23 results on '"Verkerke, H."'
Search Results
2. P‐CB‐21 | RBC Alloimmunization Responder Type and COVID‐19 Vaccine IgG Response in Patients with Sickle Cell Disease
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Nakahara, H., primary, Cheedarla, N., additional, Verkerke, H., additional, Cheedarla, S., additional, Wu, S., additional, Hendrickson, J., additional, Roback, J., additional, Neish, A., additional, Fasano, R., additional, and Stowell, S., additional
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- 2023
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3. An automated approach to determine antibody endpoint titers for COVID-19 by an enzyme-linked immunosorbent assay
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Ho, A.D., primary, Verkerke, H., additional, Allen, J.W., additional, Saeedi, B.J., additional, Boyer, D., additional, Owens, J., additional, Shin, S., additional, Horwath, M., additional, Patel, K., additional, Paul, A., additional, Wu, S.-C., additional, Chonat, S., additional, Zerra, P., additional, Lough, C., additional, Roback, J.D., additional, Neish, A., additional, Josephson, C.D., additional, Arthur, C.M., additional, and Stowell, S.R., additional
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- 2021
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4. Investigation of Blood Plasma Viral Nucleocapsid Antigen as a Marker of Active Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant Infection.
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Damhorst GL, Schoof N, Nguyen PV, Verkerke H, Wilber E, McLendon K, O'Sick W, Baugh T, Cheedarla S, Cheedarla N, Stittleburg V, Fitts EC, Neja MA, Babiker A, Piantadosi A, Roback JD, Waggoner JJ, Mavigner M, and Lam WA
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Background: Nasopharyngeal qualitative reverse-transcription polymerase chain reaction (RT-PCR) is the gold standard for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is not practical or sufficient in every clinical scenario due to its inability to distinguish active from resolved infection. Alternative or adjunct testing may be needed to guide isolation precautions and treatment in patients admitted to the hospital., Methods: We performed a single-center, retrospective analysis of residual clinical specimens and medical record data to examine blood plasma nucleocapsid antigen as a candidate biomarker of active SARS-CoV-2. Adult patients admitted to the hospital or presenting to the emergency department with SARS-CoV-2 ribonucleic acid (RNA) detected by RT-PCR from a nasopharyngeal swab specimen were included. Both nasopharyngeal swab and a paired whole blood sample were required to be available for analysis., Results: Fifty-four patients were included. Eight patients had positive nasopharyngeal swab virus cultures, 7 of whom (87.5%) had concurrent antigenemia. Nineteen (79.2%) of 24 patients with detectable subgenomic RNA and 20 (80.0%) of 25 patients with N2 RT-PCR cycle threshold ≤ 33 had antigenemia., Conclusions: Most individuals with active SARS-CoV-2 infection are likely to have concurrent antigenemia, but there may be some individuals with active infection in whom antigenemia is not detectable. The potential for high sensitivity and convenience of a blood test prompts interest in further investigation as a screening tool to reduce reliance on nasopharyngeal swab sampling and as an adjunct diagnostic test to aid in clinical decision making during the period after acute coronavirus disease 2019., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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5. Factor H autoantibodies contribute to complement dysregulation in multisystem inflammatory syndrome in children (MIS-C).
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Zerra PE, Stowell J, Verkerke H, McCoy J, Jones J, Graciaa S, Lu A, Hussaini L, Anderson EJ, Rostad CA, Stowell SR, and Chonat S
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- Child, Humans, Complement Factor H, Systemic Inflammatory Response Syndrome
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- 2023
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6. Determinants of Neutralizing Antibody Response After SARS CoV-2 Vaccination in Patients With Myeloma.
