scholarly journals Immunological Hallmarks of Inflammatory Status in Vaso-Occlusive Crisis of Sickle Cell Anemia Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander Leonardo Silva-Junior ◽  
Nadja Pinto Garcia ◽  
Evilázio Cunha Cardoso ◽  
Stephanny Dias ◽  
Andrea Monteiro Tarragô ◽  
...  
Keyword(s):  
Growth Factors ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Gm Csf ◽  
Inflammatory Status ◽  
Ifn Γ

Sickle Cell Anemia (SCA) is the most common genetic disorder around the world. The mutation in the β-globin gene is responsible for a higher hemolysis rate, with further involvement of immunological molecules, especially cytokines, chemokines, growth factors, and anaphylatoxins. These molecules are responsible for inducing and attracting immune cells into circulation, thus contributing to increases in leukocytes and other pro-inflammatory mediators, and can culminate in a vaso-occlusive crisis (VOC). This study aimed to characterize the levels of these molecules in SCA patients in different clinical conditions in order to identify potential hallmarks of inflammation in these patients. An analytical prospective study was conducted using the serum of SCA patients in steady-state (StSt; n = 27) and VOC (n = 22), along with 53 healthy donors (HD). Samples from the VOC group were obtained on admission and on discharge, in the convalescent phase (CV). Levels of chemokines (CXCL8, CXCL10, CL2, CLL3, CCL4, CL5, and CCL11), cytokines (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-17A, TNF-α, and IFN-γ) and growth factors (VEGF, FGFb, PDGF-BB, GM-CSF, and G-CSF) were measured using a Luminex assay, and anaphylatoxins (C3a, C4a, and C5a) were measured using Cytometric Bead Array. SCA patients in StSt showed a pro-inflammatory profile, and were indicated as being higher producers of CCL2, IL-1β, IL-12p70, IFN-γ, IL-17A, and GM-CSF, while VOC is highlighted by molecules IL-4 and IL-5, but also IL-2, IL-7, PDGF-BB, and G-CSF. PDGF-BB and IL-1ra seemed to be two important hallmarks for the acute-to-chronic stage, due to their significant decrease after crisis inflammation and statistical difference in VOC and CV groups. These molecules show higher levels and a strong correlation with other molecules in VOC. Furthermore, they remain at higher levels even after crisis recovery, which suggest their importance in the role of inflammation during crisis and participation in immune cell adhesion and activation. These results support a relevant role of cytokines, neutrophil and monocytes, since these may act as markers of VOC inflammation in SCA patients.

scholarly journals Sickle Cell Anemia Patients Display an Intricate Cellular and Serum Biomarker Network Highlighted by TCD4+CD69+ Lymphocytes, IL-17/MIP-1β, IL-12/VEGF, and IL-10/IP-10 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-22 ◽  
Author(s):  
Nadja Pinto Garcia ◽  
Alexander Leonardo S. Júnior ◽  
Geyse Adriana S. Soares ◽  
Thainá Cristina C. Costa ◽  
Alicia Patrine C. dos Santos ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Adaptive Immunity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Leukocyte Adhesion ◽  
Death Risk ◽  
Gm Csf ◽  
Healthy Donors ◽  
High Death

Background. Sickle cell anemia (SCA) is associated with a chronic proinflammatory state characterized by elevated leukocyte count, mortality from severe recurrent infections, and subsequent vasoocclusive complications with leukocyte adhesion to the endothelium and increased plasma levels of inflammatory cytokines. The immune system has a close connection with morbidity in SCA, but further studies are needed to uncover the involvement of innate and adaptive immunities in modulating the SCA physiopathology. We performed measurements of the frequency of innate and adaptive immunity cells, cytokines, chemokines, and growth factors and immunophenotyping of Toll-like receptor and adhesion molecule expression in the blood of SCA patients and healthy donors to evaluate the different profiles of these biomarkers, the relationship among them, and their correlation to laboratory records and death risk. Material and Methods. Immunophenotyping of cells, Toll-like receptors, and adhesion molecules were performed from peripheral blood samples of SCA patients and healthy donors by flow cytometry and cytokine/chemokine/growth factor measurement by the Luminex technique performed from the serum of the same subjects. Results. Cells of adaptive immunity such as IL-12, IL-17, and IL-10 cytokines; IL-8, IP-10, MIP-1α, MIP-1β, and RANTES chemokines; and VEGF, FGF-basic, and GM-CSF growth factors were higher in SCA patients than healthy donors regardless of any laboratorial and clinical condition. However, high death risk appears to have relevant biomarkers. Conclusion. In the SCA pathophysiology at steady state, there is a broad immunological biomarker crosstalk highlighted by TCD4+CD69+ lymphocytes, IL-12 and IL-17 inflammatory and IL-10 regulatory cytokines, MIP-1α, MIP-1β, and IP-10 chemokines, and VEGF growth factor. High expression of TLR2 in monocytes and VLA-4 in TCD8+ lymphocytes and high levels of MIP-1β and RANTES appear to be relevant in high death risk conditions. The high reticulocytosis and high death risk conditions present common correlations, and there seems to be a balance by the Th2 profile.

