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Introduction. Chronic obstructive pulmonary disease (COPD) was associated with polycythemia as a result of respiratory failure and regarded as a compensatory response of erythropoiesis to chronic hypoxia for a long time. Recent epidemiological studies have shown that anemia is observed in 17.0-24.0 % of patients with COPD and only 6.0-10.0 % of such patients have polycythemia Aim. To find out the clinical and functional features of COPD course, depending on the red branch of blood and content of soluble transferrin receptors (sTFR). Materials and methods. The study enrolled 202 patients aged >40 years with COPD who have signed the consent to participate in the study. The exclusion criteria were: severe concomitant diseases (pulmonary tuberculosis, oncopathology, alcohol and/or drug addiction, AIDS, heart failure – class ІІВ stage III, and decompensated liver failure, kidney failure, or other failures); defined source of bleeding (complications of peptic ulcer, nonspecific ulcerative colitis, chronic hemorrhoids, etc.); diagnosed true anemias (megaloblastic, aplastic, hemolytic); use of angiotensin-converting enzyme inhibitors; pregnancy or lactation; chronic administration of systemic corticosteroids. All examined patients underwent the general clinical, laboratory and instrumental examination. The degree of obstruction and severity of the disease were determined in accordance with GOLD (2014) recommendations: the degree of obstruction was determined by computer spirography (FEVp detected 15 minutes after inhalation of 400.0 mcg of salbutamol), the severity of dyspnea was determined by the modified Medical Research Council (mMRC), and quality of life was determined by COPD Assessment Test (CAT). Patients with COPD were divided into 4 study groups depending on the hemogram parameters and sTFR: 1 group included 144 patients without anemia, 2 group – 33 with anemia of chronic disease (ACD), 3 group – 12 with erythrocytosis, and 4 group – 13 with iron deficiency anemia (IDA). Statistical analysis of the results was performed using SPSS-21 program. Results. As a result of the detailed analysis of the anamnesis, objective examination and laboratory results in patients from group 4, the cause of IDA was established, namely, 5 patients were diagnosed with chronic non-atrophic gastritis, 4 had chronic gastroduodenitis, 2 had peptic ulcer of stomach, 1 had peptic ulcer of duodenum, and in 1 – chronic gastroduodenitis and chronic pancreatitis with exocrine insufficiency. It has been found that ACD is present in patients with COPD II – IV stage of obstruction and is not observe among COPD patients with degree I obstruction. It is established that the frequency of ACD increases according to the degree of obstruction and the severity of the disease. Patients with COPD with ACD and IDA had significantly lower levels of FEVj compared to patients without anemia and erythrocytosis. It was revealed that patients with COPD with ACD and COPD with IDA had a higher rate according to CAT and, lower quality of life compared with patients without anemia and erythrocytosis accordingly. As a result of the correlation analysis, it was found that there is negative correlation between the degree of obstruction and the results of mMRC (r = – 0.591; p = 0.001) and CAT (r = – 0.608; p = 0.001). Consequently, dyspnea significantly increases and the quality of life decreases in the patients with COPD and ACD with the increase of the degree of obstruction. The frequency of exacerbations was higher in patients with COPD and ACD compared with other groups. Conclusions. Anemia is detected in 22.7 % of patients with COPD, specifically, IDA – in 6.4 % of patients, and ACD – in 16.3 %. The frequency of ACH increases with the degree of obstruction and the severity of COPD. Patients with COPD with anemia (ACD or IDA) have significantly lower levels of FEVP dyspnea and quality of life are significantly worsened with the increase of the obstruction degree in patients with COPD and ACD. The frequency of exacerbations was higher in patients with COPD and ACD.

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon–nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND–Dox–TF, CDT) was 10–100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL. Significance: Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.

Introduction. In recent years, determination of soluble transferrin receptor levels has been emerging as a test that can reliably indicate iron deficiency in various states, and that is non-invasive and easy to use. The aim of this study was: to determine reference values of soluble transferrin receptor concentrations in serums in our population, to examine the reliability of this method in the diagnosis of anemia due to iron deficiency and associated iron deficiency in anemia accompanying malignant hemopathies, and to identify possible limitations of the test in certain conditions. Material and Methods. The prospective research included 86 patients with anemia: 46 patients with iron deficiency anemia, and 40 patients with malignant hemopathies. The control group consisted of 40 healthy persons aging over 18. Results. Ferritin values were reduced in 76.1% of patients, while higher levels of soluble transferrin receptors appeared in 100% of patients with iron deficiency anemia. In patients with reduced serum ferritin levels, the soluble transferrin receptor/log ferritin index was statistically significantly higher than in patients in whom ferritin concentration was in the normal range (p Conclusion. Soluble transferrin receptors are useful in the diagnosis of iron deficiency anemia, especially when ferritin values are not reduced. The calculation of soluble transferrin receptor/log ferritin index is even more reliable. In patients with malignant hemopathies, the associated iron deficiency could be best indicated by soluble transferrin receptor/log ferritin index.