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Nooka AK, Shanmugasundaram U, Cheedarla N, Verkerke H, Edara VV, Valanparambil R, Kaufman JL, Hofmeister CC, Joseph NS, Lonial S, Azeem M, Manalo J, Switchenko JM, Chang A, Linderman SL, Roback JD, Dhodapkar KM, Ahmed R, Suthar MS, Neish AS, and Dhodapkar MV
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- 2019-nCoV Vaccine mRNA-1273, Antibodies, Neutralizing, Antibodies, Viral, BNT162 Vaccine, Humans, Neutralization Tests, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Vaccination, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, Multiple Myeloma
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Purpose: Vaccine-induced neutralizing antibodies (nAbs) play a critical role in protection from SARS CoV-2. Patients with B-cell malignancies including myeloma are at increased risk of COVID-19-related mortality and exhibit variable serologic response to the vaccine. The capacity of vaccine-induced antibodies in these patients to neutralize SARS CoV-2 or its variants is not known., Methods: Sera from 238 patients with multiple myeloma (MM) undergoing SARS CoV-2 vaccination were analyzed. Antibodies against the SARS CoV-2 spike receptor-binding domain (RBD) and viral nucleocapsid were measured to detect serologic response to vaccine and environmental exposure to the virus. The capacity of antibodies to neutralize virus was quantified using pseudovirus neutralization assay and live virus neutralization against the initial SARS CoV-2 strain and the B1.617.2 (Delta) variant., Results: Vaccine-induced nAbs are detectable at much lower rates (54%) than estimated in previous seroconversion studies in MM, which did not monitor viral neutralization. In 33% of patients, vaccine-induced antispike RBD antibodies lack detectable neutralizing capacity, including against the B1.617.2 variant. Induction of nAbs is affected by race, disease, and treatment-related factors. Patients receiving mRNA1273 vaccine (Moderna) achieved significantly greater induction of nAbs compared with those receiving BNT162b2 (Pfizer; 67% v 48%, P = .006)., Conclusion: These data show that vaccine-induced antibodies in several patients with MM lack detectable virus-neutralizing activity. Vaccine-mediated induction of nAbs is affected by race, disease, vaccine, and treatment characteristics. These data have several implications for the emerging application of booster vaccines in immunocompromised hosts.
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- 2022
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7. Nucleocapsid Antigenemia in Patients Receiving Anti-CD20 Therapy With Protracted COVID-19.
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Wilber E, Piantadosi A, Babiker A, McLendon K, O'Sick W, Fitts E, Webster AS, Verkerke H, Kim JS, Phadke VK, Rouphael N, Titanji BK, Blake WT, Howard-Anderson J, Roback JD, Lam WA, and Damhorst GL
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Immunocompromised patients with prolonged coronavirus disease 2019 symptoms present diagnostic and therapeutic challenges. We measured viral nucleocapsid antigenemia in 3 patients treated with anti-CD20 immunotherapy who acquired severe acute respiratory syndrome coronavirus 2 infection and experienced protracted symptoms. Our results support nucleocapsid antigenemia as a marker of persistent infection and therapeutic response., Competing Interests: Potential conflicts of interest. The authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2022
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8. Purification of Recombinant Galectins from Different Species Using Distinct Affinity Chromatography Methods.
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Paul A, Wu SC, Patel KR, Ho AD, Allen JWL, Verkerke H, Arthur CM, and Stowell SR
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- Carbohydrates, Chromatography, Affinity, Galactose, Humans, Galectin 2, Galectins chemistry
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Galectins are lectins having the capacity to recognize β-galactose-containing glycan structures and are widely distributed among various taxa. However, the exact physiological and biochemical functions mediated by galectins that necessitate their wide occurrence among diverse species have not yet been delineated in a precise manner. Purification of recombinant galectins in active form is a fundamental requirement to elucidate their biological function. In this chapter, we are describing methods to recombinantly express and purify galectins using three different methods of affinity purification, i.e., lactosyl-Sepharose chromatography for fungal galectin Coprinopsis cinerea galectin 2 (CGL2), nickel-chromatography for histidine-tagged human galectin-7, and glutathione-Sepharose chromatography for Glutathione S-transferase-tagged (GST-tagged) human galectin-7. Step-by-step instructions are provided for obtaining the above-mentioned recombinant galectins that retain carbohydrate-binding activity and are suitable for conducting biochemical experiments., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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9. Galectins: An Ancient Family of Carbohydrate Binding Proteins with Modern Functions.
