Human Sickle Cell Disease Increases Numbers and Activation Of Peripheral Blood Myeloid Dendritic Cells, Monocytes, and Neutrophils

Abstract Sickle cell disease (SCD) is characterized by widespread vaso-occlusion in venules that is initiated by the polymerization of deoxy-hemoglobin in sickle RBCs and exacerbated by leukocyte activation and endothelial injury. In the course of the disease, episodic flare-ups result in painful vaso-occlusive crises (pVOC) and acute chest syndrome that over time result in chronic tissue injury. We have previously shown that pVOC in SCD is associated with activation of a small subset of CD1d restricted T lymphocytes known as invariant NKT (iNKT) cells that release large amounts of pro-inflammatory cytokines and propagate an inflammatory cascade. Antigen presenting cells (APCs) stimulate the activation of iNKT cells by presenting lipid antigens on CD1d and by releasing co-activating cytokines such as IL-12 and IL-18. Cytokines released by activated iNKT cells such as IFN-γ further propagate inflammation by stimulating chemotaxis of and activation of additonal leukocytes. In mice, the cytokines that are released by activated iNKT cells trans-activate monocytes and neutrophils. In this study we investigated for the first time the effect of pVOC in patients on the activation of myeloid (CD11c+/CD123-) dendritic cells (DCs) (CD45+/Lin1-/HLA-DR+), monocytes (CD3-/CD19-/CD15-/CD66b-/CD14+), and neutrophils (CD3-/CD19-/CD15+/CD66b+). Our findings indicate that like iNKT cells, myeloid DCs, monocytes, and neutrophils are increased in peripheral blood of SCD subjects relative to non-SCD controls. Plasmacytoid DCs (CD11c-/CD123+) were little affected. This increase in cell numbers is enhanced during pVOC except for myeloid DCs which decrease, possibly due to extravasation out of the blood stream. In addition, CD1d+ myeloid DCs from SCD individuals express higher levels of the activation marker, CD86, and this is further increased during pVOC. Similarly, neutrophils and monocyte subsets including classical monocytes (CD14+/CD16-) and patrolling monocytes (CD14dim/CD16+) express higher levels of activated adhesion molecules, LFA-1 (detected with KIM127 antibody) and Mac-1 (detected with CBRM1/5 antibody that recognizes active CD11b), in SCD subjects during pVOC as compared to controls and steady-state SCD patients. Taken together, these findings strongly suggest that the severity of vaso-occlusion during the clinical course of SCD correlates with an increased pro-inflammatory state reflected by increased circulating activated leukocytes. These findings are also consistent with previous murine studies showing that iNKT cells are necessary, but not sufficient for initiating and amplification of tissue inflammation and damage. The activation of CD1d+ APCs during pVOC is likely to facilitate iNKT cell activation due to the expression of co-stimulatory molecules (CD86), inflammatory cytokines, and possibly lipid antigens. Moreover, the activation of adhesion molecules on monocytes and neutrophils may enhance their propensity to contribute to vaso-occlusion. Disclosures: Field: NKT Therapeutics: Consultancy.

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Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease

Frontiers in Immunology ◽

10.3389/fimmu.2020.617962 ◽

2021 ◽

Vol 11 ◽

Author(s):

Renata Sesti-Costa ◽

Marina Dorigatti Borges ◽

Carolina Lanaro ◽

Dulcinéia Martins de Albuquerque ◽

Sara Terezinha Olalla Saad ◽

...

Keyword(s):

Dendritic Cells ◽

Sickle Cell Disease ◽

Inflammatory Cytokines ◽

Sickle Cell ◽

B Lymphocyte ◽

Cytokine Production ◽

Reticulocyte Count ◽

Cell Disease ◽

Main Component ◽

Inflammatory Dendritic Cells

Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14+ DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14+ mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.

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Berkeley Mice with Sickle Cell Disease Are Not More Immunizable to Transfused HOD Red Blood Cells Than Sickle Trait Control Mice

Blood ◽

10.1182/blood.v112.11.292.292 ◽

2008 ◽

Vol 112 (11) ◽

pp. 292-292

Author(s):

Jeanne HendricKson ◽

David R. Archer ◽

Jennifer R. Perry ◽

Christopher D. Hillyer ◽

James C. Zimring

Keyword(s):

Dendritic Cells ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Trait ◽

Antigen Presenting Cells ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Foreign Antigen ◽

