Laura Infanti , Gerda Leitner , Morten K. Moe , Vildana Pehlic , Pascal Benkert , Marco Cattaneo , Andreas Holbro , Jakob Passweg , Nina Worel , Andreas Buser
{"title":"Indices of iron homeostasis in asymptomatic subjects with HFE mutations and moderate ferritin elevation during iron removal treatment","authors":"Laura Infanti , Gerda Leitner , Morten K. Moe , Vildana Pehlic , Pascal Benkert , Marco Cattaneo , Andreas Holbro , Jakob Passweg , Nina Worel , Andreas Buser","doi":"10.1016/j.bcmd.2022.102689","DOIUrl":"10.1016/j.bcmd.2022.102689","url":null,"abstract":"<div><p>We analysed iron biomarkers and their relationships in 30 subjects with HFE mutations and moderate hyperferritinaemia undergoing iron removal at our blood donation centre.</p><p>Body mass index (BMI) and liver enzymes were assessed. Serum iron (SI), ferritin, transferrin saturation (TSAT), hepcidin and non-transferrin bound iron (NTBI) were measured serially.</p><p>Seventeen subjects had p.C282Y/p.C282Y, nine p.C282Y/p.H63D, four p.H63D/p.H63D. Median age (p = 0.582), BMI (p = 0.500) and ferritin (p = 0.089) were comparable.</p><p>At baseline, 12/17 p.C282Y/p.C282Y and 2/9 p.C282Y/p.H63D had measurable NTBI (p = 0.003). The p.C282Y/p.C282Y had higher TSAT (p < 0.001), lower hepcidin (p = 0.031) and hepcidin/ferritin ratio (p = 0.073). After treatment, iron indices were similar among groups, except TSAT (higher in p.C282Y/p.C282Y; p = 0.06).</p><p>Strong relationships were observed between ferritin and TSAT (R = 0.71), NTBI and TSAT (R = 0.61), NTBI and SI (R = 0.54) in p.C282Y/p.C282Y. Hepcidin correlated weakly with ferritin in p.C282Y/p.C282Y (R = 0.37) but strongly in p.C282Y/p.H63D (R = 0.66) and p.H63D/p.H63D (R = 0.72), while relationships with TSAT were weak (R = 0.27), moderate (R = 0.55) and strong (R = 0.61), respectively.</p><p>Low penetrance p.C282Y/p.C282Y phenotype displays hepcidin dysregulation and biochemical risk for iron toxicity.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1079979622000468/pdfft?md5=cf688afa78b79301e9e4c9359c5fc0f6&pid=1-s2.0-S1079979622000468-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40566166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Agata Kubickova , Zuzana Maceckova , Petr Vojta , Martin Ondra , Jana Volejnikova , Pavla Koralkova , Alexandra Jungova , Ondřej Jahoda , Renata Mojzikova , Ivana Hadacova , Jaroslav Cermak , Monika Horvathova , Dagmar Pospisilova , Marian Hajduch
{"title":"Missense mutation in RPS7 causes Diamond-Blackfan anemia via alteration of erythrocyte metabolism, protein translation and induction of ribosomal stress","authors":"Agata Kubickova , Zuzana Maceckova , Petr Vojta , Martin Ondra , Jana Volejnikova , Pavla Koralkova , Alexandra Jungova , Ondřej Jahoda , Renata Mojzikova , Ivana Hadacova , Jaroslav Cermak , Monika Horvathova , Dagmar Pospisilova , Marian Hajduch","doi":"10.1016/j.bcmd.2022.102690","DOIUrl":"10.1016/j.bcmd.2022.102690","url":null,"abstract":"<div><p>Diamond-Blackfan anemia (DBA) is predominantly underlined by mutations in genes encoding ribosomal proteins (RP); however, its etiology remains unexplained in approximately 25 % of patients.</p><p>We previously reported a novel heterozygous <em>RPS7</em><span><span> mutation hg38 chr2:g.3,580,153G > T p.V134F in one female patient and two asymptomatic family members, in whom mild anemia and increased erythrocyte adenosine deaminase (eADA) activity were detected. We observed that altered </span>erythrocyte metabolism<span> and oxidative stress<span> which may negatively affect the lifespan of erythrocytes distinguishes the patient from her asymptomatic family members. Pathogenicity<span> of the RPS7 p.V134F mutation was extensively validated including molecular defects in protein translational activity and ribosomal stress activation in the cellular model of this variant.</span></span></span></span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40531572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zollie White III, Kamaleldin E. Elagib, Alejandro A. Gru, Adam N. Goldfarb