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Verkerke H, Dias-Baruffi M, Cummings RD, Arthur CM, and Stowell SR
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- Cell Cycle, Glycosylation, Signal Transduction, Galectins metabolism, Immune System metabolism
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Galectins are a large family of carbohydrate binding proteins with members in nearly every lineage of multicellular life. Through tandem and en-mass genome duplications, over 15 known vertebrate galectins likely evolved from a single common ancestor extant in pre-chordate lineages. While galectins have divergently evolved numerous functions, some of which do not involve carbohydrate recognition, the vast majority of the galectins have retained the conserved ability to bind variably modified polylactosamine (polyLacNAc) residues on glycans that modify proteins and lipids on the surface of host cells and pathogens. In addition to their direct role in microbial killing, many proposed galectin functions in the immune system and cancer involve crosslinking glycosylated receptors and modifying signaling pathways or sensitivity to antigen from the outside in. However, a large body of work has uncovered intracellular galectin functions mediated by carbohydrate- and non-carbohydrate-dependent interactions. In the cytoplasm, galectins can tune intracellular kinase and G-protein-coupled signaling cascades important for nutrient sensing, cell cycle progression, and transformation. Particularly, but interconnected pathways, cytoplasmic galectins serve the innate immune system as sensors of endolysosomal damage, recruiting and assembling the components of autophagosomes during intracellular infection through carbohydrate-dependent and -independent activities. In the nucleus, galectins participate in pre-mRNA splicing perhaps through interactions with non-coding RNAs required for assembly of spliceosomes. Together, studies of galectin function paint a picture of a functionally dynamic protein family recruited during eons of evolution to regulate numerous essential cellular processes in the context of multicellular life., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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10. COVID-19 convalescent plasma donor recruitment experience from the perspective of a hospital transfusion medicine service.
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Wade J, Dent EA, Wooten MS, Moosavi M, Butler H, Lough C, Verkerke H, Kamili NA, Maier CL, Josephson CD, Roback JD, Stowell SR, and Sullivan HC
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- Hospitals, Humans, Immunization, Passive, SARS-CoV-2, COVID-19 Serotherapy, COVID-19 therapy, Transfusion Medicine
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- 2021
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11. Are We Forgetting About IgA? A Re-examination of Coronavirus Disease 2019 Convalescent Plasma.
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Verkerke H, Saeedi BJ, Boyer D, Allen JW, Owens J, Shin S, Horwath M, Patel K, Paul A, Wu SC, Wang J, Ho A, Maier CL, Zerra PE, Chonat S, Arthur CM, Roback JD, Neish AS, Lough C, Josephson CD, and Stowell SR
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- Antibodies, Viral blood, Blood Donors, Down Syndrome complications, Down Syndrome immunology, Down Syndrome therapy, Female, Heart Septal Defects complications, Heart Septal Defects immunology, Heart Septal Defects therapy, Humans, Immunity, Humoral immunology, Immunization, Passive methods, Immunoglobulin A analysis, Immunoglobulin G blood, Immunoglobulin M blood, Infant, Retrospective Studies, Serologic Tests, United States, COVID-19 Serotherapy, COVID-19 immunology, COVID-19 therapy, Convalescence, Immunoglobulin A blood, SARS-CoV-2 immunology
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Background: While convalescent plasma (CP) may benefit patients with COVID-19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG-specific anti-SARS-CoV-2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP., Study Design and Methods: Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti-SARS-CoV-2 antibody titers against the receptor-binding domain responsible for viral entry. Symptom onset was obtained by chart review., Results: Increased IgA anti-SARS-CoV-2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID-19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation., Conclusions: IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID-19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity., (© 2021 AABB.)
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- 2021
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12. Comparison of Antibody Class-Specific SARS-CoV-2 Serologies for the Diagnosis of Acute COVID-19.
