Publications by authors named "Hal Drakesmith"

70 Publications

Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection.

Med (N Y) 2021 Feb;2(2):164-179.e12

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Background: How specific nutrients influence adaptive immunity is of broad interest. Iron deficiency is the most common micronutrient deficiency worldwide and imparts a significant burden of global disease; however, its effects on immunity remain unclear.

Methods: We used a hepcidin mimetic and several genetic models to examine the effect of low iron availability on T cells and on immune responses to vaccines and viral infection in mice. We examined humoral immunity in human patients with raised hepcidin and low serum iron caused by mutant . We tested the effect of iron supplementation on vaccination-induced humoral immunity in piglets, a natural model of iron deficiency.

Findings: We show that low serum iron (hypoferremia), caused by increased hepcidin, severely impairs effector and memory responses to immunizations. The intensified metabolism of activated lymphocytes requires the support of enhanced iron acquisition, which is facilitated by IRP1/2 and TFRC. Accordingly, providing extra iron improved the response to vaccination in hypoferremic mice and piglets, while conversely, hypoferremic humans with chronically increased hepcidin have reduced concentrations of antibodies specific for certain pathogens. Imposing hypoferremia blunted the T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist and exacerbating lung inflammation and morbidity.

Conclusions: Hypoferremia, a well-conserved physiological innate response to infection, can counteract the development of adaptive immunity. This nutrient trade-off is relevant for understanding and improving immune responses to infections and vaccines in the globally common contexts of iron deficiency and inflammatory disorders.

Funding: Medical Research Council, UK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.medj.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895906PMC
February 2021

Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.

Front Immunol 2020 24;11:596841. Epub 2020 Nov 24.

Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.

Human immunodeficiency virus type 1 (HIV-1) infection triggers rapid induction of multiple innate cytokines including type I interferons, which play important roles in viral control and disease pathogenesis. The transforming growth factor (TGF)-β superfamily is a pleiotropic innate cytokine family, some members of which (activins and bone morphogenetic proteins (BMPs)) were recently demonstrated to exert antiviral activity against Zika and hepatitis B and C viruses but are poorly studied in HIV-1 infection. Here, we show that TGF-β is systemically induced with very rapid kinetics (as early as 1-4 days after viremic spread begins) in acute HIV-1 infection, likely due to release from platelets, and remains upregulated throughout infection. Contrastingly, no substantial systemic upregulation of activins A and B or BMP-2 was observed during acute infection, although plasma activin levels trended to be elevated during chronic infection. HIV-1 triggered production of type I interferons but not TGF-β superfamily cytokines from plasmacytoid dendritic cells (DCs) , putatively explaining their differing induction; whilst lipopolysaccharide (but not HIV-1) elicited activin A production from myeloid DCs. These findings underscore the need for better definition of the protective and pathogenic capacity of TGF-β superfamily cytokines, to enable appropriate modulation for therapeutic purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.596841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732468PMC
November 2020

NRF2 and Hypoxia-Inducible Factors: Key Players in the Redox Control of Systemic Iron Homeostasis.

Antioxid Redox Signal 2020 Nov 10. Epub 2020 Nov 10.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.

Oxygen metabolism and iron homeostasis are closely linked. Iron facilitates the oxygen-carrying capacity of blood, and its deficiency causes anemia. Conversely, excess free iron is detrimental for stimulating the formation of reactive oxygen species, causing tissue damage. The amount and distribution of iron thus need to be tightly regulated by the liver-expressed hormone hepcidin. This review analyzes the roles of key oxygen-sensing pathways in cellular and systemic regulation of iron homeostasis; specifically, the prolyl hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) and the Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (KEAP1/NRF2) pathways, which mediate tissue adaptation to low and high oxygen, respectively. In macrophages, NRF2 regulates genes involved in hemoglobin catabolism, iron storage, and iron export. NRF2 was recently identified as the molecular sensor of iron-induced oxidative stress and is responsible for BMP6 expression by liver sinusoidal endothelial cells, which in turn activates hepcidin synthesis by hepatocytes to restore systemic iron levels. Moreover, NRF2 orchestrates the activation of antioxidant defenses that are crucial to protect against iron toxicity. On the contrary, low iron/hypoxia stabilizes renal HIF2a inactivation of iron-dependent PHD dioxygenases, causing an erythropoietic stimulus that represses hepcidin an inhibitory effect of erythroferrone on bone morphogenetic proteins. Intestinal HIF2a is also stabilized, increasing the expression of genes involved in dietary iron absorption. An intimate crosstalk between oxygen-sensing pathways and iron regulatory mechanisms ensures that fluctuations in systemic iron levels are promptly detected and restored. The realization that redox-sensitive transcription factors regulate systemic iron levels suggests novel therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2020.8148DOI Listing
November 2020

Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.

