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1.
Pharmacogenomics with red cells: a model to study protein variants of drug transporter genes.
Flegel, WA, Srivastava, K, Sissung, TM, Goldspiel, BR, Figg, WD
Vox sanguinis. 2021;(2):141-154
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Abstract
The PharmacoScan pharmacogenomics platform screens for variation in genes that affect drug absorption, distribution, metabolism, elimination, immune adverse reactions and targets. Among the 1,191 genes tested on the platform, 12 genes are expressed in the red cell membrane: ABCC1, ABCC4, ABCC5, ABCG2, CFTR, SLC16A1, SLC19A1, SLC29A1, ATP7A, CYP4F3, EPHX1 and FLOT1. These genes represent 5 ATP-binding cassette proteins, 3 solute carrier proteins, 1 ATP transport protein and 3 genes associated with drug metabolism and adverse drug reactions. Only ABCG2 and SLC29A1 encode blood group systems, JR and AUG, respectively. We propose red cells as an ex vivo model system to study the effect of heritable variants in genes encoding the transport proteins on the pharmacokinetics of drugs. Altered pharmacodynamics in red cells could also cause adverse reactions, such as haemolysis, hitherto unexplained by other mechanisms.
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Red blood cells as an organ? How deep omics characterization of the most abundant cell in the human body highlights other systemic metabolic functions beyond oxygen transport.
Nemkov, T, Reisz, JA, Xia, Y, Zimring, JC, D'Alessandro, A
Expert review of proteomics. 2018;(11):855-864
Abstract
Recently, the classification of two 'novel' organs, the mesentere and interstitium, was saluted as a scientific breakthrough and disseminated into mainstream media. The novelty of these findings did not pertain to the characterization of some previously unexplored phenomena, rather to the appreciation that well-established tissues may play some hitherto unexplored functions critical to system homeostasis. Areas covered: Here we provocatively comment on the potential classification of red blood cells - by far the most abundant host cell in the human body (~ 83% of the total cells) - as an organ involved in many functions beyond gas transport. In this perspective article, we describe some of these functions with a special emphasis on the role erythrocytes play with respect to systemic metabolic homeostasis. We thus focus on how these functions modulate the cross talk of red blood cells among each other and with other cell types including immune cells. Expert commentary: The appreciation of RBCs as an organ impacting systemic metabolic homeostasis and other cell functions while engaging in complex metabolic activity beyond oxygen transport can foster the development of novel therapeutic interventions in pathologic hypoxemia, inflammation, neurodgenerative diseases, aging, and cancer.
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Transfusion-related immunomodulation: a reappraisal.
Youssef, LA, Spitalnik, SL
Current opinion in hematology. 2017;(6):551-557
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Abstract
PURPOSE OF REVIEW This review summarizes current and prior observations regarding transfusion-related immunomodulation (TRIM) and puts these ideas into a modern immunological context, incorporating concepts from innate, adaptive, and nutritional immunity. We propose that TRIM research focus on determining whether there are specific, well-defined immunosuppressive effects from transfusing 'pure' red blood cells (RBCs) themselves, along with the by-products produced by the stored RBCs as a result of the 'storage lesion.' Macrophages are a key cell type involved in physiological and pathological RBC clearance and iron recycling. The plasticity and diversity of macrophages makes these cells potential mediators of immune suppression that could constitute TRIM. RECENT FINDINGS Recent reports identified the capacity of macrophages and monocytes to exhibit 'memory.' Exposure to various stimuli, such as engulfment of apoptotic cells and interactions with ß-glucan and lipopolysaccharide, were found to induce epigenetic, metabolic, and functional changes in certain myeloid cells, particularly macrophages and monocytes. SUMMARY Macrophages may mediate the immunosuppressive aspects of TRIM that arise as a result of transfused RBCs and their storage lesion induced by-products.
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4.
Cellular immune responses in red blood cell alloimmunization.
Zimring, JC, Hudson, KE
Hematology. American Society of Hematology. Education Program. 2016;(1):452-456
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Abstract
In excess of 340 blood group antigens have now been described that vary between individuals. Thus, any unit of blood that is nonautologous represents a significant dose of alloantigen. Most blood group antigens are proteins, which differ by a single amino acid between donors and recipients. Approximately 1 out of every 70 individuals are transfused each year (in the United States alone), which leads to antibody responses to red blood cell (RBC) alloantigens in some transfusion recipients. When alloantibodies are formed, in many cases, RBCs expressing the antigen in question can no longer be safely transfused. However, despite chronic transfusion, only 3% to 10% of recipients (in general) mount an alloantibody response. In some disease states, rates of alloimmunization are much higher (eg, sickle cell disease). For patients who become alloimmunized to multiple antigens, ongoing transfusion therapy becomes increasingly difficult or, in some cases, impossible. While alloantibodies are the ultimate immune effector of humoral alloimmunization, the cellular underpinnings of the immune system that lead to ultimate alloantibody production are complex, including antigen consumption, antigen processing, antigen presentation, T-cell biology, and B-cell biology. Moreover, these cellular processes differ to some extent with regard to transfused RBCs as compared with other better-studied immune barriers (eg, infectious disease, vaccines, and solid organ transplantation). The current work focuses on illustrating the current paradigm of humoral immunity, with a specific focus on particulars of RBC alloimmunization and recent advances in the understanding thereof.