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Verkerke H, Horwath M, Saeedi B, Boyer D, Allen JW, Owens J, Arthur CM, Nakahara H, Rha J, Patel K, Wu SC, Paul A, Yasin N, Wang J, Shin S, Brown D, Normile K, Cole L, Meyers M, Lin H, Woods E, Isaac J, Broder K, Wade J, Kauffman RC, Patel R, Josephson CD, Reynolds S, Sherman M, Wrammert J, Alter D, Guarner J, Roback JD, Neish A, and Stowell SR
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- Antibodies, Viral, Cross-Sectional Studies, Humans, Immunoglobulin M, Sensitivity and Specificity, COVID-19, SARS-CoV-2
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Accurate diagnosis of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for appropriate management of patients with this disease. We examined the possible complementary role of laboratory-developed class-specific clinical serology in assessing SARS-CoV-2 infection in hospitalized patients. Serological tests for immunoglobulin G (IgG), IgA, and IgM antibodies against the receptor binding domain (RBD) of SARS-CoV-2 were evaluated using samples from real-time reverse transcription-quantitative PCR (qRT-PCR)-confirmed inpatient coronavirus disease 2019 (COVID-19) cases. We analyzed the influence of timing and clinical severity on the diagnostic value of class-specific COVID-19 serology testing. Cross-sectional analysis revealed higher sensitivity and specificity at lower optical density cutoffs for IgA in hospitalized patients than for IgG and IgM serology (IgG area under the curve [AUC] of 0.91 [95% confidence interval {CI}, 0.89 to 0.93] versus IgA AUC of 0.97 [95% CI, 0.96 to 0.98] versus IgM AUC of 0.95 [95% CI, 0.92 to 0.97]). The enhanced performance of IgA serology was apparent in the first 2 weeks after symptom onset and the first week after PCR testing. In patients requiring intubation, all three tests exhibit enhanced sensitivity. Among PCR-negative patients under investigation for SARS-CoV-2 infection, 2 out of 61 showed clear evidence of seroconversion IgG, IgA, and IgM. Suspected false-positive results in the latter population were most frequently observed in IgG and IgM serology tests. Our findings suggest the potential utility of IgA serology in the acute setting and explore the benefits and limitations of class-specific serology as a complementary diagnostic tool to PCR for COVID-19 in the acute setting., (Copyright © 2021 American Society for Microbiology.)
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- 2021
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13. The SARS-CoV-2 receptor-binding domain preferentially recognizes blood group A.
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Wu SC, Arthur CM, Wang J, Verkerke H, Josephson CD, Kalman D, Roback JD, Cummings RD, and Stowell SR
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- Amino Acid Sequence, COVID-19, Carbohydrate Conformation, Carbohydrate Sequence, Consensus Sequence, Erythrocyte Membrane metabolism, Galectin 4 chemistry, Galectins chemistry, Genetic Predisposition to Disease, Humans, Oligosaccharides genetics, Oligosaccharides, Branched-Chain, Organ Specificity, Protein Binding, Protein Domains, SARS-CoV-2, Sequence Alignment, Sequence Homology, Amino Acid, Spike Glycoprotein, Coronavirus chemistry, Substrate Specificity, ABO Blood-Group System genetics, Alveolar Epithelial Cells metabolism, Oligosaccharides metabolism, Spike Glycoprotein, Coronavirus metabolism
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- 2021
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14. Generation and Use of Recombinant Galectins.
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Wu SC, Paul A, Ho A, Patel KR, Allen JWL, Verkerke H, Arthur CM, and Stowell SR
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- Alkylation, Animals, Chromatography, Affinity, Galactose, Humans, Carbohydrates, Galectins metabolism
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Galectins are soluble carbohydrate binding proteins that can bind β-galactose-containing glycoconjugates by means of a conserved carbohydrate recognition domain (CRD). In mammalian systems, galectins have been shown to mediate very important roles in innate and adaptive immunity as well as facilitating host-pathogen relationships. Many of these studies have relied on purified recombinant galectins to uncover key features of galectin biology. A major limitation to this approach is that certain recombinant galectins purified using standard protocols are easily susceptible to loss of glycan-binding activity. As a result, biochemical studies that employ recombinant galectins can be misleading if the overall activity of a galectin remains unknown in a given assay condition. This article examines fundamental considerations when purifying galectins by lactosyl-sepharose and nickel-NTA affinity chromatography using human galectin-4N and -7 as examples, respectively. As other approaches are also commonly applied to galectin purification, we also discuss alternative strategies to galectin purification, using human galectin-1 and -9 as examples. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Purification of galectins using lactosyl-sepharose affinity chromatography Basic Protocol 2: Purification of human galectin-7 using a nickel-NTA affinity chromatography column Alternate Protocol 1: Iodoacetamide alkylation of free sulfhydryls on galectin-1 Alternate Protocol 2: Purification of human galectin-9 using lactosyl-sepharose column chromatography., (© 2021 Wiley Periodicals LLC.)