Muhammad Kashif Riaz,1 Xue Zhang,1 Ka Hong Wong,1 Huoji Chen,2 Qiang Liu,2 Xiaoyu Chen,1 Ge Zhang,1 Aiping Lu,1,3 Zhijun Yang1,31School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3Changshu Research Institute, Hong Kong Baptist University, Changshu Economic and Technological Development (CETD) Zone, Changshu, Jiangsu Province, People’s Republic of ChinaPurpose: Lung cancer has a high incidence rate worldwide with a 5-year survival rate of 18%, and is the leading cause of cancer-related deaths. The aim of this study is to augment therapeutic efficacy of quercetin (QR) for lung cancer therapy by targeting transferrin receptors, which are overexpressed and confined to tumor cells.Methods: In this study, T7 surface-functionalized liposomes loaded with QR (T7-QR-lip) having different T7 peptide densities (0.5%, 1% and 2%) were prepared by the film hydration method. T7 surface-functionalized liposomes were characterized and evaluated in terms of in vitro cytotoxicity and cellular uptake, 3D tumor spheroid penetration and inhibition capabilities, in vivo biodistribution and therapeutic efficacy in mice with orthotopic lung-tumor implantation by fluorescent and bioluminescent imaging via pulmonary administration.Results: In vitro, 2% T7-QR-lip exhibited significantly augmented cytotoxicity (∼3-fold), higher apoptosis induction and S-phase cell-cycle arrest. A prominent peak right-shift and enhanced mean fluorescence intensity was observed in A549 cells treated with T7 Coumarin-6 liposomes (T7-Cou6-lip), confirming the target specificity of T7 targeted liposomes; while, after treatment with T7-QR-lip and non-targeted QR-lip, no significant difference was observed in cellular uptake and in vitro cytotoxicity studies in MRC-5 (normal lung fibroblast) cells. T7-Cou6-lip showed higher fluorescence intensity in A549 cells and a significantly deeper penetration depth of 120 μm in the core of the tumor spheroids and T7-QR-lip produced significantly higher tumor-spheroid growth inhibition. The in vivo biodistribution study via pulmonary delivery of T7 1,1’-dioctadecyltetramethyl-indotricarbocyanine iodide liposomes demonstrated liposome accumulation in the lungs and sustained-release behavior up to 96 h. Further, T7-QR-lip significantly enhanced the anticancer activity of QR and lifespan of mice (p

Iron is the fundamental element for numerous physiological functions. Reduced ferrous (Fe2+) and oxidized ferric (Fe3+) are the two ionized iron states in the living organisms. In the cell membrane, divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of Fe2+, whereas transferrin receptors (TFR) carry transferrin (TF)-bound Fe3+. In this study we performed, for the first time, detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Using qPCR and immunocytochemistry we identified DMT1 and TFR in astrocytes in primary cultures, in acutely isolated astrocytes and in brain tissue preparations; in situ both DMT1 and TFR are concentrated in astroglial perivascular endfeet. Administration of Fe2+ or Fe3+ in low μM concentrations evoked Ca2+ signals in astrocytes in vitro and in vivo. Iron ions triggered increase in [Ca2+]i by acting through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibited astroglial Na+-K+-ATPase (NKA), which led to an elevation in cytoplasmic Na+ concentration (as measured by SBFI probe), thus reversing Na+/Ca2+ exchanger (NCX) thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulated phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus trigering InsP3 receptor-mediated Ca2+ release from the endoplasmic reticulum. Iron-induced Ca2+ signals promote astroglial release of arachidonic acid and prostaglandin E2 cytokines by activating cytosolic phospholipase A2 (cPLA2) and NF-κB signalling cascade. In summary, these findings reveal new mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload, in response to which astrocytes actively accumulate excessive iron and activate neuroprotective pathways.

Red blood cell production, or erythropoiesis, is a proliferative process that requires tight regulation. Erythropoietin (Epo) is a glycoprotein cytokine that plays a major role in erythropoiesis by triggering erythroid progenitors/precursors of varying sensitivity. The concentration of Epo in bone marrow is hypothesized to be suboptimal, and the survival of erythroid cells has been suggested to depend on Epo sensitivity. However, the key factors that control Epo sensitivity remain unknown. Two types of transferrin receptors (TfRs), TfR1 and TfR2, are known to play a role in iron uptake in erythroid cells. Here, we hypothesized that TfRs may additionally modulate Epo sensitivity during erythropoiesis by modulating Epo receptor (EpoR) signaling. Using an Epo-sensitive UT-7 (UT7/Epo) erythroid cell and human erythroid progenitor cell models, we report that iron-loaded transferrin, that is, holo-transferrin (holo-Tf), synergizes with suboptimal Epo levels to improve erythroid cell survival, proliferation, and differentiation. This is accomplished via the major signaling pathways of erythropoiesis, which include signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide-3-kinase (PI3K)/AKT. Furthermore, we found that this cooperation is improved by, but does not require, the internalization of TfR1. Interestingly, we observed that loss of TfR2 stabilizes EpoR levels and abolishes the beneficial effects of holo-Tf. Overall, these data reveal novel signaling properties of TfRs, which involve the regulation of erythropoiesis through EpoR signaling.

As they mature into erythrocytes during normal erythropoiesis, reticulocytes lose surface transferrin receptors before or concurrently with reticulin. Exosome release accounts for most of the loss of transferrin receptors from reticulocytes. During erythropoietic stress, reticulocytes are released early from hematopoietic tissues and have increased reticulin staining and transferrin receptors. Flow cytometry of dually stained erythrocytes of mice recovering from phlebotomy demonstrated delayed loss of reticulin and transferrin receptors during in vitro maturation compared to in vivo maturation, indicating that an in vivo process extrinsic to the reticulocytes facilitates their maturation. Splenectomy or macrophage depletion by liposomal clodronate inhibited in vivo maturation of reticulocytes and increased the numbers of reticulin-negative, transferrin receptor-positive cells during and after recovery from phlebotomy. This reticulin-negative, transferrin receptor-positive population was rarely found in normal mice. Transmission electron microscopy demonstrated that the reticulin-negative, transferrin receptor-positive cells were elongated and discoid erythrocytes, but they had intracellular and surface structures that appeared to be partially degraded organelles. The results indicate that maturation of circulating stress reticulocytes is enhanced by an extrinsic process that occurs in the spleen and involves macrophage activity. Complete loss of reticulin with incomplete loss of surface transferrin receptors in this process produces a reticulin-negative, transferrin receptor-positive erythrocyte population that has potential utility for detecting prior erythropoietic stresses including bleeding, hemolysis and erythropoietin administration, even after recovery has been completed. Am. J. Hematol. 91:875-882, 2016. © 2016 Wiley Periodicals, Inc.