Front Immunol 2020 13;11:1313. Epub 2020 Jul 13.

Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, Laboratory of Human Nutrition, ETH Zürich, Zurich, Switzerland.

Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis- type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk ( = 0.0071, = 0.0339) and 18 mo ( = 0.0182, = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk ( = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo ( = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria ( = 0.0484, = 0.0439) and pneumococcus 19 at 18 mo ( = 0.0199, = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG ( = 0.0415), seroconversion ( = 0.0531) and IgG avidity ( = 0.0425) at 11.5 mo. In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369313PMC
April 2021

The battle for iron in enteric infections.

Immunology 2020 Nov 11;161(3):186-199. Epub 2020 Aug 11.

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Iron is an essential element for almost all living organisms, but can be extremely toxic in high concentrations. All organisms must therefore employ homeostatic mechanisms to finely regulate iron uptake, usage and storage in the face of dynamic environmental conditions. The critical step in mammalian systemic iron homeostasis is the fine regulation of dietary iron absorption. However, as the gastrointestinal system is also home to >10 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter-kingdom fight for iron is never-ending. Here, we explore the molecular mechanisms of, and interactions between, host and bacterial iron homeostasis in the gastrointestinal tract. We first detail how mammalian systemic and cellular iron homeostasis influences gastrointestinal iron availability. We then focus on two important human pathogens, Salmonella and Clostridia; despite their differences, they exemplify how a bacterial pathogen must navigate and exploit this web of iron homeostasis interactions to avoid host nutritional immunity and replicate successfully. We then reciprocally explore how iron availability interacts with the gastrointestinal microbiota, and the consequences of this on mammalian physiology and pathogen iron acquisition. Finally, we address how understanding the battle for iron in the gastrointestinal tract might inform clinical practice and inspire new treatments for important diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imm.13236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576875PMC
November 2020

Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19.

Crit Care 2020 06 9;24(1):320. Epub 2020 Jun 9.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-020-03051-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280775PMC
June 2020

Antibodies against the erythroferrone N-terminal domain prevent hepcidin suppression and ameliorate murine thalassemia.

Blood 2020 02;135(8):547-557

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Erythroferrone (ERFE) is produced by erythroblasts in response to erythropoietin (EPO) and acts in the liver to prevent hepcidin stimulation by BMP6. Hepcidin suppression allows for the mobilization of iron to the bone marrow for the production of red blood cells. Aberrantly high circulating ERFE in conditions of stress erythropoiesis, such as in patients with β-thalassemia, promotes the tissue iron accumulation that substantially contributes to morbidity in these patients. Here we developed antibodies against ERFE to prevent hepcidin suppression and to correct the iron loading phenotype in a mouse model of β-thalassemia [Hbb(th3/+) mice] and used these antibodies as tools to further characterize ERFE's mechanism of action. We show that ERFE binds to BMP6 with nanomolar affinity and binds BMP2 and BMP4 with somewhat weaker affinities. We found that BMP6 binds the N-terminal domain of ERFE, and a polypeptide derived from the N terminus of ERFE was sufficient to cause hepcidin suppression in Huh7 hepatoma cells and in wild-type mice. Anti-ERFE antibodies targeting the N-terminal domain prevented hepcidin suppression in ERFE-treated Huh7 cells and in EPO-treated mice. Finally, we observed a decrease in splenomegaly and serum and liver iron in anti-ERFE-treated Hbb(th3/+) mice, accompanied by an increase in red blood cells and hemoglobin and a decrease in reticulocyte counts. In summary, we show that ERFE binds BMP6 directly and with high affinity, and that antibodies targeting the N-terminal domain of ERFE that prevent ERFE-BMP6 interactions constitute a potential therapeutic tool for iron loading anemias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046598PMC
February 2020

Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia.

