Nilotinib, (AMN 107; Novartis Pharma) is a novel Abl tyrosine kinase inhibitor specifically designed to be more selective for BcrAbl with activity against IM-resistant mutations. In the Ph + K562 cell line, nilotinib's IC50 was 30 ± 10 nm versus 600 ± 60 nM for IM consistent with its reported 20-fold increased potency. However, in primary CD34 + CML cells, nilotinib and IM were equipotent for inhibition of BcrAbl activity, with 5 lM of either compound producing equal but incomplete reduction in Crkl phosphorylation. CD 34 + cells were able to expand over 72 h with either drug up to 5 lM although there was a concentration dependent restriction of amplification. These results confirmed an anti-proliferative rather than pro-apoptotic effect of nilotinib. Morever, the most primitive cells persisted and accumulated over 72 h with nilotinib and remained caspase-3 negative. Combination of IM with nilotinib led to increased accumulation of this population suggesting at least additive anti-proliferative effects. Thus despite activity against IM resistant mutants, nilotinib may not improve clinical responses at the stem cell level with respect to IM.Introduction The study of erythroid progenitor cell proliferation and differentiation in vitro is essential if we are to achieve our goal of producing therapeutic quantities of red cells by cell culture. The mechanisms of cell regulation need to be appreciated and a cell culture environment developed for optimal cell renewal and growth. Changes in cell surface molecules and understanding of their function form an important part of the study together with knowledge about the genes involved in the erythropoietic process, including those genes involved in apoptosis. CD9, a member of the tetraspanin super family, is reportedly involved in tumour progression and metastasis and has been implicated ...
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