Background Overexpression of transferrin receptors (TfRs), which are responsible for the intracellular uptake of ferric transferrin (Tf), has been described in various cancers. Although molecular biology methods allow the identification of different types of receptors in cancer cells, they do not provide features about TfRs internalization, quantification and distribution on cell surface. This information can, however, be accessed by fluorescence techniques. In this work, the quantum dots (QDs)' unique properties were explored to strengthen our understanding of TfRs in cancer cells. Methods QDs were conjugated to Tf by covalent coupling and QDs-(Tf) bioconjugates were applied to quantify and evaluate the distribution of TfRs in two human glioblastoma cells lines, U87 and DBTRG-05MG, and also in HeLa cells by using flow cytometry and confocal microscopy. Results HeLa and DBTRG-05MG cells showed practically the same TfR labeling profile by QDs-(Tf), while U87 cells were less labeled by bioconjugates. Furthermore, inhibition studies demonstrated that QDs-(Tf) were able to label cells with high specificity. Conclusions HeLa and DBTRG-05MG cells presented a similar and a higher amount of TfR than U87 cells. Moreover, DBTRG-05MG cells are more efficient in recycling the TfR than the other two cells types. General significance This is the first study about TfRs in human glioblastoma cells using QDs. This new fluorescent tool can contribute to our understanding of the cancer cell biology and can help in the development of new therapies targeting these receptors.

Leukemia is a typical blood cancer that is characterized by the numerous duplication and proliferation of white blood cells. The main aim of this study was to develop PTX-loaded multifunctional nanoparticles and target to leukemia cells. In this study, transferrin-decorated paclitaxel-loaded lipid nanoparticle (TPLN) was prepared with an aim to increase the chemotherapeutic efficacy in the leukemia cells. Results clearly showed the superior targeting potential of TPLN to the HL-60 cancer cells compared to that of the paclitaxel-loaded nanoparticles (PLN). To be specific, TPLN showed a significantly higher cytotoxic effect in the cancer cells compared to that of the PLN indicating the superior targeting efficiency of the Tf-decorated nanoparticle system. The IC50 value of TPLN was 0.45 μg/ml compared to 2.8 μg/ml for PLN. TPLN induced a most remarkable apoptosis of the cancer cells and much of the cells were distorted with huge presence of the apoptotic body formation. Importantly, TPLN showed a remarkable reduction in the viable cells proportion to ~ 65% with around ~ 30% apoptosis cells (early and late apoptosis). Overall, results clearly showed the targeting potential of ligand-conjugated lipid nanoparticle system to the leukemia cells that might pave the way for the successful cancer treatment.

Because both the host and pathogen require iron, the innate immune response carefully orchestrates control over iron metabolism to limit its availability during times of infection. Nutritional iron deficiency can impair host immunity, while iron overload can cause oxidative stress to propagate harmful viral mutations. An emerging enigma is that many viruses use the primary gatekeeper of iron metabolism, the transferrin receptor, as a means to enter cells. Why and how this iron gate is a viral target for infection are the focus of this review.

Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.

ObjectiveTo investigate associations between nutritional and non-nutritional variables and Fe status parameters, i.e. serum ferritin and soluble transferrin receptors (sTfR).DesignCross-sectional design. Fe status parameters were determined on a fasting venous blood sample. Nutritional variables were assessed using a 2 d food record and non-nutritional variables by a general questionnaire. A general linear model was used to investigate associations between the variables and Fe status parameters.SettingRegion of Ghent, Dutch-speaking part of Belgium.SubjectsRandom sample of 788 women (aged 18–39 years).ResultsMedian (interquartile range) ferritin and sTfR were 26·3 (15·9, 48·9) ng/ml and 1·11 (0·95, 1·30) mg/l, respectively. BMI and alcohol intake were positively associated and tea intake was negatively associated with serum ferritin. Women who used a non-hormonal intra-uterine device, who gave blood within the past year or who had been pregnant within the past year had lower serum ferritin values than their counterparts. Significant determinants of sTfR were smoking habit and pregnancy, with higher values for non-smokers and women who had been pregnant within the past year.ConclusionsThe present study indicates that contraceptive use, time since last blood donation, time since last pregnancy, BMI, alcohol and tea intake are determinants of Fe stores, whereas smoking habit and time since last pregnancy are determinants of tissue Fe needs. When developing strategies to improve Fe status, special attention should be given to women who use a non-hormonal intra-uterine device, gave blood within the past year and had been pregnant within the past year.

The inhibitory C-type lectin-like immunoreceptor KLRG1 enables mature NK cells and differentiated T cells to sense cadherin-expressing cells by ligating “classical” cadherins. Upon engagement of the KLRG1 ectodomain, an inhibitory signal emanates from the cytoplasmic immunoreceptor-tyrosine-based inhibition motif (ITIM), dampening functional responses of these lymphocytes. Malignancy-associated loss of cadherins has been proposed to relieve KLRG1-mediated inhibition of cytotoxic lymphocytes and thereby to contribute to tumor surveillance by an alternate mode of “missing self-recognition”. In this issue of the European Journal of Immunology, Schweier et al. [Eur. J. Immunol. 2014. 44: 1851–1856] propose another intriguing mechanism that may relieve KLRG1-mediated inhibition in the course of lymphocyte activation. Subsequent to identification of the transferrin receptor (TfR) as a component of a high molecular mass KLRG1 complex, they demonstrate that a fraction of mouse KLRG1 molecules undergoes disulfide-bonding with TfRs and colocalises with the latter at the cell surface. In functional terms, high levels of TfRs such as those found on activated lymphocytes were found to be associated with decreased KLRG1 inhibitory function, indicating that TfRs may sequester KLRG1 from interacting with cadherins. Hence, this unexpected liaison between KLRG1 and TfR may represent a regulatory link between metabolic activation and responses of lymphocytes.