Lancet Glob Health 2019 11;7(11):e1564-e1574

Medical Research Council (MRC) Unit The Gambia at London School of Hygiene & Tropical Medicine (LSHTM), Serrekunda, The Gambia; LSHTM, London, UK. Electronic address:

Background: WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron.

Methods: We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2·5 μg/L or UNIMMAP without iron if hepcidin was ≥2·5 μg/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5·0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180.

Findings: Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2·2 g/L (95% CI -4·6 to 0·1) with the 60 mg screen-and-treat approach and -2·7 g/L (-5·0 to -0·5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1·0, 95% CI 0·7 to 1·6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0·7, 95% CI 0·5 to 1·1). No participants died during the study.

Interpretation: The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought.

Funding: Bill & Melinda Gates Foundation and the UK Medical Research Council.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2214-109X(19)30393-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109523PMC
November 2019

Transcriptomic profiling of the myeloma bone-lining niche reveals BMP signalling inhibition to improve bone disease.

Nat Commun 2019 10 4;10(1):4533. Epub 2019 Oct 4.

NIHR Oxford Biomedical Research Centre Blood Theme, University of Oxford, Oxford, UK.

Multiple myeloma is an incurable, bone marrow-dwelling malignancy that disrupts bone homeostasis causing skeletal damage and pain. Mechanisms underlying myeloma-induced bone destruction are poorly understood and current therapies do not restore lost bone mass. Using transcriptomic profiling of isolated bone lining cell subtypes from a murine myeloma model, we find that bone morphogenetic protein (BMP) signalling is upregulated in stromal progenitor cells. BMP signalling has not previously been reported to be dysregulated in myeloma bone disease. Inhibition of BMP signalling in vivo using either a small molecule BMP receptor antagonist or a solubilized BMPR1a-FC receptor ligand trap prevents trabecular and cortical bone volume loss caused by myeloma, without increasing tumour burden. BMP inhibition directly reduces osteoclastogenesis, increases osteoblasts and bone formation, and suppresses bone marrow sclerostin levels. In summary we describe a novel role for the BMP pathway in myeloma-induced bone disease that can be therapeutically targeted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12296-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778199PMC
October 2019

Minihepcidins improve ineffective erythropoiesis and splenomegaly in a new mouse model of adult β-thalassemia major.

Haematologica 2020 07 3;105(7):1835-1844. Epub 2019 Oct 3.

Department of Pediatrics, Division of Hematology, The Children's Hospital of Philadelphia (CHOP), Philadelphia, PA, USA

Minihepcidins are hepcidin agonists that have been previously shown to reverse iron overload and improve erythropoiesis in mice affected by non-transfusion-dependent thalassemia. Given the extreme anemia that occurred with the previous model of transfusion-dependent thalassemia, that model was inadequate for investigating whether minihepcidins can improve red blood cell quality, lifespan and ineffective erythropoiesis. To overcome this limitation, we generated a new murine model of transfusion-dependent thalassemia with severe anemia and splenomegaly, but sufficient red cells and hemoglobin production to test the effect of minihepcidins. Furthermore, this new model demonstrates cardiac iron overload for the first time. In the absence of transfusions, minihepcidins improved red blood cell morphology and lifespan as well as ineffective erythropoiesis. Administration of a minihepcidin in combination with chronic red blood cell transfusion further improved the ineffective erythropoiesis and splenomegaly and reversed cardiac iron overload. These studies indicate that drugs such as minihepcidins have therapeutic potential for patients with transfusion-dependent thalassemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.212589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327634PMC
July 2020

Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features.

Pharmaceuticals (Basel) 2019 Sep 9;12(3). Epub 2019 Sep 9.

Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph12030132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789780PMC
September 2019

Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.

Nat Metab 2019 05 13;1(5):519-531. Epub 2019 May 13.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-019-0063-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609153PMC
May 2019

Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children.

Sci Adv 2019 03 27;5(3):eaav9020. Epub 2019 Mar 27.

MRC Unit The Gambia at LSHTM, Atlantic Road, Fajara, The Gambia.