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Malaria parasites and red cell variants: when a house is not a home.
Taylor, SM, Fairhurst, RM
Current opinion in hematology. 2014;(3):193-200
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Abstract
PURPOSE OF REVIEW Multiple red cell variants are known to confer protection from malaria. Here, we review advances in identifying new variants that modulate malaria risk and in defining molecular mechanisms that mediate malaria protection. RECENT FINDINGS New red cell variants, including an innate variant in the red cell's major Ca²⁺ pump and the acquired state of iron deficiency, have been associated with protection from clinical falciparum malaria. The polymorphisms hemoglobin C (HbC) and hemoglobin S (HbS) - known to protect carriers from severe falciparum malaria - enhance parasite passage to mosquitoes and may promote malaria transmission. At the molecular level, substantial advances have been made in understanding the impact of HbS and HbC upon the interactions between host microRNAs and Plasmodium falciparum protein translation; remodeling of red cell cytoskeletal components and transport of parasite proteins to the red cell surface; and chronic activation of the human innate immune system, which induces tolerance to blood-stage parasites. Several polymorphisms have now been associated with protection from clinical vivax malaria or reduced Plasmodium vivax density, including Southeast Asian ovalocytosis and two common forms of glucose-6-phosphate dehydrogenase deficiency. SUMMARY Red cell variants that modulate malaria risk can serve as models to identify clinically relevant mechanisms of pathogenesis, and thus define parasite and host targets for next-generation therapies.
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Human erythrocyte remodelling during Plasmodium falciparum malaria parasite growth and egress.
Mbengue, A, Yam, XY, Braun-Breton, C
British journal of haematology. 2012;(2):171-9
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Abstract
The intra-erythrocyte growth and survival of the malarial parasite Plasmodium falciparum is responsible for both uncomplicated and severe malaria cases and depends on the parasite's ability to remodel its host cell. Host cell remodelling has several functions for the parasite, such as acquiring nutrients from the extracellular milieu because of the loss of membrane transporters upon erythrocyte differentiation, avoiding splenic clearance by conferring cytoadhesive properties to the infected erythrocyte, escaping the host immune response by exporting antigenically variant proteins at the red blood cell surface. In addition, parasite-induced changes at the red blood cell membrane and sub-membrane skeleton are also necessary for the efficient release of the parasite progeny from the host cell. Here we review these cellular and molecular changes, which might not only sustain parasite growth but also prepare, at a very early stage, the last step of egress from the host cell.
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The eye in cerebral malaria: what can it teach us?
Maude, RJ, Dondorp, AM, Abu Sayeed, A, Day, NP, White, NJ, Beare, NA
Transactions of the Royal Society of Tropical Medicine and Hygiene. 2009;(7):661-4
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Abstract
The pathophysiology of coma in cerebral malaria (CM) is not well understood. Obstruction of microcirculatory flow is thought to play a central role, but other hypotheses include roles for parasite- and host-derived factors such as immune mediators, and for increased blood-brain barrier permeability leading to raised intracranial pressure. The retinal vasculature is a direct extension of the cerebral vasculature. It is the only vascular bed easily accessible for visualisation and provides a unique opportunity to observe vascular pathology and its effect on neurological tissue. A specific retinopathy has been well described in African children with CM and its severity correlates with outcome. This retinopathy has been less well described in adults. The central mechanism causing malarial retinopathy appears to be microvascular obstruction, which has been demonstrated in affected retinas by fluorescein angiography. The presence in a central nervous system tissue of microvascular obstruction strongly supports the hypothesis that the sequestration of erythrocytes in small blood vessels and consequent obstruction of microcirculatory flow is an important mechanism causing coma and death in CM. Despite advances in the antimalarial treatment of severe malaria, its mortality remains approximately 15-20%. Adjunctive treatment targeting sequestration is a promising strategy to further lower mortality.
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Red blood cell transfusion therapy and iron chelation in patients with myelodysplastic syndromes.