Hypochromic microcytic anaemia includes iron deficiency, anaemia of chronic disorders, beta thalassemia trait and sideroblastic anaemia. To rule out the cause of hypochromic microcytic anaemia is a diagnostic difficulty. The conventional laboratory tests used for diagnosis have few disadvantages. Serum transferrin receptor (sTfR) is the most reliable method for assessment of body iron. Eighty four children were included in this study. They were further divided into four groups: iron deficiency anaemia (IDA), anaemia of chronic disorders (ACD), beta thalassemia trait (β TT) and controls. Children withIDAand ACD were diagnosed on the basis of history and serum iron profile. Subjects with β TT had HbA2 > 3.5%. sTfR were performed on all subjects. Level of sTfR in patients withIDAwas 5.79 μg/ml ± 1.3 μg/ml. In patients with anaemia of chronic disorders (ACD), β thalassemia trait and controls mean sTfR were 2.18 μg/ml ± 0.6 μg/ml, 2.1μg/ml ± 0.5 μg/ml and 2.0 μg/ml ± 0.5 μg/ml respectively. These results show level of sTfR was raised in IDA when compared with controls or ACD and β TT (p value

Purpose: The purpose of the study was to determine the incidence of iron deficiency in children undergoing therapy for phenylketonuria using serum transferrin receptor and ferritin concentrations. Methods: A 1-year study was conducted in 37 children 2 < 13 years old with phenylketonuria (8 fed Periflex [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14 fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor, and ferritin concentrations were assessed at baseline and 12 months and intakes of protein, iron, and vitamin C were evaluated at baseline and at 3-month intervals. Transferrin receptor and ferritin concentrations were analyzed for group differences by analysis of variance. Results: Mean protein, iron, and vitamin C intakes of all 3 groups of children were greater than Recommended Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children failed to contain 100% of Recommended Dietary Intakes for iron during study. The following number of children had iron status indices outside reference ranges at study end: 7 children, transferrin receptor/ferritin ratios; 4 children, transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation was found between iron intake and any index of iron status. Conclusions: The transferrin receptor/ferritin ratio appeared to be the most sensitive index of iron deficiency in this study. Reasons for iron deficiency with greater than recommended iron intakes by children with phenylketonuria may be multiple. Early assessment and therapy of iron deficiency may improve cognitive and behavioral outcomes of children with PKU.

Eighty multi-transfused beta-thalassemics--40 of them on regular transfusion (RT) (every 3-4 weeks) and 40 irregularly transfused (IT)-and 20 age- and-sex-matched controls were evaluated for serum erythropoietin (sEpo) and soluble serum transferrin receptors (sTfr) as indicators of erythropoietic activity. All subjects were studied for pre-transfusion hemoglobin (Hb), reticulocytic index (RI), serum ferritin, sEpo and sTfr. Results showed that the mean RI, sEpo and sTfr values were significantly higher in the IT group (2.8; 80 mU/ml; and 19 microg/ml, respectively) compared to the RT group (1.2; 35.2 mU/ml; and 13.9 microg/ml, respectively) and controls (1.1; 22.6 mU/ml; and 7 microg/ml, respectively) (p < 0.05); while only the mean sTfr value was significantly higher in the RT group compared to controls. The mean pre-transfusion Hb was significantly lower in the IT group (8 g/dl) compared to both the RT group (9.3 g/dl) and controls (12.5 g/dl) (p < 0.05); while the RT group level was significantly lower than controls. There was an inverse correlation between Hb level on one hand and sEpo (r = 0.324,p < 0.05), sTfr (r = -0.651, p < 0.05) and RI (r = -0.451, p < 0.05) on the other. In summary, sEpo, sTfr and RI could be used as accurate and reliable indicators of successful erythroid marrow suppression and for the determination of optimal pre-transfusion Hb level in thalassemia on an individual basis, with sTfr being the most sensitive indicator.

Aims—To determine eVects of maternal iron depletion and smoking on iron status of term babies using serum transferrin receptors (STfR) and their ratio to ferritin (TfR-F index) in cord blood. Methods—Iron, ferritin, STfR, and haemoglobin (Hb) concentration were measured and TfR-F index calculated in 67 cord /maternal blood pairs. Twenty six mothers were iron depleted (ferritin

To test the hypothesis that the quantities of circulating transferrin receptors are reduced in iron overload, we studied serum transferrin receptors and indirect measures of iron status in 150 subjects from rural Zimbabwe. We found significant inverse correlations between serum concentrations of transferrin receptors and ferritin, the ratio of ferritin to aspartate aminotransferase, and transferrin saturation (r ≥0.44; P 300 μg/L and transferrin saturation >60%) was 1.55 ± 0.61 mg/L, significantly lower than the 2.50 ± 0.62 mg/L in 75 subjects with normal iron stores (ferritin 20–300 μg/L and transferrin saturation 15–55%; P

The regulation of transferrin-receptor synthesis was studied in J2E erythroid cells induced to differentiate with erythropoietin. Nuclear run-on assays demonstrated that transcription of the transferrin-receptor gene rose markedly after erythropoietin treatment. In addition, transferrin-receptor mRNA was stabilised and this was associated with an increase in the activity of the RNA-binding protein IRP (iron regulatory protein). As a result of increased transcription and mRNA stabilisation, steady-state RNA levels increased 10-20-fold. However, despite these large increases in mRNA, translation only doubled; consequently, modest increases in total protein and surface transferrin receptors were observed. Moreover, this rise in transferrin receptors was transient, and correlated with a burst of proliferation shortly after erythropoietin treatment. The expected inverse relationship between transferrin receptors and ferritin did not occur during J2E maturation as translation of both ferritin subunits increased when transferrin-receptor mRNA levels rose. Analysis of mutant J2E clones incapable of synthesising haemoglobin revealed that surface transferrin-receptor levels were only 15-25% that of the parental erythroid line. We propose that the surface expression of transferrin receptors in J2E cells is governed by three factors: basal levels essential for normal growth in culture; elevated levels needed for haemoglobin synthesis; and a transient erythropoietin-induced increase that is required for the final burst of proliferation. It was concluded that the regulation of transferrin-receptor production in erythropoietin-stimulated J2E cells is complex and that there are several sites of control.