Iron deficiency anemia (IDA) is the most prevalent nutritional condition worldwide. We studied the contribution of hepcidin-mediated iron blockade to IDA in African children. We measured hepcidin and hemoglobin weekly, and hematological, inflammatory, and iron biomarkers at baseline, 7 weeks, and 12 weeks in 407 anemic (hemoglobin < 11 g/dl), otherwise healthy Gambian children (6 to 27 months). Each child maintained remarkably constant hepcidin levels ( < 0.0001 for between-child variance), with half consistently maintaining levels that indicate physiological blockade of iron absorption. Hepcidin was strongly predicted by nurse-ascribed adverse events with dominant signals from respiratory infections and fevers (all < 0.0001). Diarrhea and fecal calprotectin were not associated with hepcidin. In multivariate analysis, C-reactive protein was the dominant predictor of hepcidin and contributed to iron blockade even at very low levels. We conclude that even low-grade inflammation, especially associated with respiratory infections, contributes to IDA in African children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aav9020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436921PMC
March 2019

Author Correction: The influence of haemoglobin and iron on in vitro mycobacterial growth inhibition assays.

Sci Rep 2019 Apr 3;9(1):5596. Epub 2019 Apr 3.

The Jenner Institute, University of Oxford, Oxford, UK.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-41387-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447576PMC
April 2019

Rapid growth is a dominant predictor of hepcidin suppression and declining ferritin in Gambian infants.

Haematologica 2019 08 7;104(8):1542-1553. Epub 2019 Feb 7.

WHO Collaborating Center for New Vaccines Surveillance, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia, Africa

Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, seasonality, and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth cohorts of infants in rural Gambia (n=114 and n=193). This setting is characterized by extreme seasonality, prevalent childhood anemia, undernutrition, and frequent infection. Plasma was collected from infants at birth and at regular intervals, up to 12 months of age. Hepcidin, ferritin and plasma iron concentrations declined markedly during infancy, with reciprocal increases in soluble transferrin receptor and transferrin concentrations, indicating declining iron stores and increasing tissue iron demand. In cross-sectional analyses at 5 and 12 months of age, we identified expected relationships of hepcidin with iron and inflammatory markers, but also observed significant negative associations between hepcidin and antecedent weight gain. Correspondingly, longitudinal fixed effects modeling demonstrated weight gain to be the most notable dynamic predictor of decreasing hepcidin and ferritin through infancy across both cohorts. Infants who grow rapidly in this setting are at particular risk of depletion of iron stores, but since hepcidin concentrations decrease with weight gain, they may also be the most responsive to oral iron interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.210146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669141PMC
August 2019

Antiviral activity of bone morphogenetic proteins and activins.

Nat Microbiol 2019 02 3;4(2):339-351. Epub 2018 Dec 3.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41564-018-0301-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590058PMC
February 2019

Hemoglobinopathies in the Fetal Position.

N Engl J Med 2018 Oct;379(17):1675-1677

From the Walter and Eliza Hall Institute of Medical Research, the Department of Medical Biology, University of Melbourne, the Department of Diagnostic Haematology, Royal Melbourne Hospital, and Clinical Haematology at the Peter MacCallum Cancer Centre and the Royal Melbourne Hospital - all in Parkville, VIC, Australia (S.-R.P.); and the Weatherall Institute of Molecular Medicine, Medical Research Council Human Immunology Unit, and Haematology Theme, Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom (H.D.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMcibr1809628DOI Listing
October 2018

Intravenous Irons: From Basic Science to Clinical Practice.

Pharmaceuticals (Basel) 2018 Aug 27;11(3). Epub 2018 Aug 27.

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK.

Iron is an essential trace mineral necessary for life, and iron deficiency anaemia (IDA) is one of the most common haematological problems worldwide, affecting a sixth of the global population. Principally linked to poverty, malnutrition and infection in developing countries, in Western countries the pathophysiology of IDA is primarily linked to blood loss, malabsorption and chronic disease. Oral iron replacement therapy is a simple, inexpensive treatment, but is limited by gastrointestinal side effects that are not inconsequential to some patients and are of minimal efficacy in others. Third generation intravenous (IV) iron therapies allow rapid and complete replacement dosing without the toxicity issues inherent with older iron preparations. Their characteristic, strongly-bound iron-carbohydrate complexes exist as colloidal suspensions of iron oxide nanoparticles with a polynuclear Fe(III)-oxyhydroxide/oxide core surrounded by a carbohydrate ligand. The physicochemical differences between the IV irons include mineral composition, crystalline structure, conformation, size and molecular weight, but the most important difference is the carbohydrate ligand, which influences complex stability, iron release and immunogenicity, and which is a unique feature of each drug. Recent studies have highlighted different adverse event profiles associated with third-generation IV irons that reflect their different structures. The increasing clinical evidence base has allayed safety concerns linked to older IV irons and widened their clinical use. This review considers the properties of the different IV irons, and how differences might impact current and future clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ph11030082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161004PMC
August 2018