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- 2021
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15. Antigen density dictates RBC clearance, but not antigen modulation, following incompatible RBC transfusion in mice.
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Arthur CM, Allen JWL, Verkerke H, Yoo J, Jajosky RP, Girard-Pierce K, Chonat S, Zerra P, Maier C, Rha J, Fasano R, Josephson CD, Roback JD, and Stowell SR
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- Animals, Antigenic Modulation, Erythrocytes, Humans, Mice, Mice, Inbred C57BL, Antigens, Erythrocyte Transfusion
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Incompatible red blood cell (RBC) transfusion can result in life-threatening transfusion complications that can be challenging to manage in patients with transfusion-dependent anemia. However, not all incompatible RBC transfusions result in significant RBC removal. One factor that may regulate the outcome of incompatible RBC transfusion is the density of the incompatible antigen. Despite the potential influence of target antigen levels during incompatible RBC transfusion, a model system capable of defining the role of antigen density in this process has not been developed. In this study, we describe a novel model system of incompatible transfusion using donor mice that express different levels of the KEL antigen and recipients with varying anti-KEL antibody concentrations. Transfusion of KEL+ RBCs that express high or moderate KEL antigen levels results in rapid antibody-mediated RBC clearance. In contrast, relatively little RBC clearance was observed following the transfusion of KEL RBCs that express low KEL antigen levels. Intriguingly, unlike RBC clearance, loss of the KEL antigen from the transfused RBCs occurred at a similar rate regardless of the KEL antigen density following an incompatible transfusion. In addition to antigen density, anti-KEL antibody levels also regulated RBC removal and KEL antigen loss, suggesting that antigen density and antibody levels dictate incompatible RBC transfusion outcomes. These results demonstrate that antibody-induced antigen loss and RBC clearance can occur at distinct antigen density thresholds, providing important insight into factors that may dictate the outcome of an incompatible RBC transfusion., (© 2021 by The American Society of Hematology.)
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- 2021
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16. Complement Inhibition in Severe COVID-19 Acute Respiratory Distress Syndrome.
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Raghunandan S, Josephson CD, Verkerke H, Linam WM, Ingram TC, Zerra PE, Arthur CM, Stowell SR, Briones M, and Chonat S
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Most children with COVID-19 have asymptomatic or mild illness. Those who become critically ill suffer from acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). The rapid deterioration of lung function has been linked to microangiopathic and immune-mediated processes seen in the lungs of adult patients with COVID-19. The role of complement-mediated acute lung injury is supported by animal models of SARS-CoV, evaluation of lung tissue in those who died from COVID-19 and response of COVID-19 ARDS to complement inhibition. We present a summary of a child with COVID-19 disease treated with convalescent plasma and eculizumab and provide a detailed evaluation of the inflammatory pathways., Competing Interests: CJ receives research funds from Terumo BCT, Octapharma and Medtronics. SC is a scientific advisor to Alexion, Novartis and Agios pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Raghunandan, Josephson, Verkerke, Linam, Ingram, Zerra, Arthur, Stowell, Briones and Chonat.)
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- 2020
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17. Role of complement in alloimmunization and hyperhemolysis.