{"title":"Liver kinase B1 (LKB1) in murine erythroid progenitors modulates erythropoietin setpoint in association with maturation control","authors":"Zollie White III, Kamaleldin E. Elagib, Alejandro A. Gru, Adam N. Goldfarb","doi":"10.1016/j.bcmd.2022.102688","DOIUrl":"10.1016/j.bcmd.2022.102688","url":null,"abstract":"<div><p><span><span>Erythropoiesis is a tightly regulated process. It is stimulated by decreased oxygen in circulation, which leads to the secretion of the hormone </span>erythropoietin (Epo) by the kidneys. An additional layer of control involves the coordinated sensing and use of nutrients. Much cellular machinery contributes to sensing and responding to nutrient status in cells, and one key participant is the kinase LKB1. The current study examines the role of LKB1 in erythropoiesis using a murine in vivo and </span>ex vivo<span> conditional knockout system. In vivo analysis showed erythroid loss of LKB1 to be associated with a robust increase in serum Epo and mild reticulocytosis. Despite these abnormalities, no evidence of anemia or hemolysis was found. Further characterization using an ex vivo progenitor culture assay demonstrated accelerated erythroid maturation in the LKB1-deficient cells. Based on pharmacologic evidence, this phenotype appeared to result from impaired AMP-activated protein kinase (AMPK) signaling downstream of LKB1. These findings reveal a role for LKB1 in fine-tuning Epo-driven erythropoiesis in association with maturational control.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39991812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Han Bai , Junpeng Ma , Weikang Mao , Xuan Zhang , Yijun Nie , Jingcan Hao , Xiaorui Wang , Hongyu Qin , Qiqi Zeng , Fang Hu , Xin Qi , Xiaobei Chen , Dong Li , Binghong Zhang , Bingyin Shi , Chengsheng Zhang
{"title":"Identification of TCR repertoires in asymptomatic COVID-19 patients by single-cell T-cell receptor sequencing","authors":"Han Bai , Junpeng Ma , Weikang Mao , Xuan Zhang , Yijun Nie , Jingcan Hao , Xiaorui Wang , Hongyu Qin , Qiqi Zeng , Fang Hu , Xin Qi , Xiaobei Chen , Dong Li , Binghong Zhang , Bingyin Shi , Chengsheng Zhang","doi":"10.1016/j.bcmd.2022.102678","DOIUrl":"10.1016/j.bcmd.2022.102678","url":null,"abstract":"<div><p>The T cell-mediated immune responses associated with asymptomatic infection (AS) of SARS-CoV-2 remain largely unknown. The diversity of T-cell receptor (TCR) repertoire is essential for generating effective immunity against viral infections in T cell response. Here, we performed the single-cell TCR sequencing of the PBMC samples from five AS subjects, 33 symptomatic COVID-19 patients and eleven healthy controls to investigate the size and the diversity of TCR repertoire. We subsequently analyzed the TCR repertoire diversity, the V and J gene segment deference, and the dominant combination of αβ VJ gene pairing among these three study groups. Notably, we revealed significant TCR preference in the AS group, including the skewed usage of TRAV1-2-J33-TRBV6-4-J2-2 and TRAV1-2-J33-TRBV6-1-J2-3. Our findings may shed new light on understanding the immunopathogenesis of COVID-19 and help identify optimal TCRs for development of novel therapeutic strategies against SARS-CoV-2 infection.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10395140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jin Wang , Jin Zhang , Jinjin Huang, Yu Mei, Zhenya Hong
{"title":"The differences of hemogram, myelogram, and driver gene mutations in classic myeloproliferative neoplasms","authors":"Jin Wang , Jin Zhang , Jinjin Huang, Yu Mei, Zhenya Hong","doi":"10.1016/j.bcmd.2022.102698","DOIUrl":"10.1016/j.bcmd.2022.102698","url":null,"abstract":"<div><p>The aim of this study was to explore and compare routine blood features and pathological characteristics of bone marrow tissues in essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis, prefibrotic stage (prePMF) and overt fibrotic stage (overtPMF), and the correlation between common driver gene mutations and clinical manifestations of myeloproliferative neoplasms (MPN). Methods: We analyzed 259 MPN patients treated at Tongji Hospital of Huazhong University of Science and Technology from January 2016 to December 2020. Results: Among ET, PV, prePMF, and overtPMF, the median leukocyte counts of PV and prePMF were significantly higher than those of ET. The average hemoglobin level of overtPMF was significantly lower than that of ET, PV, and prePMF. ET and prePMF had higher platelet counts than PV and overtPMF, whereas ET had the lowest platelet distribution width. Regarding hematopoietic tissues in the bone marrow, enlarged megakaryocytes were easily found in ET, PV, and prePMF, whereas the average diameter of megakaryocytes in prePMF was smaller than in ET, and PV showed various sizes of megakaryocytes. An increased M/E ratio and dilation of sinus were seen more frequently in PMF. Additionally, JAK2-positive patients tended to have significantly higher leukocyte counts than CALR-positive patients in ET and PMF.