Dysfunction of cell membrane is a recognized consequence of the pathogenetic process underlying the β-thalassemia syndromes and it is reasonable to hypothesize that surface structures crucial for the development of erythroid lineage may also be affected. The study included six adult splenectomized patients with β-thalassemia intermedia. Expression of α4β1 integrin (CD49d/CD29), α5β1 integrin (CD49e/CD29) and transferrin receptor (CD71) on peripheral blood and bone marrow erythroblasts and on erythroid precursors grown in vitro was studied by flow cytometry and immunocytochemistry. Serum soluble transferrin receptor levels (sCD71) were also measured with enzyme-linked immunosorbent assay. In β-thalassemic patients, significant reduction of CD49d, CD29 and CD71 expression was found in peripheral blood nucleated red cells, compared to patients presenting with erythroblasts in the circulation because of other diseases. Marrow erythroblasts were also deficient for the same molecules against the erythroblasts in iron deficiency anemia. All molecules tested were greatly diminished on erythroid precursors developed in vitro from the patients' cells. Serum sCD71 levels were much higher in thalassemic patients in comparison to both patients with iron deficiency anemia and healthy individuals. The loss of certain integrins and CD71 from erythroid precursors in β-thalassemia intermedia could be attributed to a generalized membrane dysfunction, perhaps affecting the integrity of their transmembrane domains. The elevation of serum sCD71 levels may be the result of the increased red cell lineage turnover or, alternatively, may indicate increased shedding from the cells to prevent iron overload. In any case, further molecular study of the membrane components is warranted to provide a better understanding of the pathogenetic process in β-thalassemia syndromes.

A prospective hospital-based study was conducted to evaluate the efficacy of serum transferrin receptors in the detection of iron deficiency in pregnant women. The iron status of 100 pregnant women with single uncomplicated term pregnancies in the first stage of labor was established using standard laboratory measures. These included complete hemogram, red cell indices, serum iron, percent transferrin saturation, and serum ferritin. In addition, serum transferrin receptor (STFR) was estimated. The results of 81 women with complete laboratory profiles were analyzed. Thirty-five (43.2%) women were anemic (hemoglobin

Inoculation with viable, but not inactivated, Coxiella burnetii resulted in the increased expression of transferrin receptors (TfR) in the murine macrophage-like cell line J774A.1. This upregulation was evident in immunoblots as early as 6 h postinfection, with TfR levels continuing to increase through the first 24 h of infection. Fluorescent labeling revealed that TfR upregulation occurred throughout infected monolayers, eliminating the possibility that it reflected a response by a minor subset of host cells. In addition, TfR trafficking did not appear to be affected by C. burnetii infection. Consistent with the increase in TfRs, inoculation with viable C. burnetii resulted in a 2.5-fold increase in total cellular iron by 12 h postinoculation. Our further findings that the chelation of intracellular iron arrests C. burnetii replication and that C. burnetii metabolic activities in vitro are affected by iron concentration suggest that TfR upregulation is a salient factor in C. burnetii infection, and we speculate that it may represent a significant virulence mechanism.

Agonist-regulated redistribution of human beta 2-adrenergic receptors was examined in 293 cells. A specific antiserum recognizing the carboxyl-terminal hydrophilic domain of the receptor was developed, characterized, and used for immunocytochemical localization of receptors in fixed cells by conventional fluorescence and confocal fluorescence microscopy. The beta-adrenergic agonist isoproterenol induced redistribution of receptors from the surface of cells into small (less than 1 micron diameter) punctuate accumulations which were detected in cells within 2 min of agonist addition. The time course of receptor redistribution paralleled that of receptor sequestration measured by ligand binding, and receptor redistribution was reversible in the presence of the beta-adrenergic antagonist alprenolol. Optical sections imaged through cells by confocal microscopy localized receptor accumulations within the cytoplasm. To address the question of receptor internalization further, a mutant receptor possessing an engineered antigenic epitope in the amino-terminal hydrophilic domain was constructed, transfected into cells, and localized using both a monoclonal antibody recognizing the epitope tag (receptor ectodomain) and an antiserum recognizing the carboxyl terminus (receptor endodomain). In untreated cells most receptor antigen was detected at the cell surface, as assessed by accessibility to ectodomain antibodies in unpermeabilized specimens. In isoproterenol-treated cells, however, little receptor antigen was detected at the cell surface. Punctate receptor accumulations present in isoproterenol-treated cells were labeled by antibodies only following permeabilization of cells, as expected if these receptor accumulations were intracellular. Finally, internalized beta-adrenergic receptors colocalized with transferrin receptors, which are markers of endosomal membranes. These data provide several lines of evidence establishing that beta-adrenergic receptors undergo ligand-regulated internalization, they suggest that internalized receptors may be recycled back to the cell surface, and they provide the first direct indication that these processes involve the same endosomal membrane system passaged by constitutively recycling receptors.

Transferrin receptor expression in the monocyte-like cell line U937 was investigated during in vitro cultivation. U937 cells expressed a single class of high affinity surface transferrin receptors (KD approximately 4 nM), with apparent subunit Mr of 90-95,000 Da as determined by SDS-reducing PAGE. [125I]-transferrin binding studies on detergent-solubilized cells revealed that half to two-thirds of the total functional binding sites were located intracellularly. Radioligand binding, immunofluorescence and flow cytometry studies were performed on intact, detergent-solubilized, or saponin-permeabilized cells, using either transferrin or the anti-transferrin receptor monoclonal antibody OKT9 IgG. These studies demonstrated that functional and antigenic transferrin receptor levels were maximal on cells 24 h after subculture at low density and declined during the culture period. Scatchard analysis of radioligand binding data suggested that the decline in functional transferrin binding sites resulted from a decline in the number of available receptors. These results demonstrate that in U937 cells there is a density-dependent regulation of transferrin receptor expression, resulting in a loss of functional and antigenic receptors from both plasma membrane and intracellular locations.