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Chonat S, Mener A, Verkerke H, and Stowell SR
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- Anemia, Hemolytic, Autoimmune etiology, Anemia, Hemolytic, Autoimmune immunology, Anemia, Hemolytic, Autoimmune pathology, Animals, Blood Group Incompatibility etiology, Blood Group Incompatibility pathology, Erythrocytes immunology, Erythrocytes pathology, Humans, Isoantibodies immunology, Blood Group Incompatibility immunology, Complement System Proteins immunology, Erythrocyte Transfusion adverse effects, Hemolysis, Isoantigens immunology
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Purpose of Review: The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC) transfusion, the formation of alloantibodies following RBC alloantigen exposure, and the development of hyperhemolysis in patients with sickle cell disease (SCD)., Recent Findings: Recent studies demonstrate that complement can accelerate alloantibody-mediated removal of target alloantigens from the RBC surface following incompatible transfusion. Complement also influences alloantigen availability during developing alloimmune responses and serves as a unique mediator of CD4 T-cell-independent alloantibody formation following RBC alloantigen exposure. Finally, alternative complement pathway activation appears to play a key role in the development of acute hemolytic episodes in patients with SCD, providing a potential druggable target to prevent acute complications in patients with this disease., Summary: Recent studies suggest that complement can regulate a wide variety of processes germane to hematology, from transfusion complications to baseline hemolysis in patients with SCD. As the role of complement in various disease processes becomes more fully understood, the ability to leverage recently developed complement modulating drugs will only continue to enhance providers' ability to favorably intervene in many hematological diseases.
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- 2020
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18. COVID-19 convalescent plasma clears SARS-CoV-2 refractory to remdesivir in an infant with congenital heart disease.
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Rodriguez Z, Shane AL, Verkerke H, Lough C, Zimmerman MG, Suthar M, Wrammert J, MacDonald H, Wolf M, Clarke S, Roback JD, Arthur CM, Stowell SR, and Josephson CD
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- Adenosine Monophosphate analogs & derivatives, Adenosine Monophosphate therapeutic use, Alanine analogs & derivatives, Alanine therapeutic use, Antibodies, Neutralizing therapeutic use, Antiviral Agents therapeutic use, COVID-19, Coronavirus Infections drug therapy, Coronavirus Infections immunology, Down Syndrome, Female, Heart Diseases congenital, Heart Diseases physiopathology, Humans, Infant, Pandemics, Pneumonia, Viral drug therapy, Pneumonia, Viral immunology, Respiratory Insufficiency etiology, Coronavirus Infections therapy, Heart Diseases complications, Immunization, Passive, Pneumonia, Viral therapy
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- 2020
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19. Fc Gamma Receptors and Complement Component 3 Facilitate Anti-fVIII Antibody Formation.
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Zerra PE, Arthur CM, Chonat S, Maier CL, Mener A, Shin S, Allen JWL, Baldwin WH, Cox C, Verkerke H, Jajosky RP, Tormey CA, Meeks SL, and Stowell SR
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- Animals, Antibody Formation, Complement C3 deficiency, Complement C3 genetics, Disease Models, Animal, Factor VIII administration & dosage, Female, Hemophilia A blood, Hemophilia A drug therapy, Hemophilia A genetics, Isoantigens administration & dosage, Mice, Inbred C57BL, Mice, Knockout, Receptors, IgG deficiency, Receptors, IgG genetics, Complement C3 metabolism, Factor VIII immunology, Hemophilia A immunology, Isoantibodies blood, Isoantigens immunology, Receptors, IgG metabolism
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Anti-factor VIII (fVIII) alloantibodies, which can develop in patients with hemophilia A, limit the therapeutic options and increase morbidity and mortality of these patients. However, the factors that influence anti-fVIII antibody development remain incompletely understood. Recent studies suggest that Fc gamma receptors (FcγRs) may facilitate recognition and uptake of fVIII by recently developed or pre-existing naturally occurring anti-fVIII antibodies, providing a mechanism whereby the immune system may recognize fVIII following infusion. However, the role of FcγRs in anti-fVIII antibody formation remains unknown. In order to define the influence of FcγRs on the development of anti-fVIII antibodies, fVIII was injected into WT or FcγR knockout recipients, followed by