The filovirus, Ebola virus (EBOV), causes outbreaks of EBOV disease (EVD) throughout equatorial Africa. ERVEBO is a replication-competent recombinant vesicular stomatitis virus-vectored vaccine encoding the EBOV glycoprotein (recombinant vesicular stomatitis virus [rVSV]/EBOV), which is licensed to control EVD outbreaks. EVD outbreaks occur in regions endemic for Plasmodium-caused malaria. Plasmodium infections persist due in part to the parasite's ability to evade sterilizing immunity, which also dampens immune responses to heterologous vaccines. Acute murine Plasmodium infection at the time of rVSV/EBOV vaccination reduced vaccine-mediated protection against mouse-adapted EBOV (ma-EBOV) challenge. Decreased protection was associated with a Plasmodium-induced interferon gamma-mediated decrease of rVSV/EBOV replication in lymph node macrophages, resulting in reduced primary anti-EBOV glycoprotein antibody responses. Higher doses of rVSV/EBOV partially overcame the antibody deficits and elicited protective responses. Evidence of the negative impact of Plasmodium on the efficacy of low-dose rVSV/EBOV vaccine protocols supports the use of high antigen loads in the effective management of EVD outbreaks. IMPORTANCE:We show that a blood-stage murine Plasmodium infection negatively impacts the primary antibody response elicited by low-dose recombinant vesicular stomatitis virus (rVSV)/Ebola virus (EBOV) vaccination and results in reduced protection against a lethal dose of mouse-adapted EBOV. This defect occurs within the draining lymph node due to the elevation of interferon gamma elicited in Plasmodium yoelii (Py)-infected mice. The Py-imposed decrease in vaccine-mediated protection can be overcome with higher doses of rVSV/EBOV. While the strong protection conferred by rVSV/EBOV and significant side effects known to be associated with this vaccine have led to the suggestion that the vaccine dosage be reduced, our studies provide a rationale for maintaining the current higher dose.

Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4+ T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8+ T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8+ T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease through the engagement of MHC Class-I in recipient mice. Here, we show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and CD11b+ cDC) in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to adopt a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4+ T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced CD11b+ cDC through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on CD11b+ cDC. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as Foxo3, in both cDC subsets with enrichment of pathways involved in immune regulation and T cell differentiation. Our study highlights a novel mechanism in which myelin-reactive CD8+ T cells directly interact with cDC1 and modulate CD11b+ cDC through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4+ T cell responses and reduced EAE pathogenesis.

Electronic medical records (EMRs) allow for the creation of “fictional” and unknown patients within the EMR production environment. Surprisingly, there is sparse literature regarding the use cases for these patients or the challenges associated with their existence in the EMR. Here, we identified three classes of patients in regular use at our institution: true fictional patients with medical record numbers (MRNs) used to test EMR functions in the production environment, “confidential patients” used to store sensitive data, and “unknown” patients that are assigned temporary MRNs in emergency situations until additional information can be acquired. A further layer of complexity involving the merging of records for unknown patients once they are identified is also explored. Each class of patients, real or fictional, poses a variety of challenges from a clinical laboratory standpoint, which are often dealt with on a case-by-case basis. Here, we present a series of instructional cases adapted from actual patient safety events at our institution involving fictional, confidential, and unknown patient records. These illustrative cases highlight the utility of these fictional and unknown patients, as well as the challenges they pose on an institutional and individual level, including issues that arise from merging clinical data from temporary MRNs to identified patient charts. Lastly, we provide recommendations on how best to manage similar scenarios that may arise.