Malcovati, L
Clinical lymphoma & myeloma. 2009;:S305-11
Abstract
Anemia is the most frequent peripheral cytopenia observed in myelodysplastic syndromes (MDS) and has been recognized among the most important factors affecting the outcome of patients with MDS. In patients who are not candidates for potentially curative approaches, therapeutic options for symptomatic anemia include red blood cell (RBC) transfusion and iron chelation, hematopoietic growth factors, immunosuppression, immune-modulatory drugs, and hypomethylating agents. In about 40% of patients, regular RBC transfusions are the only therapeutic option that can be offered. The onset of a regular transfusion requirement significantly worsens the survival of patients with MDS. Transfusion-dependent patients invariably develop secondary iron overload. Elevated serum ferritin was proven to be associated with worse survival in transfusion-dependent patients, and recent data obtained using magnetic resonance imaging show both hepatic and myocardial iron accumulation in heavily transfused patients. According to evidence-based guidelines, patients with sideroblastic anemia, 5q- syndrome, or other forms of refractory anemia, in whom long-term transfusion therapy is likely, are recognized as the best candidates to receive iron chelation therapy. In addition, patients who are candidates for allogeneic stem cell transplantation might also benefit from chelation therapy because iron overload is associated with increased transplantation-related mortality. RBC transfusions and iron chelation are the mainstay of therapy for many individuals with MDS. However, critical issues remain to be clarified in order to optimize treatment, including the identification of target hemoglobin levels to prevent anemia-related morbidity and more accurate information on the effect of iron-mediated organ damage on the outcome of patients with MDS.
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[Hereditary enzyme defects of erythrocytes: glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency].
Sedano, II, Röthlisberger, B, Huber, AR
Therapeutische Umschau. Revue therapeutique. 2006;(1):47-56
Abstract
Possible causes for a normocytic hyperregeneratory anemia are beside an incomplete treatment of iron deficiency, vitamin B12 deficiency or folic acid deficiency notably a hemolysis. After exclusion of other causes of hemolysis like immune hemolytic anemias, microangiopathic hemolytic anemias and hemoglobinopathies, an enzyme deficiency of erythrocytes should be considered. By far the most common form worldwide is the Glucose-6-phosphate deficiency. In the most frequent variants of this disease hemolysis occurs only during stress, imposed for example by infection, "oxidative" drugs or after ingestion of fava beans. The most serious clinical complication of the Glucose-6-phosphate deficiency is the rarely observed neonatal icterus. Some enzyme variants can cause chronic hemolysis which is described as chronic nonsperocytic hemolytic anemia. This form of chronic anemia can also be caused by other enzyme deficiencies, most frequently by the Pyruvate kinase deficiency. All other deficiencies of glycolytic enzymes are even rarer. It should be noted that in some of these very rare forms neurological rather than hematological symptoms predominate the clinical syndrome. If there is suspicion, on the basis of clinical symptoms and/or familial history, diagnosis of an enzyme deficiency can be achieved relatively easy by measurement of the enzyme activity. Accurate diagnosis might be helpful in therapeutic decisions (e.g. splenectomy in certain forms) and it is essential for genetic counseling, since certain deficiencies are transmitted as autosomal recessive disorders (e.g. pyruvate kinase deficiency), while the most common form, the glucose-6-phosphate dehydrogenase deficiency is linked to the X-chromosome.
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The impact of different intensities of regular donor plasmapheresis on humoral and cellular immunity, red cell and iron metabolism, and cardiovascular risk markers.
Tran-Mi, B, Storch, H, Seidel, K, Schulzki, T, Haubelt, H, Anders, C, Nagel, D, Siegler, KE, Vogt, A, Seiler, D, et al
Vox sanguinis. 2004;(3):189-97
Abstract
BACKGROUND AND OBJECTIVES Major studies are still lacking on the impact of differing intensities of long-term donor plasmapheresis, not only on total serum protein, albumin and immunoglobulin G (IgG), but also on humoral and cellular immunity, red cell and iron metabolism, and biochemical cardiovascular risk markers. MATERIALS AND METHODS Three groups of donors, comprising 483 individuals undergoing differing intensities of long-term serial plasmapheresis, were entered into a cross-sectional study. A fourth control group consisted of 100 non-donors. In addition to measuring total protein, albumin and IgG levels, we determined parameters of humoral and cellular immunity, red cell and iron metabolism and recognized biochemical cardiovascular risk factors. RESULTS The median annual net amount of plasma donated by the three donor groups was 37, 16 and 10 l, respectively (P < 0.0001). Donors had significantly lower total serum protein, albumin and IgG levels than non-donors (P < 0.0001), but the intensity of plasmapheresis had no influence on those parameters. Like non-donors, all plasma donors had normal humoral and cellular immunity. No increased rates of iron store depletion were observed in the three groups of plasma donors. Plasma donors were not at increased cardiovascular risk. CONCLUSIONS Regular donor plasmapheresis of up to 45 l of plasma per year appears to be as safe as more moderate plasmapheresis programmes, with respect to the parameters analysed in this study. Individuals donating under these conditions did not develop impaired humoral and cellular immunity, iron store depletion, or increased cardiovascular risk with regard to established biochemical risk markers. Prospective studies are required to determine more exactly than in retrospective analyses the reasons why donors withdraw from plasmapheresis programmes.