evaluation of anti-fVIII antibodies. Anti-fVIII antibodies were readily observed following fVIII injection into FcγR knockouts, with similar anti-fVIII antibody levels occurring in FcγR knockouts as detected in WT mice injected in parallel. As antibodies can also fix complement, providing a potential mechanism whereby anti-fVIII antibodies may influence anti-fVIII antibody formation independent of FcγRs, fVIII was also injected into complement component 3 (C3) knockout recipients in parallel. Similar to FcγR knockouts, C3 knockout recipients developed a robust response to fVIII, which was likewise similar to that observed in WT recipients. As FcγRs or C3 may compensate for each other in recipients only deficient in FcγRs or C3 alone, we generated mice deficient in both FcγRs and C3 to test for potential antibody effector redundancy in anti-fVIII antibody formation. Infusion of fVIII into FcγRs and C3 (FcγR × C3) double knockouts likewise induced anti-fVIII antibodies. However, unlike individual knockouts, anti-fVIII antibodies in FcγRs × C3 knockouts were initially lower than WT recipients, although anti-fVIII antibodies increased to WT levels following additional fVIII exposure. In contrast, infusion of RBCs expressing distinct alloantigens into FcγRs, C3 or FcγR × C3 knockout recipients either failed to change anti-RBC levels when compared to WT recipients or actually increased antibody responses, depending on the target antigen. Taken together, these results suggest FcγRs and C3 can differentially impact antibody formation following exposure to distinct alloantigens and that FcγRs and C3 work in concert to facilitate early anti-fVIII antibody formation., (Copyright © 2020 Zerra, Arthur, Chonat, Maier, Mener, Shin, Allen, Baldwin, Cox, Verkerke, Jajosky, Tormey, Meeks and Stowell.)
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- 2020
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20. Rapid generation of neutralizing antibody responses in COVID-19 patients.
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Suthar MS, Zimmerman M, Kauffman R, Mantus G, Linderman S, Vanderheiden A, Nyhoff L, Davis C, Adekunle S, Affer M, Sherman M, Reynolds S, Verkerke H, Alter DN, Guarner J, Bryksin J, Horwath M, Arthur C, Saakadze N, Smith GH, Edupuganti S, Scherer EM, Hellmeister K, Cheng A, Morales JA, Neish AS, Stowell SR, Frank F, Ortlund E, Anderson E, Menachery V, Rouphael N, Metha A, Stephens DS, Ahmed R, Roback J, and Wrammert J
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SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to understand the dynamics, specificity, and neutralizing potency of the humoral immune response during acute infection. Herein, we report the dynamics of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed patients (n=231). These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines.
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- 2020
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21. Malnutrition Is Associated with Protection from Rotavirus Diarrhea: Evidence from a Longitudinal Birth Cohort Study in Bangladesh.
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Verkerke H, Sobuz S, Ma JZ, Petri SE, Reichman D, Qadri F, Rahman M, Haque R, and Petri WA Jr
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- Adult, Bangladesh epidemiology, Child, Preschool, Female, Humans, Incidence, Infant, Infant, Newborn, Longitudinal Studies, Male, Pregnancy, Young Adult, Child Development, Diarrhea epidemiology, Diarrhea immunology, Disease Resistance, Malnutrition complications, Rotavirus Infections epidemiology, Rotavirus Infections immunology
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Rotavirus is a leading cause of dehydrating diarrhea and death among infants and children globally, particularly in communities of the developing world. While numerous studies have described the complex relationships among infectious diarrhea, growth faltering, and poverty, the impact of nutritional status on susceptibility to rotavirus diarrhea is not well understood. In a longitudinal study conducted over the first 3 years of life among 626 slum-dwelling infants enrolled at birth in Dhaka, Bangladesh, we observed that common measures of healthy growth and development were positively associated with a risk of symptomatic rotavirus infection. This finding runs counter to the idea that improving childhood nutrition will implicitly decrease the incidence of symptomatic infection by enteric pathogens. As childhood nutrition improves worldwide, rotavirus infection may remain a public health challenge, making universal vaccination of even greater importance., (Copyright © 2016 Verkerke et al.)
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- 2016
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22. Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan.