BACKGROUND:Red blood cell exchange is often used prophylactically in patients with sickle cell disease, with the goal to maintain hemoglobin S (HbS) below a target threshold level. We reviewed whether the daily "rate of rise" (RoR) in HbS that occurs between procedures can be used for patient management. For some patients not achieving their HbS goals despite efficient exchanges, the post-procedure hematocrit (Hct) target is increased to potentially suppress HbS production. This case series explores the utility of this approach, other clinical uses of the daily RoR in HbS, and the factors that influence it. STUDY DESIGN AND METHODS:A total of 660 procedures from 24 patients undergoing prophylactic RBC depletion/exchange procedures were included. Laboratory values and clinical parameters were collected and used to calculate the daily RoR in HbS. Factors such as Hct or medications that might influence the RoR in HbS were evaluated. RESULTS:The RoR in HbS varied widely between patients but remained relatively stable within individuals. Surprisingly, this value was not significantly influenced by changes in post-procedure Hct or concurrent hydroxyurea use. A patient's average RoR in HbS effectively predicted the pre-procedure HbS at the following visit (R2 = 0.65). DISCUSSION:The RoR in HbS is a relatively consistent parameter for individual patients that is unaffected by medication use or procedural Hct targets and may be useful in determining intervals between procedures.

To reduce septic transfusion reactions due to bacterial contamination of platelets, several mitigation strategies have been implemented that impact the shelf-life of the unit. Large volume delayed sampling ≥48 h (LVDS48) for platelet bacterial testing allows for 7-day storage and has been widely adopted. A previous study demonstrated an increase in transfusion reaction rates from Days 3 to 5; however, it is unknown whether this trend will continue with Days 6–7 platelets. If older platelets are associated with increased reactions, this could lead to an increase in product wastage, testing, and labor costs for sites using LVDS48 platelets. Transfusion reaction rates to platelets aged 4–7 days were determined over a 3-year period (2018–2021) at two independent academic institutions. After exclusion of platelets given to patients <1-year-old, our final dataset contained 19,276 platelet transfusions (5813 + 13,463) in 4376 unique patients (1700 + 2676). Differences in practice between sites include universal product irradiation at one site and non-mandatory reporting of mild allergic reactions at the other site. Multivariable Bayesian hierarchical regression models accounting for sex, patient age, blood type, compatibility, date, site, patient, and hospital were used to determine the odds ratio (OR) and statistical significance for differences in reaction rates by storage age. A p-value less than .05 denotes statistical significance. Overall transfusion reaction rates differed between institutions (2.3% and 0.7%), likely due to differences in reporting practices. However, there was no statistical difference in transfusion reaction rates when comparing Days 4–5 platelets to Days 6–7 platelets (1.1% vs. 1.4%, respectively; OR = 1.11, p = .51). When the data were subdivided by transfusion reaction type, this finding remained the same for febrile nonhemolytic transfusion reactions at both institutions separately and in the combined data set (OR = 1.29, p = .30), and when stratified by ABO compatibility (Identical: OR = 1.28, p = .46; Not Identical: OR = 1.27, p = .48). Allergic transfusion reactions demonstrated an increased rate of reaction in non-ABO identical transfusions (OR = 3.32, p = .0005) only at the institution that required reporting of all allergic reactions. This collaborative multicenter retrospective review of platelet transfusion reaction rates did not overall demonstrate a significant increase in transfusion reaction rates with increased storage age. This study provides reassurance that the implementation of LVDS48 for platelet bacterial testing is unlikely to significantly increase the burden of transfusion reactions due to the increased use of older platelet units.

Point-of-care testing is widely used in a variety of clinical settings. While this testing provides immediate and actionable clinical information, it is prone to error in both the interpretation and reporting of results. Point-of-care urinalysis presents unique opportunities for errors, ranging from variation in visual interpretation to input of results. The data included here represent the results from 63,279 urinalyses from 36,780 unique patients performed over a span of three years at an academic medical center and its associated clinics. The data include the patient age/legal sex, methodology (instrument and test strip used), and the available test results (color, clarity, glucose, bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrite, and leukocyte esterase). Additionally, we include the method of interface between the testing instrumentation and our electronic medical record (EMR). These fell into one of three broad categories: "Interfaced" (results directly transmitted from the urinalysis instrument to the EMR via specialized data interface), "Manual" (results input by selecting from a drop-down menu in the laboratory information system), and "Enter/Edit" (results typed freely into a text field in the EMR). Analysis of this data was primarily a direct comparison of detectable errors (typos, uninterpretable results, and results outside the reportable range) as a function of the method of entry into the EMR. Secondary analysis comparing the impact of restricting drop-down menu options for urine color and clarity was also performed. These data are of use to others as they are diverse in terms of the test performed and the method of interface. Others may wish to analyze these data when making decisions as to how to perform and report these tests and when estimating risks of error with various methods of data entry.