Erythroferrone inhibits the induction of hepcidin by BMP6.

Blood 2018 10 10;132(14):1473-1477. Epub 2018 Aug 10.

Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in β-thalassemia. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, and ERFE suppresses hepatic hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for hepcidin control, and we show that EPO suppressed hepcidin and other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron. In vitro, ERFE decreased SMAD1, SMAD5, and SMAD8 phosphorylation and inhibited expression of BMP target genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand trap generated by stimulated erythropoiesis to regulate the availability of iron.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-06-857995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238155PMC
October 2018

Reducing anaemia in low income countries: control of infection is essential.

BMJ 2018 Aug 1;362:k3165. Epub 2018 Aug 1.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.k3165DOI Listing
August 2018

Decreased Hepcidin Levels Are Associated with Low Steady-state Hemoglobin in Children With Sickle Cell Disease in Tanzania.

EBioMedicine 2018 Aug 25;34:158-164. Epub 2018 Jul 25.

School of Tropical Medicine & Global Health, Nagasaki University, Nagasaki, Japan; London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

Background: The contribution of hepcidin as a regulator of iron metabolism & erythropoiesis on the severity of anemia in sickle cell disease (SCD) remains poorly characterized, especially in Sub-Saharan African populations. The aims of the study were to determine if hepcidin is associated with severity of steady-state anemia in SCD and to investigate factors associated with hepcidin and anemia in SCD.

Methods: Archived samples from 199 Tanzanian children, 56% boys aged 3-18 with laboratory-confirmed SCD were analysed based on recorded averaged steady-state hemoglobin (ASSH) quartiles (lowest vs. highest). Univariable and multivariable logistic regression was used to assess associations with ASSH quartiles.

Findings: In univariable analysis, hepcidin <5·5 ng/mL was associated with increased odds of being in the lowest ASSH quartile (OR 2·20; 95%CI 1·2-3·93) but which was limited to girls (OR 4·85, 95%CI 1·79-13·09, p = .046 for interaction). In multivariable analyses including either reticulocyte percentage or erythropoietin, lower hepcidin remained significantly associated with lowest ASSH quartile, although the hepcidin-sex interaction no longer reached statistical significance. No associations with ASSH quartile were observed for markers of inflammation, hemolysis or potential iron markers except for microcytosis, associated with higher ASSH, but which was confounded by reticulocyte percentage and alpha-thalassaemia status.

Interpretation: Hepcidin is lower in more severely anaemic children with SCD independent of inflammation or markers of erythropoiesis.

Funding: Funding sources include The Wellcome Trust (080025, 095009, 094780 & 070114), MRC-UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation ("Hepcidin and Iron in Global Health", OPP1055865).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2018.07.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116423PMC
August 2018

Serum hepcidin potentially identifies iron deficiency in survivors of critical illness at the time of hospital discharge.

Br J Haematol 2019 01 24;184(2):279-281. Epub 2018 Jan 24.

MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15067DOI Listing
January 2019

Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M.tb infection model.

PLoS One 2018 11;13(1):e0191038. Epub 2018 Jan 11.

Jenner Institute, University of Oxford, Oxford, United Kingdom.

Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191038PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764373PMC
March 2018

Role of Activins in Hepcidin Regulation during Malaria.

Infect Immun 2017 12 17;85(12). Epub 2017 Nov 17.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of -infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/IAI.00191-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695100PMC
December 2017

Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.

Nat Commun 2017 09 1;8(1):403. Epub 2017 Sep 1.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3.Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00500-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581335PMC
September 2017

Improving iron supplements: cooking with GOS.