Inflammatory Status ◽

Antigen Presenting

Abstract Background: Patients with sickle cell disease have higher rates of red blood cell (RBC) alloimmunization following transfusion than any other patient population. However, it is unclear if they are inherently more immunizable, or if the high rates of RBC alloimmunization are simply due to antigenic differences between donors/recipients and heightened transfusion frequency. Utilizing a murine model, we have previously shown that rates of alloimmunization are influenced by the inflammatory status of the recipient at the time of the transfusion. Thus, we hypothesized that sickle patients may be more immunizable, due in part to the baseline inflammation associated with their disease. Herein, we present a reductionist murine sickle model of RBC alloimmunization, and investigate the hypothesis that mice with sickle cell disease are more likely to become alloimmunized following transfusion of RBCs containing a foreign antigen than sickle trait controls. Materials/Methods: Berkeley mice (with human α and βS-globin) were determined to be homozygous (sickle cell disease) or heterozygous (sickle cell trait) by cellulose acetate electrophoresis. We generated the HOD mouse, with RBC specific expression of the model humoral antigen hen egg lysozyme (HEL) fused to the model minor histocompatibility antigen ovalbumin (OVA), linked to the cell membrane by a human blood group antigen (Duffy). The inclusion of OVA in the HOD construct allows presentation of HOD peptides from H-2b MHC; thus, Berkeley mice are able to process and present the HOD antigen. 100 microliters of packed HOD RBCs were transfused IV into mice with sickle cell disease or sickle cell trait; alloimmunization to the HEL antigen was assessed by anti-HEL IgG ELISA 2 weeks following transfusion. Given that co-stimulatory molecule expression on antigen presenting cells in part determines the response of the CD4+ T cell to the antigen being presented, we examined baseline expression of B7-1, B7-2, Ox40L, CD70, 41BBL, CD30L, and CD40 on macrophages (F480 high) and dendritic cells (CD11c high) in sickle cell disease and sickle trait mice. Results: Data for a standard curve was fit to one phase exponential association, with a non-linear best fit regression analysis (R2 of 0.96). Utilizing the OD 415 value of the anti-HEL IgG ELISA, data was combined from 3 separate experiments (n=31 mice). An unpaired two-tailed t-test showed a mean of 6.25e-5, SD 5.87e-5 for sickle disease mice, and a mean of 4.14e-5, SD 2.84e-5 for sickle trait mice, p=0.217 (see figure). Baseline co-stimulatory molecule expression of all molecules examined on macrophages and dendritic cells was similar in both sickle cell disease and sickle trait mice. Figure Figure Conclusions: Generation of the HOD mouse, containing a model humoral antigen capable of being presented by the antigen presenting cells in the Berkeley mice, allowed these studies to be performed. These data rule out the hypothesis that Berkeley mice with sickle cell disease are substantially more immunizable to a single transfusion of RBCs containing the HOD foreign antigen than are those with sickle cell trait. However, there is a large standard deviation in alloantibody response between individual mice with sickle cell disease. The varied response may be explained by differing levels of illness in individual mice; ongoing studies are investigating such a potential correlation. Clinically, many patients with sickle cell disease are transfused in times of illness (i.e. acute chest syndrome), and the possibility that illness alters alloantibody response cannot be ruled out by these studies. Furthermore, although the model was designed to be as reductionist as possible, these studies are limited by the highly heterogeneous genetic background of the Berkeley mice (including FVB/N, 129, DBA/2, C57BL/6, and Black Swiss); this diverse background likely influences response to foreign antigen and makes identifying control groups difficult. Finally, although Berkeley mice with sickle cell disease are known to have baseline inflammation associated with their disease, this does not appear to influence co-stimulatory molecule expression on their antigen presenting cells.

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Repeat Peripheral Blood Stem Cell Transplantation for Patients With Sickle Cell Disease and Falling Donor Myeloid Chimerism Levels

Case Medical Research ◽

10.31525/ct1-nct04008368 ◽

2019 ◽

Author(s):

Keyword(s):

Stem Cell ◽

Sickle Cell Disease ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Sickle Cell ◽

Peripheral Blood ◽

Peripheral Blood Stem Cell ◽

Blood Stem Cell ◽

Cell Disease ◽

Blood Stem Cell Transplantation

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ECMO Therapy in Acute Chest Syndrome for Patients with Sickle Cell Disease: a Case Report and Literature Review

SN Comprehensive Clinical Medicine ◽

10.1007/s42399-021-00987-0 ◽

2021 ◽

Author(s):

Soi Avgeridou ◽

Ilija Djordjevic ◽

Anton Sabashnikov ◽

Kaveh Eghbalzadeh ◽

Laura Suhr ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Scientific Data ◽

Acute Chest Syndrome ◽

Data Sets ◽

Limited Data ◽

Cell Disease ◽

Life Saving ◽

Institutional Experience ◽

Ecmo Therapy

AbstractExtracorporeal membrane oxygenation (ECMO) plays an important role as a life-saving tool for patients with therapy-refractory cardio-respiratory failure. Especially, for rare and infrequent indications, scientific data is scarce. The conducted paper focuses primarily on our institutional experience with a 19-year-old patient suffering an acute chest syndrome, a pathognomonic pulmonary condition presented by patients with sickle cell disease. After implementation of awake ECMO therapy, the patient was successfully weaned off support and discharged home 22 days after initiation of the extracorporeal circulation. In addition to limited data and current literature, further and larger data sets are necessary to determine the outcome after ECMO therapy for this rare indication.