TP53 mutation status guides early therapeutic decisions in the treatment of clonal myeloid disorders and serves as a simple means of monitoring response to treatment. We aim here to develop a standardized protocol for evaluating TP53 mutation status in myeloid disorders using immunohistochemistry assisted by digital image analysis and further compare this approach to manual interpretation alone. To accomplish this, we obtained 118 bone marrow biopsies from patients with hematologic malignancy and molecular testing for mutations associated with acute myeloid leukemia was performed. Clot or core biopsy slides were stained for p53 and digitally scanned. Overall mutation burden was assessed digitally using two different metrics to determine positivity, compared to the results of manual review, and correlated with molecular results. Using this approach, we found that digital analysis of immunohistochemistry stained slides performed worse than manual categorization alone in predicting TP53 mutation status in our cohort (PPV 91%, NPV 100% vs. PPV 100%, NPV 98%). While digital analysis reduced inter- and intraobserver variability when assessing mutation burden, there was poor correlation between the quantity and intensity of p53 staining and molecular analysis (R2 = 0.204). Therefore, digital image analysis of p53 immunohistochemistry accurately predicts TP53 mutation status as confirmed by molecular testing but does not offer a significant advantage over manual categorization alone. However, this approach offers a highly standardized methodology for monitoring disease status or response to treatment once a diagnosis has been made.

INTRODUCTION:Screening for hepatitis C virus (HCV) is performed by testing for anti-HCV antibodies, which may yield false-positive results leading to additional testing and other downstream consequences for the patient. We report our experience in a low prevalence population (<0.05%) using a two-assay algorithm aimed at testing specimens with borderline or weak positive anti-HCV reactivity in the screening assay by a second anti-HCV assay prior to confirming positive anti-HCV results with RT-PCR.MATERIALS AND METHODS:Retrospective analysis of 58,908 plasma samples was obtained over a 5-year period. Samples were initially tested using the Elecsys Anti-HCV II assay (Roche Diagnostics), with borderline or weakly positive results (defined in our algorithm as a Roche cutoff index of 0.9-19.99) reflexively analyzed using the Architect Anti-HCV assay (Abbott Diagnostics). The Abbott anti-HCV results dictated the final anti-HCV interpretation for reflexed samples.RESULTS:Our testing algorithm resulted in 180 samples requiring second-line testing, with final anti-HCV results interpreted as 9% positive, 87% negative, and 4% indeterminate. The positive predictive value (PPV) of a weakly positive Roche result was 12%, which was significantly lower than the PPV using our two-assay approach (65%).CONCLUSIONS:The incorporation of a two-assay serological testing algorithm in a low prevalence population provides a cost-effective method of improving the PPV of HCV screening in specimens with borderline or weakly positive anti-HCV results.