Gut 2017 11 3;66(11):1881-1882. Epub 2017 Aug 3.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2017-314593DOI Listing
November 2017

Hepatic iron is the major determinant of serum ferritin in NAFLD patients.

Liver Int 2018 01 29;38(1):164-173. Epub 2017 Jul 29.

Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

Background And Aims: Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD.

Methods: Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation.

Results: Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin.

Conclusions: While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.13513DOI Listing
January 2018

Serum Hepcidin Concentrations Decline during Pregnancy and May Identify Iron Deficiency: Analysis of a Longitudinal Pregnancy Cohort in The Gambia.

J Nutr 2017 06 19;147(6):1131-1137. Epub 2017 Apr 19.

MRC Unit The Gambia-MRC International Nutrition Group and London School of Hygiene and Tropical Medicine, London, United Kingdom.

Antenatal anemia is a risk factor for adverse maternal and fetal outcomes and is prevalent in sub-Saharan Africa. Less than half of antenatal anemia is considered responsive to iron; identifying women in need of iron may help target interventions. Iron absorption is governed by the iron-regulatory hormone hepcidin. We sought to characterize changes in hepcidin and its associations with indexes of iron stores, erythropoiesis, and inflammation at weeks 14, 20, and 30 of gestation and to assess hepcidin's diagnostic potential as an index of iron deficiency. We measured hemoglobin and serum hepcidin, ferritin, soluble transferrin receptor (sTfR), and C-reactive protein (CRP) at 14, 20, and 30 wk of gestation in a cohort of 395 Gambian women recruited to a randomized controlled trial. Associations with hepcidin were measured by using linear regression, and hepcidin's diagnostic test accuracy [area under the receiver operating characteristic curve (AUC), sensitivity, specificity, cutoffs] for iron deficiency at each time point was analyzed. The prevalence of anemia increased from 34.6% at 14 wk of gestation to 50.0% at 20 wk. Hepcidin concentrations declined between study enrollment and 20 wk, whereas ferritin declined between 20 and 30 wk of gestation. The variations in hepcidin explained by ferritin, sTfR, and CRP declined over pregnancy. The AUC values for hepcidin to detect iron deficiency (defined as ferritin <15 μg/L) were 0.86, 0.83, and 0.84 at 14, 20, and 30 wk, respectively. Hepcidin was superior to hemoglobin and sTfR as an indicator of iron deficiency. In Gambian pregnant women, hepcidin appears to be a useful diagnostic test for iron deficiency and may enable the identification of cases for whom iron would be beneficial. Hepcidin suppression in the second trimester suggests a window for optimal timing for antenatal iron interventions. Hemoglobin does not effectively identify iron deficiency in pregnancy. This trial was registered at www.isrctn.com as ISRCTN49285450.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3945/jn.116.245373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443464PMC
June 2017

Short-Term versus Long-Term Blood Storage.

N Engl J Med 2017 03;376(11):1092

University of Oxford, Oxford, United Kingdom

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMc1700464DOI Listing
March 2017

The influence of haemoglobin and iron on in vitro mycobacterial growth inhibition assays.

Sci Rep 2017 03 3;7:43478. Epub 2017 Mar 3.

The Jenner Institute, University of Oxford, Oxford, UK.

The current vaccine against tuberculosis, live attenuated Mycobacterium bovis BCG, has variable efficacy, but development of an effective alternative is severely hampered by the lack of an immune correlate of protection. There has been a recent resurgence of interest in functional in vitro mycobacterial growth inhibition assays (MGIAs), which provide a measure of a range of different immune mechanisms and their interactions. We identified a positive correlation between mean corpuscular haemoglobin and in vitro growth of BCG in whole blood from healthy UK human volunteers. Mycobacterial growth in peripheral blood mononuclear cells (PBMC) from both humans and macaques was increased following the experimental addition of haemoglobin (Hb) or ferric iron, and reduced following addition of the iron chelator deferoxamine (DFO). Expression of Hb genes correlated positively with mycobacterial growth in whole blood from UK/Asian adults and, to a lesser extent, in PBMC from South African infants. Taken together our data indicate an association between Hb/iron levels and BCG growth in vitro, which may in part explain differences in findings between whole blood and PBMC MGIAs and should be considered when using such assays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep43478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335253PMC
March 2017