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Streptococcus pneumoniae and Its Virulence Factors H2O2 and Pneumolysin Are Potent Mediators of the Acute Chest Syndrome in Sickle Cell Disease

Toxins ◽

10.3390/toxins13020157 ◽

2021 ◽

Vol 13 (2) ◽

pp. 157

Author(s):

Joyce Gonzales ◽

Trinad Chakraborty ◽

Maritza Romero ◽

Mobarak Abu Mraheil ◽

Abdullah Kutlar ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Sickle Cell Disease ◽

Virulence Factors ◽

Sickle Cell ◽

Biological Activities ◽

Acute Chest Syndrome ◽

Antibiotics Resistance ◽

Cell Disease ◽

Antibiotic Drug ◽

Tract Infections

Sickle cell disease (SCD) is one of the most common autosomal recessive disorders in the world. Due to functional asplenia, a dysfunctional antibody response, antibiotic drug resistance and poor response to immunization, SCD patients have impaired immunity. A leading cause of hospitalization and death in SCD patients is the acute chest syndrome (ACS). This complication is especially manifested upon infection of SCD patients with Streptococcus pneumoniae (Spn)—a facultative anaerobic Gram-positive bacterium that causes lower respiratory tract infections. Spn has developed increased rates of antibiotics resistance and is particularly virulent in SCD patients. The primary defense against Spn is the generation of reactive oxygen species (ROS) during the oxidative burst of neutrophils and macrophages. Paradoxically, Spn itself produces high levels of the ROS hydrogen peroxide (H2O2) as a virulence strategy. Apart from H2O2, Spn also secretes another virulence factor, i.e., the pore-forming exotoxin pneumolysin (PLY), a potent mediator of lung injury in patients with pneumonia in general and particularly in those with SCD. PLY is released early on in infection either by autolysis or bacterial lysis following the treatment with antibiotics and has a broad range of biological activities. This review will discuss recent findings on the role of pneumococci in ACS pathogenesis and on strategies to counteract the devastating effects of its virulence factors on the lungs in SCD patients.

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To Give or Not to Give: RhD Immunoglobulin for an RHD*39 Pregnant Woman with Sickle Cell Disease

Transfusion Medicine and Hemotherapy ◽

10.1159/000512644 ◽

2021 ◽

pp. 1-5

Author(s):

Justin E. Juskewitch ◽

Craig D. Tauscher ◽

Sheila K. Moldenhauer ◽

Jennifer E. Schieber ◽

Eapen K. Jacob ◽

...

Keyword(s):

Pregnant Woman ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Pregnancy Termination ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Childbearing Age ◽

Procedural Complications ◽

History Of ◽

Chronic Hemolysis

Introduction: Patients with sickle cell disease (SCD) have repeated episodes of red blood cell (RBC) sickling and microvascular occlusion that manifest as pain crises, acute chest syndrome, and chronic hemolysis. These clinical sequelae usually increase during pregnancy. Given the racial distribution of SCD, patients with SCD are also more likely to have rarer RBC antigen genotypes than RBC donor populations. We present the management and clinical outcome of a 21-year-old pregnant woman with SCD and an RHD*39 (RhD[S103P], G-negative) variant. Case Presentation: Ms. S is B positive with a reported history of anti-D, anti-C, and anti-E alloantibodies (anti-G testing unknown). Genetic testing revealed both an RHD*39 and homozygous partial RHCE*ceVS.02 genotype. Absorption/elution testing confirmed the presence of anti-G, anti-C, and anti-E alloantibodies but could not definitively determine the presence/absence of an anti-D alloantibody. Ms. S desired to undergo elective pregnancy termination and the need for postprocedural RhD immunoglobulin (RhIG) was posed. Given that only the G antigen site is changed in an RHD*39 genotype and the potential risk of RhIG triggering a hyperhemolytic episode in an SCD patient, RhIG was not administered. There were no procedural complications. Follow-up testing at 10 weeks showed no increase in RBC alloantibody strength. Discussion/Conclusion: Ms. S represents a rare RHD*39 and partial RHCE*ceVS.02 genotype which did not further alloimmunize in the absence of RhIG administration. Her case also highlights the importance of routine anti-G alloantibody testing in women of childbearing age with apparent anti-D and anti-C alloantibodies.

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Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease

Hematology ◽

10.1182/asheducation-2007.1.84 ◽

2007 ◽

Vol 2007 (1) ◽

pp. 84-90 ◽

Cited By ~ 27

Author(s):

Marilyn J. Telen

Keyword(s):

Sickle Cell Disease ◽

Red Blood Cells ◽

Adhesion Molecules ◽

Sickle Cell ◽

Vascular Endothelium ◽

Blood Cells ◽

Cell Disease ◽

Adhesive Interactions ◽

Lines Of Evidence

AbstractA number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.

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