PURPOSE:A critical component of optimizing peripheral blood (PB) hematopoietic stem cell (HSC) collections is accurately determining the processed blood volume required to collect the targeted number of HSCs. Fundamental to most truncation equations employed to determine this volume is the procedure's estimated collection efficiency (CE), which is typically applied uniformly across all HSC collections. Few studies have explored the utility of using different CEs in subpopulations of donors that have substantially different CEs than the institutional average.METHODS:Initial procedures from 343 autologous and 179 allogeneic HSC collections performed from 2018 to 2021 were retrospectively analyzed. Predictive equations were developed to determine theoretical truncation rates in various donor subgroups.RESULTS:Quantitative variables (pre-procedure cell counts) and qualitative variables (relatedness to recipient, gender, method of venous access, and mobilization strategy) were found to significantly impact CE. However, much of the variability in CE between donors could not be explained by the variables assessed. Analyses of procedures with high pre-collection PB cell counts identified lower CE values for these donors' truncation equations which still allow truncation but minimize risk of collecting less CD34+ cells than requested.CONCLUSIONS:Individualized CE does not substantially improve truncation volume calculations over use of a fixed CE and adds complexity to these calculations. The optimal fixed CE varies between autologous and allogeneic donors, and donors with high pre-collection PB cell counts in either of these groups. This model will be clinically validated and continuously refined through analysis of future HSC collections.

Macrophages are critical in the pathogenesis of a diverse group of viral pathogens, both as targets of infection and for eliciting primary defense mechanisms. Our prior in vitro work identified that CD40 signaling in murine peritoneal macrophages protects against several RNA viruses by eliciting IL-12, which stimulates the production of interferon gamma (IFN-γ). Here, we examine the role of CD40 signaling in vivo. We show that CD40 signaling is a critical, but currently poorly appreciated, component of the innate immune response using two distinct infectious agents: mouse-adapted influenza A virus (IAV, PR8) and recombinant VSV encoding the Ebola virus glycoprotein (rVSV-EBOV GP). We find that stimulation of CD40 signaling decreases early IAV titers, whereas loss of CD40 elevated early titers and compromised lung function by day 3 of infection. Protection conferred by CD40 signaling against IAV is dependent on IFN-γ production, consistent with our in vitro studies. Using rVSV-EBOV GP that serves as a low-biocontainment model of filovirus infection, we demonstrate that macrophages are a CD40-expressing population critical for protection within the peritoneum and T-cells are the key source of CD40L (CD154). These experiments reveal the in vivo mechanisms by which CD40 signaling in macrophages regulates the early host responses to RNA virus infection and highlight how CD40 agonists currently under investigation for clinical use may function as a novel class of broad antiviral treatments.

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is arranged as a trimer on the virus surface, composed of three S1 and three S2 subunits. Infected and vaccinated individuals generate antibodies against spike, which can neutralize the virus. Most antibodies target the receptor-binding domain (RBD) and N-terminal domain (NTD) of S1; however, antibodies against other regions of spike have also been isolated. The interhost variability in domain specificity and relative neutralization efficacy of the antibodies is still poorly characterized. To this end, we tested serum and plasma samples collected from 85 coronavirus disease 2019 (COVID-19) convalescent subjects. Samples were analyzed using seven immunoassays that employ different domains, subunits, and oligomeric forms of spike to capture the antibodies. Samples were also tested for their neutralization of pseudovirus containing SARS-CoV-2 spike and of replication-competent SARS-CoV-2. While the total amount of anti-spike antibodies produced varied among convalescent subjects, we observed an unexpectedly fixed ratio of RBD- to NTD-targeting antibodies. The relative potency of the response (defined as the measured neutralization efficacy relative to the total level of spike-targeting antibodies) also exhibited limited variation between subjects and was not associated with the overall amount of antispike antibodies produced. These studies suggest that host-to-host variation in the polyclonal response elicited against SARS-CoV-2 spike in early pandemic subjects is primarily limited to the quantity of antibodies generated rather than their domain specificity or relative neutralization potency. IMPORTANCE Infection by SARS-CoV-2 elicits antibodies against various domains of the spike protein, including the RBD and NTD of subunit S1 and against subunit S2. The antibody responses of different infected individuals exhibit different efficacies to inactivate (neutralize) the virus. Here, we show that the observed variation in the neutralizing activity of the antibody responses in COVID-19 convalescent subjects is caused by differences in the amounts of antibodies rather than their recognition properties or the potency of their antiviral activity. These findings suggest that COVID-19 vaccine strategies that focus on enhancing the overall level of the antibodies will likely elicit a more uniformly efficacious protective response.