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Liang Y, Guttman M, Williams JA, Verkerke H, Alvarado D, Hu SL, and Lee KK
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- AIDS Vaccines immunology, Antibodies, Neutralizing immunology, Cell Line, Epitopes immunology, Glycoproteins immunology, Glycosylation, HEK293 Cells, HIV Antibodies immunology, HIV Envelope Protein gp120 immunology, HIV-1, Humans, Binding Sites immunology, CD4 Antigens immunology, Polysaccharides immunology, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Unlabelled: The envelope glycoprotein (Env) is the major target for HIV-1 broadly neutralizing antibodies (bNAbs). One of the mechanisms that HIV has evolved to escape the host's immune response is to mask conserved epitopes on Env with dense glycosylation. Previous studies have shown that the removal of a particular conserved glycan at N197 increases the neutralization sensitivity of the virus to antibodies targeting the CD4 binding site (CD4bs), making it a site of significant interest from the perspective of vaccine design. At present, the structural consequences that result from the removal of the N197 glycan have not been characterized. Using native-like SOSIP trimers, we examine the effects on antigenicity and local structural dynamics resulting from the removal of this glycan. A large increase in the binding of CD4bs and V3-targeting antibodies is observed for the N197Q mutant in trimeric Env, while no changes are observed with monomeric gp120. While the overall structure and thermostability are not altered, a subtle increase in the flexibility of the variable loops at the trimeric interface of adjacent protomers is evident in the N197Q mutant by hydrogen-deuterium exchange mass spectrometry. Structural modeling of the glycan chains suggests that the spatial occupancy of the N197 glycan leads to steric clashes with CD4bs antibodies in the Env trimer but not monomeric gp120. Our results indicate that the removal of the N197 glycan enhances the exposure of relevant bNAb epitopes on Env with a minimal impact on the overall trimeric structure. These findings present a simple modification for enhancing trimeric Env immunogens in vaccines., Importance: The HIV-1 Env glycoprotein presents a dense patchwork of host cell-derived N-linked glycans. This so-called glycan shield is considered to be a major protective mechanism against immune recognition. While the positions of many N-linked glycans are isolate specific, some are highly conserved and are believed to play key functional roles. In this study, we examine the conserved, CD4 binding site-proximal N197 glycan and demonstrate that its removal both facilitates neutralizing antibody access to the CD4 binding site and modestly impacts the structural dynamics at the trimer crown without drastically altering global Env trimer stability. This indicates that surgical glycosylation site modification may be an effective way of sculpting epitope presentation in Env-based vaccines., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)
- Published
- 2016
- Full Text
- View/download PDF
23. Kinetics of leptin binding to the Q223R leptin receptor.
- Author
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Verkerke H, Naylor C, Zabeau L, Tavernier J, Petri WA Jr, and Marie C
- Subjects
- Animals, HEK293 Cells, Humans, Kinetics, Mice, Protein Binding, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Surface Plasmon Resonance, Amino Acid Substitution, Leptin metabolism, Mutant Proteins genetics, Mutant Proteins metabolism, Receptors, Leptin genetics, Receptors, Leptin metabolism
- Abstract
Studies in human populations and mouse models of disease have linked the common leptin receptor Q223R mutation to obesity, multiple forms of cancer, adverse drug reactions, and susceptibility to enteric and respiratory infections. Contradictory results cast doubt on the phenotypic consequences of this variant. We set out to determine whether the Q223R substitution affects leptin binding kinetics using surface plasmon resonance (SPR), a technique that allows sensitive real-time monitoring of protein-protein interactions. We measured the binding and dissociation rate constants for leptin to the extracellular domain of WT and Q223R murine leptin receptors expressed as Fc-fusion proteins and found that the mutant receptor does not significantly differ in kinetics of leptin binding from the WT leptin receptor. (WT: ka 1.76×106±0.193×106 M-1 s-1, kd 1.21×10-4±0.707×10-4 s-1, KD 6.47×10-11±3.30×10-11 M; Q223R: ka 1.75×106±0.0245×106 M-1 s-1, kd 1.47×10-4±0.0505×10-4 s-1, KD 8.43×10-11±0.407×10-11 M). Our results support earlier findings that differences in affinity and kinetics of leptin binding are unlikely to explain mechanistically the phenotypes that have been linked to this common genetic variant. Future studies will seek to elucidate the mechanism by which this mutation influences susceptibility to metabolic, infectious, and malignant pathologies.
- Published
- 2014
- Full Text
- View/download PDF
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