Sickle Cell Anemia in a Child with Three β-Globin Clusters (β-S/β-S, β-A): Loss of LCR and 3' HS1 in the Duplicated Wild-Type β-Globin Cluster Does Not Fully Abrogate Its Transcript

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3371-3371
Author(s):  
N. Scott Reading ◽  
Barnaby E. Clark ◽  
Jihyun Song ◽  
Claire C. Shooter ◽  
Robin E. Miller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Regulatory Elements ◽  
Human Model ◽  
Globin Genes ◽  
Wild Type ◽  
Transformed Cell Lines

Abstract Transcriptional regulation of β-globin cluster genes follows a complex, highly conserved system of gene expression with developmental and tissue-specific control. The DNase I hypersensitivity (HS) sites in the upstream locus control region (LCR) and 3' HS1 element are thought to interact with β-globin cluster genes involving long range DNA interactions mediated by various transcription factors to drive the regulation of β-like globin gene expression. The majority of studies have focused on the role of the LCR on active transcription and globin gene switching. Various in vitro and in vivo studies have shown that the LCR interacts with one gene at a time and that absence of the LCR results in a dramatic decrease (10 -100 fold) in globin transcripts (Kiefer et. al., Mutat. Res. 2008, 647:68, Noordermeer et. al., IUBMB Life 2008, 60: 824). However, the role of the 3'HS1 downstream and other distal cis -regulatory elements are not entirely understood, with recent studies in mouse and cell-culture models suggesting they play a role in the insulation of globin genes from silencing chromatin (Bender et. al., Blood 2008, 106: 1395). Our knowledge of the β-globin LCR and 3'HS1 function is still incomplete and much can still be learned from human mutations affecting these regulatory elements. We report a unique head-to-tail duplication of the β-globin cluster in a patient phenotypically expressing homozygous HbS (sickle-cell anemia, SCA) that provides insight into the regulatory role of the β-LCR and 3'HS1 on wild-type β-globin (β-A) expression in a background of SCA. The studies were driven by an apparent discrepancy between hemoglobin analysis of an infant with a SCA phenotype and no detectable HBA, and Sanger sequencing of the β-globin genes which showed a heterozygous genotype. Analyses of parents' blood samples and DNA revealed that each were carriers for sickle cell allele. Hemoglobin analysis showed the father expressed HbS fraction at 41.3% and the mother at 33.3%, while the proband had a majority of HbS, some HbF and no detectable HbA. The reduced HbS fraction in the mother could be explained by co-inheritance of α-thalassemia (αα/α-3.7). The proband did not inherit α-thalassemia from the mother. Multiplex ligation-dependent probe amplification analysis of the proband's DNA suggested duplication of the β-globin cluster, resulting in three copies of the HBB gene in the genome. Subsequent next-generation sequencing confirmed that the duplication occurred immediately adjacent to the first iteration of sequence, in head-to-tail orientation and resulted in an intact β-S cluster having both LCR and HS1 elements, followed by the duplicated β-A cluster (β-S, β-A) that excluded a part of HBE (epsilon globin) and the upstream β-LCR regions, extending through to LINE L1LBP1 ([hg19] chr11:4640332-5290168). Further analyses revealed that the duplicated β-A cluster, which encompassed approximately 650 kb sequence, lacked a DNA segment containing the 3'HS1 element (figure 1). The proband's β genotype is thus (β-S/β-S, β-A). DNA analysis showed that the father carried the duplicated β-globin cluster with genotype (β-A/β-S, β-A), and the mother, a heterozygous HbS genotype (β-A/β-S). Reverse transcription, quantitative polymerase chain reaction (RT-qPCR) was used to assess transcription levels of β-A and β-S mRNA for each family member. Analysis of the parents' reticulocyte RNA showed that the β-globin (β-A and β-S) transcript levels were nearly balanced. RT-qPCR of proband's reticulocyte RNA showed no convincing detection of β-A transcript, but the β-A transcript was clearly detected by digitalPCR, albeit at a very low level (0.4% of total HBB transcript) (figure 2). The β-globin cluster duplication on one chromosome in a background of a phenotypically homozygous (HbSS) SCA patient has provided a unique opportunity to assess the effect of the LCR and 3'HS1 regions on the transcription of a β-A gene in an unbiased environment. Prior studies in transformed cell-lines or mouse models have shown the down regulatory effect of LCR loss and potential protective effect of the 3'HS1 element. Within the human model, the observed transcription from the duplicated, distally displaced (~650 kb) β-A cluster demonstrates that the loss of LCR and flanking HS sites does not lead to complete silencing of β-globin transcription. VD was supported by project IGA MzCR NT13587. Disclosures No relevant conflicts of interest to declare.