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) requires that several clinical criteria are met, and often relies on the identification of rare hemophagocytic cells in the bone marrow. Given the challenge in making the diagnosis, additional signs of immune dysregulation in the bone marrow would have practical clinical use in cases where overt hemophagocytosis is not seen. We present here a case of secondary HLH in a patient with autoimmune hemolysis ultimately diagnosed as Evans syndrome that initially presented with profound dyserythropoeisis in both the peripheral blood and bone marrow. We also explore an association between dyserythropoeisis and HLH in a series of cases previously seen at our institution.

Hematopoietic stem cells (HSCs) form the foundation of treatment for many hematologic and neoplastic diseases. The ability to collect HSCs that have been released into peripheral blood (PB) rather than harvesting from bone marrow (BM) directly has dramatically improved the likelihood of successful collection while minimizing donor discomfort [ [1] Bensinger W.I. Martin P.J. Storer B. Clift R. Forman S.J. Negrin R. et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001; 344: 175-181 Crossref PubMed Scopus (851) Google Scholar ]. To facilitate the release of HSCs into PB, cytokines that stimulate cell proliferation and agents that directly antagonize stromal adherence factors are administered for several days pre-collection. The quantification of these mobilized HSCs is often performed pre-collection, based on the expression of the cell-surface marker CD34 [ [2] Weaver C.H. Hazelton B. Birch R. Palmer P. Allen C. Schwartzberg L. et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood. 1995; 86: 3961-3969 Crossref PubMed Google Scholar ]. Importantly, CD34 expression is not restricted to HSCs; it is a general marker of immaturity, thus it is also useful in the diagnosis of hematologic malignancies such as myeloid/lymphoid leukemias and myelodysplastic syndromes. For HSC collection, the number of circulating CD34+ cells is useful in assuring adequate mobilization and may also be used to estimate the blood volume necessary to process to meet collection goals [ [3] Trickett A.E. Smith S. Kwan Y.L. Accurate calculation of blood volume to be processed by apheresis to achieve target CD34+ cell numbers for PBPC transplantation. Cytotherapy. 2001; 3: 5-10 Abstract Full Text PDF PubMed Scopus (14) Google Scholar ]. To provide perspective, the mean pre-apheresis CD34+ cell count in autologous HSC donors at our institution from 2018 to 2021 was 47.3 cells/µl (median 35.3 cells/µl). Furthermore, < 10% of donors had CD34+ cell counts > 100 cells/µl, and the highest value was 465 cells/µl. This report details two autologous HSC donors with circulating CD34+ cell counts exceeding 1000 cells/µl, with differing treatment decisions following further investigation.

Pain, in the appropriate context, is an essential component of life. It alerts us to danger, promotes healing, and plays a critical psychological role in normal growth and development. Chronic pain, in contrast, is physically and emotionally debilitating, and lies at the heart of some of the greatest challenges to our modern society. According to the Centers for Disease Control and Prevention, approximately 1 in 5 Americans suffer from chronic pain, costing an estimated $560 billion annually due to lost productivity, direct healthcare expenditures, and disability. Furthermore, well-intentioned efforts to combat chronic pain have contributed to an opioid crisis that has claimed an estimated 500 000 lives and continues to ravage vulnerable communities. Here we highlight recent studies seeking to better understand the physiologic underpinning of pain by examining the close relationship between the peripheral nervous system and cells of the immune system. In a recent review, Kavelaars and Heinjen explore the interface between neurons and cells of the innate and adaptive immune systems, providing compelling evidence that the two are tightly intertwined within the context of pain (1). The language through which neurons and immune cells communicate, namely cytokines and chemokines, is fundamental to the understanding of this so-called “neuroimmune pain circuit.” If one broadly divides these chemical signals, and the cells producing them, into pro- and anti-inflammatory groups, it is becoming increasingly evident that pro-inflammatory cytokines facilitate the transmission of and sensitization to pain, whereas anti-inflammatory signals mediate pain tolerance and promote its resolution. Several lines of evidence now support this notion and indeed, these observations fit nicely into the larger conceptual framework in immunology that seeks to classify subpopulations of cells by their pro- or anti-inflammatory phenotype.