We aimed to study the response of serum transferrin receptors (sTfR) to Fe supplementation in women of childbearing age with Fe-deficiency erythropoiesis (IDE) and Fe-deficiency anaemia (IDA). Primary screening was performed in 942 women ranging in age from 18 to 45 years. After Fe-related biochemical indices such as serum ferritin, Zn protoporphyrin and Hb were determined, the subjects were divided into four groups: normal, Fe store depletion, IDE and IDA. A total of 131 women were randomly selected from the normal, IDE and IDA groups. Subsequently, seventy-six women with IDE and IDA were given various doses of Fe (14 mg/d for IDE; 28 mg/d for IDA) with ferrousl-threonate capsules for twelve consecutive weeks. After receiving Fe supplements, the levels of Fe and sTfR were determined at weeks 0, 3, 6, 9 and 12.The levels of sTfR in women of childbearing age with IDE and IDA were significantly higher than those in the normal group. After receiving Fe supplements, the levels of sTfR were significantly decreased in women of childbearing age with IDE and IDA, while the levels of serum ferritin were significantly increased. In conclusion, STfR can be used as a reliable indicator for assessing the efficacy of Fe supplements.

AIMS--To investigate the proliferative activity (given by the Ki67 index) of the normal, atypical, and neoplastic urothelium and its relation to the cellular reactivity for the epidermal growth factor (EGFr) and transferrin (Tfr) receptors. METHODS--The Ki67 index and the level of EGFr and Tfr reactivity were determined on frozen sections from 82 patients with urothelial cancer. Relevant clinical material was reviewed to establish correlations with the degree of atypia and invasion. RESULTS--Morphologically normal urothelium, whether derived from controls or patients with cancer, exhibited a low Ki67 index (less than 0.1%) and weak receptor reactivity. In transitional cell carcinomas (TCCs) the Ki67 index was increased: it ranged between 0.7% and 10% in non-invasive and exceeded 10% in 88% of the invasive TCCs. Strong positive reactions for EGFr were seen only in invasive TCCs, but in 47% of invasive TCCs the EGFr was not "overexpressed" and did not match the Ki67 index. A better correlation was found between the Ki67 index and the Tfr which was positive in 26% of the non-invasive and in 71% of the invasive tumours. All three variables were increased in severe atypia but varied considerably in lesser degrees of atypia. CONCLUSIONS--Despite the absence of a close correlation, accelerated growth and enhanced receptor expression were characteristic of invasive cancers. These results suggest that the growth rate in TCCs is not causally related to overexpression of growth factor receptors but that the latter is an abnormality which may accompany the malignant phenotype.

The transferrin receptor or transferrin-binding proteins (Tbps) of 50 strains of Neisseria meningitidis belonging to different serogroups were examined by Western blotting using two rabbit antisera raised against Tbp purified from N. meningitidis strains B16B6 and M982. On the basis of the reactivity of Tbp2 with the antisera two patterns were observed and allowed the classification of 74% of the strains in group I (M982-like strains) and 26% in group II (B16B6-like strains). Southern blot analysis was performed on the genomic DNA of 16 meningococcal strains and showed that under stringent conditions, the tbp2 probes were specific for each group identified. Both immunological and genomic analyses have led to the identification within N. meningitidis strains of two major families distinguished on the basis of the characteristics of Tbp2 molecules, independently of serogroup, type or subtype.

We have characterized a new CHO cell line (12-4) derived from a parental line, TRVb-1, that expresses the human transferrin receptor. This mutant belongs to the end2 complementation group of endocytosis mutants. Like other end2 mutants, the endosomes in 12-4 cells show a partial acidification defect. These cells internalize LDL and transferrin at 70% of the rate of parental cells and externalize transferrin at 55% of the parental rate (Johnson, L. S., J. F. Presley, J. C. Park, and T. E. McGraw. J. Cell Physiol. 1993). In this report, we have used fluorescence microscopy to determine which step in receptor trafficking is affected in the mutants. Transferrin is sorted from LDL and is delivered to a peri-centriolar recycling compartment at rates similar to parental cells. However, the rate constant for exit of transferrin from the recycling compartment in mutant cells is 0.025 min-1 vs 0.062 min-1 in the parental line. We also measured the trafficking of a bulk membrane marker, 6-[N-[7-nitrobenzo-2-oxa-1,3-diazol-4-yl]-amino]hexanoyl- sphingosylphosphorylcholine (C6-NBD-SM) that labels the exofacial side of the plasma membrane. C6-NBD-SM enters the same recycling compartment as transferrin, and it exits the recycling compartment at a rate of 0.060-0.065 min-1 in both parental and 12-4 cells. We conclude that bulk membrane flow in the recycling pathway of 12-4 cells is normal, but exit of transferrin from the recycling compartment is slowed due to retention in this compartment. Thus, in the mutant cell line the recycling compartment carries out a sorting function, retaining transferrin over bulk membrane.

To assess whether an abnormality in transferrin receptor expression or regulation could represent an underlying metabolic defect in the reticuloendothelial (RE) system in hemochromatosis, monocytes were analyzed for the expression of the transferrin receptor using a monoclonal antibody (Act II) to the transferrin receptor (CD71) and flow cytometric analysis. Hemochromatosis patients (n = 14), and normal volunteers with no clinical evidence of iron overload (n = 14) were studied. A significant inverse relationship was observed for the relationship between the expression of transferrin receptor on monocytes and log(hepatic iron concentration) in hemochromatosis patients (r = -0.59, P less than .02) and also for the relationship between the expression of transferrin receptor and log(serum ferritin) in normal volunteers (r = -0.90, P less than .001). There was no significant difference in the mean expression of monocyte transferrin receptor between hemochromatosis patients and normal volunteers. However, the expression of the transferrin receptor in hemochromatosis patients was disproportionately higher than would be predicted from the relationship between serum ferritin and transferrin receptor expression in normal volunteers. The inverse relationship of the monocyte transferrin receptor relative to body iron stores in hemochromatosis is consistent with observations in other tissues, and suggests that non-transferrin iron metabolism, including ferritin, requires further investigation in the RE cell in hemochromatosis.