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1079979622000559/pdfft?md5=1338c0b5cdb166d145444adf0cc69d5a&pid=1-s2.0-S1079979622000559-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40574018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular mechanisms underlying the role of HLA-DQ in systemic immune activation in severe aplastic anemia.","authors":"Y. Shao, Bingnan Liu, Li He, Chunyan Liu, R. Fu","doi":"10.2139/ssrn.4131058","DOIUrl":"https://doi.org/10.2139/ssrn.4131058","url":null,"abstract":"Severe aplastic anemia (SAA) is a bone marrow failure disorder caused by autoimmune dysfunction. The presentation by dendritic cells (DCs) is the key step in initiating the immune response against unknown antigens in SAA patients. In the previous phase, we found that compared to healthy controls, patients with SAA had an increased proportion of circulating myeloid/conventional dendritic cells (mDCs/cDCs) with enhanced phagocytosis, more secretion of Th1-type cytokines (IL-2, TNF-α, IFN-γ) in the bone marrow, and a reduced proportion of Treg cells. In this study, we found that cDCs sorted from SAA patients had higher expression level of HLA-DQ, co-stimulatory molecules CD86, PTK and ERK1/2 than the remission SAA patients and healthy controls. Moreover, downregulation of HLA-DQ protein levels on cDCs derived from SAA patients resulted in reduced phagocytosis rate and CD86 expression of cDCs. When the cDCs above were co-cultured with CD4+ cells from the same patients, reduced secretion of Th1 type of lymphocyte cytokines was observed. Analysis of clinically relevant data suggests that HLA-DQ expression levels were closely related to disease severity and immune status of patients. These findings show that the role of HLA-DQ in the immunopathogenesis of SAA is potentially important and worth further study.","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47638425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The significance of surface neutrophilic MPO expression level in NETosis and NETosis-associated coagulopathies in covid-19 infected patients","authors":"Elham Jamali , Mojdeh Abbasi , Akbar Hashemi Tayer , Ali Arabi Monfared , Parisa Tandel , Gholamhossein Tamaddon , Ehsan Sarraf Kazerooni , Shahrokh Rakhshandehroo , Reza Ranjbaran","doi":"10.1016/j.bcmd.2022.102676","DOIUrl":"10.1016/j.bcmd.2022.102676","url":null,"abstract":"<div><h3>Introduction</h3><p>Inflammatory response-induced coagulopathy is a common complication associated with severe form of covid-19 infection. Evidences suggest that neutrophil extracellular traps (NETs) play a significant role in triggering the immunothrombosis in this condition. We aimed to evaluate the diagnostic value of surface neutrophilic myeloperoxidase (MPO) as NETosis biomarker for predicting the risk of covid-19-associated coagulopathies.</p></div><div><h3>Methods</h3><p>Covid-19 infection was assessed by real-time-PCR and plasma d-dimer levels were measured by ELFA. Based on the covid-19 infection and d-dimer level outcomes, patients were categorized into four groups. Any alteration in the serum level of IL-6, H3Cit and neutrophilic surface MPO were analyzed by CLIA, ELISA, and flow cytometry, respectively.</p></div><div><h3>Results</h3><p>H3Cit variations and different d-dimer values confirmed the association between NETosis and coagulopathies. Findings showed that the expression of neutrophilic MPO reduced in cases with NETosis, which was correlated with increased levels of H3Cit. ANC/MPO ratio was signified as a valuable marker to discriminate the covid-19 and non covid-19-associated coagulopathies and could be considered as a prognostic factor due to its noteworthy correlation with serum IL-6 concentration.</p></div><div><h3>Conclusion</h3><p>Declined levels of surface neutrophilic MPO in NETosis correlate with covid-19-associated coagulopathies and increased IL-6 levels, as a potential biomarker of covid-19 disease severity.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10394892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ze Wen Zhang , Da Ming Xu , Jin Feng Qiu , Wen Jun Yu , Jing Xing Yi , Cheng Wei Xu , Chun Ling He , Xian Ru Xu , Jie Song Xu , Jun Yin