The orientation of sickle hemoglobin fibers within fascicles

1988 ◽  
Vol 46 ◽  
pp. 400-401
Author(s):  
Christopher A. Miller ◽  
Bridget Carragher ◽  
William A. McDade ◽  
Robert Josephs
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Relative Orientation ◽  
Unit Cell ◽  
Red Cell ◽  
High Ph ◽  
Sickle Hemoglobin ◽  
Polar Crystal ◽  
Helical Configuration

Highly ordered bundles of deoxyhemoglobin S (HbS) fibers, termed fascicles, are intermediates in the high pH crystallization pathway of HbS. These fibers consist of 7 Wishner-Love double strands in a helical configuration. Since each double strand has a polarity, the odd number of double strands in the fiber imparts a net polarity to the structure. HbS crystals have a unit cell containing two double strands, one of each polarity, resulting in a net polarity of zero. Therefore a rearrangement of the double strands must occur to form a non-polar crystal from the polar fibers. To determine the role of fascicles as an intermediate in the crystallization pathway it is important to understand the relative orientation of fibers within fascicles. Furthermore, an understanding of fascicle structure may have implications for the design of potential sickling inhibitors, since it is bundles of fibers which cause the red cell distortion responsible for the vaso-occlusive complications characteristic of sickle cell anemia.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

scholarly journals Variants of ZBTB7A (LRF) and its β-globin gene cluster binding motifs in sickle cell anemia

2016 ◽  
Vol 59 ◽  
pp. 49-51 ◽  
Author(s):  
Elmutaz M. Shaikho ◽  
Alawi H. Habara ◽  
Abdulrahman Alsultan ◽  
A.M. Al-Rubaish ◽  
Fahad Al-Muhanna ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Binding Motifs ◽  
Globin Gene Cluster

scholarly journals Sickle Cell Anemia and Babesia Infection

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1435
Author(s):  
Divya Beri ◽  
Manpreet Singh ◽  
Marilis Rodriguez ◽  
Karina Yazdanbakhsh ◽  
Cheryl Ann Lobo
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Current Knowledge ◽  
Globin Gene ◽  
Environmental Niche ◽  
Parasite Resistance ◽  
The Usa ◽  
Human Infections

Babesia is an intraerythrocytic, obligate Apicomplexan parasite that has, in the last century, been implicated in human infections via zoonosis and is now widespread, especially in parts of the USA and Europe. It is naturally transmitted by the bite of a tick, but transfused blood from infected donors has also proven to be a major source of transmission. When infected, most humans are clinically asymptomatic, but the parasite can prove to be lethal when it infects immunocompromised individuals. Hemolysis and anemia are two common symptoms that accompany many infectious diseases, and this is particularly true of parasitic diseases that target red cells. Clinically, this becomes an acute problem for subjects who are prone to hemolysis and depend on frequent transfusions, like patients with sickle cell anemia or thalassemia. Little is known about Babesia’s pathogenesis in these hemoglobinopathies, and most parallels are drawn from its evolutionarily related Plasmodium parasite which shares the same environmental niche, the RBCs, in the human host. In vitro as well as in vivo Babesia-infected mouse sickle cell disease (SCD) models support the inhibition of intra-erythrocytic parasite proliferation, but mechanisms driving the protection of such hemoglobinopathies against infection are not fully studied. This review provides an overview of our current knowledge of Babesia infection and hemoglobinopathies, focusing on possible mechanisms behind this parasite resistance and the clinical repercussions faced by Babesia-infected human hosts harboring mutations in their globin gene.

scholarly journals Deletion of cftr leads to an excessive neutrophilic response and defective tissue repair in a zebrafish model of sterile inflammation

2019 ◽  
Author(s):  
Audrey Bernut ◽  
Catherine A. Loynes ◽  
R. Andres Floto ◽  
Stephen A. Renshaw
Keyword(s):  
Cystic Fibrosis ◽  
Tissue Repair ◽  
Cell Function ◽  
Immune Cell ◽  
Genetic Disorder ◽  
Innate Immune ◽  
Lung Damage ◽  
Tanshinone Iia ◽  
Sterile Inflammation ◽  
Inflammatory Status

AbstractInflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used CFTR-depleted zebrafish larvae as an innovative in vivo vertebrate model, mimicking aspects of the inflammatory pathology of CF-related lung, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF.We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the pro-resolution molecule Tanshinone IIA successfully re-balances inflammation both by accelerating inflammation resolution and by improving tissue repair in CFTR-deficient animal.Larval zebrafish giving a unique insight into innate immune cell function in CFTR deficiency, our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.

scholarly journals Prevalence of Sickle Cell Disease and Other Haemoglobin Variants in Calabar, Cross River State, Nigeria

2019 ◽  
pp. 1-6
Author(s):  
Akaba Kingsley ◽  
Ofem Enang ◽  
Ofonime Essien ◽  
Annette Legogie ◽  
Omini Cletus ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Specific Gene ◽  
Cell Disease ◽  
Cellulose Acetate Electrophoresis ◽  
Genetic Changes ◽  
Female Ratio ◽  
Cross River State

Background: Sickle cell disease (SCD) is the commonest genetic disorder worldwide with a global prevalence of 20-25 million. About 12-15 million affected persons are in Sub-Sahara Africa with Nigeria bearing the highest burden of people living with sickle cell disease. SCD is a disease characterized as an autosomal, recessive, heterogeneous, and a monogenetic disorder caused by an A-to-T point mutation in the β-globin gene responsible for the production of abnormal hemoglobin S (HbS), which polymerizes in the deoxygenated state and results in the sickling of erythrocytes.  Haemoglobin variants are mutant forms of haemoglobin in a population usually occurring as a result of genetic changes in specific genes, or globins that causes change on alterations in the amino acid. They could affect the structure, behavior, the production rate and the stability of the specific gene. Well-known haemoglobin variants such as sick-cell anaemia are responsible for diseases and are considered haemoglobinopathies. Other variants cause no detectable pathology and are thus considered as non-pathological variants. Aim: The study is aimed at evaluating the burden of sickle cell disease and other haemoglobin variants in Calabar, South-South Nigeria. Methods: This is a retrospective study done at the haematology laboratory of University of Calabar Teaching Hospital, Calabar. Cellulose acetate electrophoresis at alkaline pH was used for the evaluation of haemoglobinopathies. The data were entered into Microsoft Excel 2016 spreadsheet and analysed with the IBM SPSS Version 22. Data were summarized into percentage of different phenotypes. Results: Results of the total 3648 haemoglobin electrophoresis recorded, 1368 (37.50%) were male while the remaining 2280 (62.5%) females given a male to female ratio of 1:1.7. Five haemoglobin phenotypes were identified as HbAA, HbAS, HbAC, HbSC and HbSS. The overall average values of their prevalence were HbAA 64.78%, HbAS 32.62%, HbSS 2.14%, HbAC 0.33%, HbSC 0.14%. Thus, the prevalence of SCD (Prevalence of HbSS+HbSC) was 2.28%. The highest proportion of SCD was observed in 2011 with least in 2016 and 2017 respectively. Conclusion: The prevalence of SCD and other haemoglobin variants in Calabar is similar to that of the national prevalence rate. There is need for continuous enlightenment and premarital counselling on the pattern of inheritance of SCD most especially with the increased burden of sickle traits in the environment has reported in this study.

Evaluation Of Some Coagulation Profile (PT, APTT) In Sudanese Pregnant Women With Sickle Cell Anemia

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Amged Hussein Abdelrhman ◽  
Abdelgadir Ahmed Abdelgadir
Keyword(s):  
Pregnant Women ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Case Control Study ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Coagulation System ◽  
Cell Disease ◽  
Duration Of Disease ◽  
Control Study

Background: Sickle cell disease refers to group of genetic disorder characterized by the predominance of hemoglobin S. Changes in the coagulation system seem to play an important role in the clinical manifestations of this disorder. Objective: This study aimed to determine the change in PT and APTT test in Sudanese pregnant women with sickle cell anemia. Material and methods: Fifty pregnant women with SCA with different age and different trimester, admitted to Mohammed Alamin Hamid hospital for children, were included case control study. Eleven healthy and pregnant women without SCA. Blood sample from three group were collected and investigated for PT and APTT. Results: The study revealed that in comparison with control mean PT (P=0.000) and APTT (p=0.000) high significant , in comparison with pregnant without SCA mean PT (P=0.000) and APTT (p=0.000) high significant ,no significant in comparison between all trimester mean PT (P=0.168) APTT (P=0.757) ,high significant in comparison with treatment mean PT(P=0,0000) APTT (P=0.000) ,in comparison with duration of disease and age mean PT(P=0.043) low significant with age APTT (P=0.558) no significant. Conclusion: The study concluded that these is hypercoagulable state in pregnant women with SCA indicated by prolongation in PT and APTT.

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