It is not yet known what properties distinguish macrophages which can kill facultative intracellular bacteria, such as Listeria monocytogenes, from those which cannot. Listeria is an organism which requires iron for growth, yet macrophage listericidal mechanisms are also likely to be iron dependent. We show here that resident peritoneal macrophages and thioglycollate-elicited macrophages cannot kill listeria, but proteose peptone-elicited and FCS-elicited macrophages can. All these cell populations phagocytose listeria. Transferrin receptor expression is low on resident cells, intermediate on peptone- and FCS-elicited cells, and high on thioglycollate-elicited cells. Transferrin transports iron into cells via the transferrin receptor: thus, iron content of resident cells is low, of peptone- and FCS-elicited cells is intermediate, and of thioglycollate-elicited cells is high. Moreover, antibody to transferrin, which prevents it binding its receptor, inhibits listericidal macrophages from killing this bacterium. Finally, nonlistericidal cells with high transferrin receptor expression and high intracellular iron become listericidal if they are incubated with apotransferrin, an iron-free ligand which prevents iron uptake by cells. These data suggest that macrophages must have enough available intracellular iron to support listericidal mechanisms, but too much iron favors growth of the bacterium, which no longer can be killed by the macrophage.

Background Chronic pulmonary disease and progressive tissue hypoxia are major causes of morbidity and mortality in cystic fibrosis (CF). Normally the body adapts to tissue hypoxia by increasing the red cell mass and decreasing the Hb-O 2 affinity. These adaptations are commonly observed in patients with cyanotic heart disease and individuals living at high altitude. However, patients with CF not only have an impaired erythroid response to hypoxia, but also are frequently anaemic. Methods In order to evaluate erythroid marrow activity and tissue oxygenation in 37 patients with CF we measured: the haematological and blood chemistry parameters; including red cell indices, ferritin, erythropoietin (Epo) and soluble transferrin receptors (sTfR) levels; arterial blood gases, P 50 and oxygen release to the tissues (O 2 R ) and the 2,3-BPG levels. Results The main results showed that a) patients with CF have a mild degree of tissue hypoxia which is expressed by the moderately decreased of P 50 and O 2 R values and the relative increase of Epo level, b) 2,3-BPG synthesis in patients with CF is normal and c) sTfR levels are significantly increased (3-fold normal) in patients with CF compared to normal controls. Conclusions The above observations indicate that erythroid marrow activity in patients with CF is increased.

Since Szent-Gyorgyi first purified ascorbic acid (vitamin C) in 1928 (1), a number of associations between ascorbic acid and iron metabolism have been described. At the molecular level, ascorbic acid mobilizes iron from the crystal core of ferritin in vitro by reducing Fe3 to Fe2 (2). Intracellularly, ascorbic acid enhances iron-induced translation of ferritin (3) by favoring the conversion of the iron regulatory protein (IRP) from the RNA binding form to aconitase (3). Ascorbic acid also retards degradation of ferritin by blocking lysosomal autophagy of ferritin and transformation to hemosiderin (4)(5). In humans, the oral administration of ascorbic acid enhances the absorption of non-heme iron from the diet (6) and leads to increases in serum iron in subjects with iron overload and ascorbic acid deficiency (7). Moreover, iron overload states are associated with reduced ascorbic acid concentrations, possibly because of increased catabolism of ascorbic acid (7)(8). The amount of labile iron in the cytosol influences the stability of transferrin receptor mRNA and the translation of ferritin mRNA (9)(10)(11). Posttranscriptional regulation occurs by means of an interaction between IRPs, proteins that sense changes in the chelatable intracellular iron pool, and iron-responsive elements located on untranslated regions of transferrin receptor mRNA and ferritin mRNA (12)(13)(14). In states of iron abundance, an IRP has aconitase activity and does not bind to iron-responsive elements, producing increased transferrin receptor mRNA degradation and increased ferritin mRNA translation. Conversely, when iron is deficient, an IRP loses aconitase activity and binds to iron-responsive elements, causing increased transferrin receptor mRNA stability and a repression of ferritin mRNA translation (15)(16). Thus, intracellularly, the presence of iron leads to inhibition of transferrin receptor expression and promotion of higher ferritin expression, whereas the deprivation of …

OBJECTIVE—To study iron status at different gestational ages using cord blood serum transferrin receptors (STfRs). METHODS—STfRs, iron, ferritin, total iron binding capacity, haemoglobin, and reticulocytes were measured in 144 cord blood samples. The babies were divided into three groups according to gestation (26 very preterm (24-29 weeks); 50 preterm (30-36 weeks); 68 term (37-41 weeks)). RESULTS—Serum iron, ferritin, and total iron binding capacity were highest at term, whereas reticulocytes were highest in the very preterm. STfR levels were not influenced by gestation. Haemoglobin (r = 0.46; p < 0.0001) and reticulocytes (r = 0.42; p < 0.0001) were the only indices that independently correlated with STfR levels. CONCLUSIONS—STfR levels in cord blood are not directly influenced by gestation and probably reflect the iron requirements of the fetus for erythropoiesis.

Changes in transferrin-receptor numbers and iron utilisation were monitored during erythropoietin-induced maturation of J2E erythroid cells. Uptake of transferrin and iron doubled 24 h after exposure to erythropoietin, due to a twofold rise in surface transferrin receptors. In addition, a tenfold increase in iron incorporation into haem was observed after erythropoietin stimulation, as iron taken up from transferrin was directed towards haem biosynthesis and away from storage in ferritin. The rise in iron chelation into haem correlated extremely well with haemoglobin synthesis. However, the increase in numbers of transferrin receptors was not essential for haemoglobin synthesis; rather, it was linked with a burst in proliferation stimulated by erythropoietin. We have shown previously that amiloride blocks erythropoietin-enhanced proliferation of J2E cells, but potentiates maturation [Callus, B. A., Tilbrook, P. A., Busfield, S. J. & Klinken, S. P. (1995) Exp. Cell Res. 219, 39–46]. Here we demonstrate that amiloride suppressed the hormone-induced increase in transferrin receptors, whereas the enhanced incorporation of iron into haem was not inhibited. Similarly, when sodium butyrate was used to induce differentiation of J2E cells, proliferation ceased and surface transferrin receptors remained unaltered, while haemoglobin production was accelerated. It was concluded from these experiments that the erythropoietin-stimulated rise in transferrin receptors during the final stages of J2E cell maturation is linked to cell division, and is not essential for haemoglobin synthesis.

