IFN-I promotes T cell-independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD.

The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T cell-independent (TI) and T cell-dependent (TD) antigens. Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I IFN (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of antigen administration.

Hemolysis-driven IFNα production impairs erythropoiesis by negatively regulating EPO signaling in sickle cell disease.

Disordered erythropoiesis is a feature of many hematologic diseases, including sickle cell disease (SCD). However, very little is known about erythropoiesis in SCD. Here, we show that although bone marrow (BM) erythroid progenitors and erythroblasts in Hbbth3/+ thalassemia mice were increased more than twofold, they were expanded by only ∼40% in Townes sickle mice (SS).

The role of T cells and myeloid-derived suppressor cells in refractory immune thrombocytopenia.

Immune thrombocytopenia (ITP) is characterized by a dysregulated immune response against platelets, affecting both their destruction and production. A role for an abnormal T-cell compartment has been established in ITP pathogenesis and treatments that increase platelet counts in patients with ITP have shown improvements in T-cell profiles. On the other hand, patients who were refractory to treatment appear to retain the T-cell abnormalities as before.

Hemolysis dictates monocyte differentiation via two distinct pathways in sickle cell disease vaso-occlusion.

Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by painful vaso-occlusive crises (VOC) and chronic hemolysis. The mononuclear phagocyte system is pivotal to SCD pathophysiology, but the mechanisms governing monocyte/macrophage differentiation remain unknown. This study examined the influence of hemolysis on circulating monocyte trajectories in SCD.

Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease.

Sickle cell disease (SCD) is hallmarked by an underlying chronic inflammatory condition, which is contributed by heme-activated proinflammatory macrophages. Although previous studies addressed heme ability to stimulate macrophage inflammatory skewing through Toll-like receptor4 (TLR4)/reactive oxygen species signaling, how heme alters cell functional properties remains unexplored. Macrophage-mediated immune cell recruitment and apoptotic cell (AC) clearance are relevant in the context of SCD, in which tissue damage, cell apoptosis, and inflammation occur owing to vaso-occlusive episodes, hypoxia, and ischemic injury.

The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.

Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis.

Global Metabolomic Profiling of Host Red Blood Cells Infected with Babesia divergens Reveals Novel Antiparasitic Target Pathways.

Babesia divergens is an apicomplexan parasite that infects human red blood cells (RBCs), initiating cycles of invasion, replication, and egress, resulting in extensive metabolic modification of the host cells. Babesia is an auxotroph for most of the nutrients required to sustain these cycles. There are currently limited studies on the biochemical pathways that support these critical processes, necessitating the high-resolution global metabolomics approach described here to uncover the metabolic interactions between parasite and host RBC.

Identification and characterization of extracellular vesicles from red cells infected with and .

Babesiosis is a zoonosis and an important blood-borne human parasitic infection that has gained attention because of its growing infection rate in humans by transfer from animal reservoirs. represents a potential threat to the blood supply because asymptomatic infections in man are common, and blood from such donors can cause severe disease in certain recipients. Extracellular vesicles (EVs) are vesicles released by cells that contain a complex mixture of proteins, lipids, glycans, and genetic information that have been shown to play important roles in disease pathogenesis and susceptibility, as well as cell-cell communication and immune responses.

Elucidating parasite and host-cell factors enabling Babesia infection in sickle red cells under hypoxic/hyperoxic conditions.

Sickle red blood cells (RBCs) represent a naturally existing host-cell resistance mechanism to hemoparasite infections. We investigate the basis of this resistance using Babesia divergens grown in sickle (SS) and sickle trait (AS) cells. We found that oxygenation and its corresponding effect on RBC sickling, frequency of fetal hemoglobin positive (HbF+) cells, cellular redox environment, and parasite proliferation dynamics, all played a role in supporting or inhibiting Babesia proliferation.

Analyses of erythropoiesis from embryonic stem cell-CD34 and cord blood-CD34 cells reveal mechanisms for defective expansion and enucleation of embryomic stem cell-erythroid cells.

Red blood cells (RBCs) generated ex vivo have the potential to be used for transfusion. Human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) possess unlimited self-renewal capacity and are the preferred cell sources to be used for ex vivo RBC generation. However, their applications are hindered by the facts that the expansion of ES/iPS-derived erythroid cells is limited and the enucleation of ES/iPS-derived erythroblasts is low compared to that derived from cord blood (CB) or peripheral blood (PB).

Intermediate monocytes induced by IFN-γ inhibit cancer metastasis by promoting NK cell activation through FOXO1 and interleukin-27.

Background: Circulating monocytes are functionally heterogeneous and can be divided into classical (CMo), intermediate (IMo), and non-CMo/patrolling monocyte (PMo) subsets. CMo can differentiate into PMo through IMo. PMos have been shown to inhibit cancer metastasis but the role of IMo is unclear.