{"title":"Investigation on abnormal gene loci of a Chinese pedigree with hereditary combined deficiency of blood coagulation factor XI, XII, and protein S","authors":"Ze Wen Zhang , Da Ming Xu , Jin Feng Qiu , Wen Jun Yu , Jing Xing Yi , Cheng Wei Xu , Chun Ling He , Xian Ru Xu , Jie Song Xu , Jun Yin","doi":"10.1016/j.bcmd.2022.102677","DOIUrl":"10.1016/j.bcmd.2022.102677","url":null,"abstract":"<div><h3>Objective</h3><p><span>In order to clarify the interaction mechanism, the phenotype and abnormal gene loci of </span>FXI<span>, FXII, and PS were investigated in this study.</span></p></div><div><h3>Methods</h3><p><span>Chinese pedigree with hereditary combined deficiency of coagulation factor<span> (F) XI, FXII, and PS was enrolled in our study. Activated partial thromboplastin time (APTT), partial thromboplastin time (PT), FXI:C, FXII:C, and protein S (PS):C were determined using the one-stage coagulation method. FXI:antigen (Ag), FXII:Ag, and PS:Ag were detected using enzyme-linked immunosorbent assay (ELISA). Exons and introns of the FXI, FXII, and PS genes were amplified by </span></span>polymerase chain reaction (PCR), and gene sequencing results were analyzed using Chromas software.</p></div><div><h3>Results</h3><p><span><span>A deletion of two bases located in introns A-149 and-150 within the FXI gene of the proband, his father, wife, and both sons. A </span>missense variant in exon 14 (GGT → AGT, Gly542Ser) within FXII of the proband, his parents, and both sons. Four variants in exon 4 within the PS gene of all members of the pedigree: </span>GTT → GTG (Val46Val), CGC → CTC (Arg49Leu), CGT → CAT (Arg60His), and CAG → TAG (Gln61stop).</p></div><div><h3>Conclusions</h3><p>None of the pedigree members showed a tendency for bleeding or thrombosis. Therefore, we speculated that the lack of coagulation factors counteracted the lack of PS, restoring the balance between the coagulation and anticoagulation<span> systems. Another possible explanation is that these defects individually have only partial penetrance.</span></p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49101434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meishan Yan , Minghui Xu , Zhanni Li , Yao An , Zelong Wang , Shuli Li , Yingli Chen , Yanshi Xia , Liqiu Wang , Longlong Wang , Shuting Ji , Weijun Dong , Jialan Shi , Chunyan Gao
{"title":"TMEM16F mediated phosphatidylserine exposure and microparticle release on erythrocyte contribute to hypercoagulable state in hyperuricemia","authors":"Meishan Yan , Minghui Xu , Zhanni Li , Yao An , Zelong Wang , Shuli Li , Yingli Chen , Yanshi Xia , Liqiu Wang , Longlong Wang , Shuting Ji , Weijun Dong , Jialan Shi , Chunyan Gao","doi":"10.1016/j.bcmd.2022.102666","DOIUrl":"10.1016/j.bcmd.2022.102666","url":null,"abstract":"<div><p><span>The link between hyperuricemia<span><span><span> (HUA) and the risk of venous thromboembolism<span> (VTE) has been well established. However, the mechanisms of thrombus generation and the effect of HUA on </span></span>procoagulant activity (PCA) of erythrocytes remain unclear no matter in </span>uremia<span> or hyperuricemia. Here, phosphatidylserine<span> (PS) exposure, microparticles (MPs) release, cytosolic Ca</span></span></span></span><sup>2+</sup><span><span>, TMEM16F expression, reactive oxygen species<span> (ROS) and lipid peroxidation of erythrocyte were detected by flow cytometer. PCA was assessed by coagulation time, purified coagulation complex and fibrin production assays. The </span></span>fibrin formation<span><span> was observed by scanning electron microscopy (SEM). We found that PS exposure, MPs generation, TMEM16F expression and consequent PCA of erythrocyte in HUA patients significantly increased compared to those in healthy volunteers. Furthermore, high UA<span> induced PS exposure, and MPs release of erythrocyte in concentration and time-dependent manners in vitro, which enhanced the PCA of erythrocyte and was inhibited by lactadherin, a PS inhibitor. Additionally, using SEM, we also observed compact </span></span>fibrin clots<span> with highly-branched networks and thin fibers supported by red blood cells<span> (RBCs) and RBC-derived MPs (RMPs). Importantly, we demonstrated UA enhanced the production of ROS and lipid peroxidation and reduced the generation of glutathione (GSH) of erythrocyte, which enhanced TMEM16F activity and followed PS externalization and RMPs formation. Collectively, these results suggest that Ca</span></span></span></span><sup>2+</sup>-dependent TMEM16F activation may be responsible for UA-induced PS exposure and MPs release of RBC, which thereby contribute to the prothrombotic risk in HUA.</p></div>","PeriodicalId":8972,"journal":{"name":"Blood Cells Molecules and Diseases","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45336091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}