In this study the analytical performances of two recently introduced assays for soluble transferrin receptors in serum were tested. The Ramco transferrin assay was compared with the Eurogenetics assay. In a small clinical study serum samples from patients with anaemia of chronic disease, iron deficiency and myelodysplastic syndrome were analysed, as well as sera from healthy volunteers. The analytical performances of the Ramco assay were found to be acceptable. In the Eurogenetics test however, inter-assay imprecision and the end of run drift were unacceptably high. We were able to confirm that in patients with uncomplicated iron deficiency the concentration of soluble transferrin receptors is higher than in healthy volunteers. In cases of anaemia of chronic and inflammatory disease, the levels of soluble transferrin receptors in serum are slightly, but not significantly, higher than in normal subjects. Measurement of soluble transferrin receptors in serum provides a good differentiation between anaemia of chronic disease and iron deficiency.

It is well established that a proportion of newly synthesized lysosomal enzymes and class II major histocompatibility complex antigens are delivered directly to the endocytic pathway from the Golgi complex. Here we show that a significant proportion of newly synthesized transferrin receptors can be detected in endosomes before reaching the cell surface. These newly synthesized transferrin receptors are delivered to the endosome more efficiently than either constitutively secreted soluble proteins or glycophosphatidylinositol-anchored plasma membrane proteins suggesting that their transfer to the endosome is signal-dependent. Identification of a signal-dependent transfer step for proteins like the transferrin receptor operating on the exocytic pathway has important implications for membrane biogenesis, especially in the establishment of cell surface polarity.

The effects of tumour necrosis factor-alpha on transferrin receptor expression in a human chronic myelocytic leukaemia cell line, K 562 cells, were studied. Cytofluorometry studies showed that the numbers of transferrin receptors in exponentially growing K 562 cells were increased when the cells were incubated with tumour necrosis factor-alpha for 24 h. The induction of transferrin receptors by tumour necrosis factor-alpha may be mediated by a mechanism that is independent of growth since cell growth in treated cultures did not differ from that in the controls. The DNA contents of K 562 cells treated with tumour necrosis factor-alpha showed that after 24 h there were less cells in the G1 and S phases and more cells in the G2/M phase than in the control group. The phase of upregulation of transferrin receptors induced by tumour necrosis factor-alpha may be dependent on the cell cycle. This new evidence that tumour necrosis factor-alpha upregulates transferrin receptors suggests a cancer-anaemia cascade in which the cancer burden state activates macrophage release of tumour necrosis factor-alpha as a result of transferrin receptor expression.

Contrary to most other epithelia, trophoblasts in the human placenta, which form the physical barrier between the fetal and the maternal blood circulation, express high numbers of transferrin receptors on their apical cell surface. This study describes the establishment of a polarized trophoblast-like cell line BeWo, which exhibit a high expression of transferrin receptors on the apex of the cells. Cultured on permeable filter supports, BeWo cells formed a polarized monolayer with microvilli on their apical cell surface. Across the monolayer a transepithelial resistance developed of approximately 600 omega.cm2 within 4 d. Depletion of Ca2+ from the medium decreased the resistance to background levels, showing its dependence on the integrity of tight junctions. Within the same period of time the secretion of proteins became polarized. In addition, the compositions of integral membrane proteins at the apical and basolateral plasma membrane domains were distinct as determined by domain-selective iodination. Similar to placental trophoblasts, binding of 125I-labeled transferrin to BeWo monolayers revealed that the transferrin receptor was expressed at both plasma membrane domains. Apical and basolateral transferrin receptors were found in a 1:2 surface ratio and exhibited identical dissociation constants and molecular weights. After uptake, transferrin recycled predominantly to the domain of administration, indicating separate recycling pathways from the apical and basolateral domain. This was confirmed by using diaminobenzidine cytochemistry, a technique by which colocalization of endocytosed 125I-labeled and HRP-conjugated transferrin can be monitored. No mixing of the two types of ligands was observed, when both ligands were simultaneously internalized for 10 or 60 min from opposite domains, demonstrating that BeWo cells possess separate populations of apical and basolateral early endosomes. In conclusion, the trophoblast-like BeWo cell line can serve as a unique model to compare the apical and basolateral endocytic pathways of a single ligand, transferrin, in polarized epithelial cells.

The retinal pigment epithelium (RPE) is unique in that Na,K-ATPase is predominantly localized on its apical surface. We studied the distributions of Na,K-ATPase and glucose transporter GLUT1, insulin and transferrin receptors in developing rat RPE cells immunocytochemically. Na,K-ATPase, first detected in 17-day-old embryonic eyes, was already distributed predominantly on the apical surface. This reversed distribution of Na,K-ATPase was maintained throughout their life. Insulin receptor and transferrin receptor were distributed exclusively on the basolateral surface. By quantitative immunogold electron microscopic technique we found that glucose transporter GLUT1 is distributed almost equal in amount on both the apical and basolateral surfaces of RPE cells, thus presumably constructing an efficient pathway for glucose transport from the choriocapillaries to the neural retina through the blood-retinal barrier. These results suggest that in the RPE cells the intrinsic basolateral plasma membrane proteins are sorted out at least in three different ways.

In anemia of chronic disease (ACD) in rheumatoid arthritis (RA) a decreased iron uptake and transferrin binding by erythroblasts are postulated to play a pathophysiological role. To examine whether this is related to changes in transferrin receptor expression by erythroblasts, we studied bone marrow from 5 healthy controls, 5 nonanemic RA patients, and 9 RA patients with ACD. Bone marrow mononuclear cells were incubated with increasing concentrations of 125I-transferrin and specific binding data were analyzed by the method of Scatchard. The number of transferrin receptors on erythroblasts from RA patients with ACD was significantly lower as compared to nonanemic RA patients (P < .05) and controls (P < .02). The affinity of the transferrin receptor tended to be lower in ACD. These preliminary data may indicate that transferrin receptor expression by erythroblasts is impaired in ACD. Since the rate of erythroid iron uptake is mainly determined by the number of transferrin binding sites, this may explain a decrease in erythroblast iron availability in ACD in RA.