Sickle Cell Anemia and Infection.

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.

Vesicular formation regulated by ERK/MAPK pathway mediates human erythroblast enucleation.

Enucleation is a key event in mammalian erythropoiesis responsible for the generation of enucleated reticulocytes. Although progress is being made in developing mechanistic understanding of enucleation, our understanding of mechanisms for enucleation is still incomplete. The MAPK pathway plays diverse roles in biological processes, but its role in erythropoiesis has yet to be fully defined.

Murine bone marrow mesenchymal stromal cells have reduced hematopoietic maintenance ability in sickle cell disease.

Sickle cell disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contribute to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease, but their functionality in SCD remains unclear. We identified for the first time that murine SCD MSCs have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis.

Evidence for continued dose escalation of plerixafor for hematopoietic progenitor cell collections in sickle cell disease.

We present data from our study of plerixafor mobilization (NCT02193191) relevant to the question of whether further dose escalation of plerixafor can address inconsistent adequacy of CD34+ mobilization for gene therapy of sickle cell disease (SCD). We found that, in the same patient, higher plerixafor dosing was associated with higher fold increases in PB CD34+ count, but not necessarily higher absolute CD34+ counts. Variation in pre-apheresis absolute CD34+ counts was related to intra-individual variation in baseline PB CD34+ counts and inter-individual variation in responsiveness to plerixafor.

Type I interferon is induced by hemolysis and drives antibody-mediated erythrophagocytosis in sickle cell disease.

Patients with sickle cell disease (SCD) suffer from intravascular hemolysis-associated vascular injury and tissue damage. Classical monocytes (CMo), which are the most abundant of circulating monocytes, are activated in SCD, but the cause and consequences of activation remain incompletely understood. We found a positive correlation between total plasma heme levels and circulating interferon-α (IFN-α) in patients with SCD along with upregulation of the type I IFN (IFN-I) inducible genes in sort-purified SCD patients' CMo by transcriptome analysis.

Process and procedural adjustments to improve CD34+ collection efficiency of hematopoietic progenitor cell collections in sickle cell disease.

Background: Adequate CD34+ collection efficiency (CE) is critical to achieve target CD34+ cell doses in hematopoietic progenitor cell (HPC) collections. Autologous HPC collection in sickle cell disease (SCD) is associated with unstable collection interfaces and low CD34+ CEs. We hypothesized that variables specific to SCD, activation of blood cells and elevated viscosity, might contribute to these issues and made adjustments to the collection process and procedure to address our hypothesis.

EpoR-tdTomato-Cre mice enable identification of EpoR expression in subsets of tissue macrophages and hematopoietic cells.

The erythropoietin receptor (EpoR) has traditionally been thought of as an erythroid-specific gene. Notably, accumulating evidence suggests that EpoR is expressed well beyond erythroid cells. However, the expression of EpoR in non-erythroid cells has been controversial.

Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency.

Histone deacetylases (HDACs) are a group of enzymes that catalyze the removal of acetyl groups from histone and nonhistone proteins. HDACs have been shown to have diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined.

Characteristics of coronavirus disease 19 convalescent plasma donors and donations in the New York metropolitan area.

Background: Convalescent plasma (CP) is an important initial treatment in pandemics and the New York (NY) metropolitan area is likely to remain a hotspot for collection and distribution of such units. This study reports characteristics of coronavirus disease 19 CP (CCP) donors and their donations to the New York Blood Center (NYBC).

Study Design And Methods: All CCP data from our first day of collection on March 26th through July 7th, 2020 are included in this retrospective analysis.

Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease.

Red blood cell alloimmunization remains a barrier for safe and effective transfusions in sickle cell disease (SCD), but the associated risk factors remain largely unknown. Intravascular hemolysis, a hallmark of SCD, results in the release of heme with potent immunomodulatory activity, although its effect on SCD humoral response, specifically alloimmunization, remains unclear. Here, we found that cell-free heme suppresses human B-cell plasmablast and plasma cell differentiation by inhibiting the DOCK8/STAT3 signaling pathway, which is critical for B-cell activation, as well as by upregulating heme oxygenase 1 (HO-1) through its enzymatic byproducts, carbon monoxide and biliverdin.

Serological Assays Estimate Highly Variable SARS-CoV-2 Neutralizing Antibody Activity in Recovered COVID-19 Patients.

The development of neutralizing antibodies (NAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) following infection or vaccination is likely to be critical for the development of sufficient population immunity to drive cessation of the coronavirus disease of 2019 (COVID-19) pandemic. A large number of serologic tests, platforms, and methodologies are being employed to determine seroprevalence in populations to select convalescent plasma samples for therapeutic trials and to guide policies about reopening. However, the tests have substantial variations in sensitivity and specificity, and their ability to quantitatively predict levels of NAbs is unknown.