Phosphatidylserine (PS) receptors are PS binding proteins that mediate uptake of apoptotic bodies. Many enveloped viruses utilize this PS/PS receptor mechanism to adhere to and internalize into the endosomal compartment of cells and this is termed apoptotic mimicry. For viruses that have a mechanism(s) of endosomal escape, apoptotic mimicry is a productive route of virus entry. We evaluated if PS receptors serve as cell surface receptors for SARS-CoV-2 and found that the PS receptors, AXL, TIM-1 and TIM-4, facilitated virus infection when low concentrations of the SARS-CoV-2 cognate receptor, ACE2, was present. Consistent with the established mechanism of PS receptor utilization by other viruses, PS liposomes competed with SARS-CoV-2 for binding and entry. We demonstrated that this PS receptor enhances SARS-CoV-2 binding to and infection of an array of human lung cell lines and is an under-appreciated but potentially important host factor facilitating SARS-CoV-2 entry.

Vaccination has been shown to stimulate remarkably high antibody levels in donors who have recovered from COVID-19. Our objective was to measure patient antibody levels before and after transfusion with COVID-19 Convalescent Plasma (CCP) and compare the antibody levels following transfusion of CCP from vaccinated and nonvaccinated donors. Plasma samples before and after transfusion were obtained from 25 recipients of CCP and COVID-19 antibody levels measured. Factors that effect changes in antibody levels were examined. In the 21 patients who received CCP from nonvaccinated donors, modest increases in antibody levels were observed. Patients who received two units were more likely to seroconvert than those receiving just one unit. The strongest predictor of changes in patient antibody level was the CCP dose, calculated by the unit volume multiplied by the donor antibody level. Using patient plasma volume and donor antibody level, the post-transfusion antibody level could be predicted with reasonable accuracy(R2> 0.90). In contrast, the 4 patients who received CCP from vaccinated donors all had dramatic increases in antibody levels following transfusion of a single unit. In this subset of recipients, antibody levels observed after transfusion of CCP were comparable to those seen in donors who had fully recovered from COVID-19. If available, CCP from vaccinated donors with very high antibody levels should be used. One unit of CCP from vaccinated donors increases patient antibody levels much more than 1 or 2 units of CCP from unvaccinated donors.

Humoral immunity is critical for limiting Plasmodium parasite infections and the severity of malaria. Naturally acquired immunity against malaria occurs inefficiently and protection is relatively short-lived. Here we review recent advances and explore emerging hypotheses regarding the molecular and cellular pathways that regulate Plasmodium parasite-specific B cell responses and durable anti-malarial humoral immunity.

Therapeutic plasma exchange (PLEX) involves the removal of detrimental substances, commonly pathogenic antibodies or toxins, from a patient's blood by exchanging their plasma with a replacement fluid. While a variety of replacement fluids are available, human albumin (4-5 %) is the most commonly used, as it is widely available, easily stored, and generally well tolerated. Despite its excellent safety profile, adverse reactions to albumin are well documented, ranging in severity from mild allergic symptoms to severe anaphylaxis. This report describes two cases of patients receiving frequent PLEX who developed sensitivities to human albumin. These patients differed substantially in the manifestations of their symptoms, the duration of their treatment, and their medical indication for PLEX. In both cases, symptom onset occurred shortly after completion of plasma exchange procedures and lasted for several hours. Symptoms disappeared when the patients were switched to albumin from a different manufacturer, suggesting that the reaction was specific to that formulation of albumin and not to the albumin itself. These cases highlight the possibility of manufacturer-specific acquired albumin sensitivities and provide a simple framework for the initial approach to the management of such reactions.

Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite-infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.