Browsing by Subject "Antibodies"

Now showing 1 - 10 of 24
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    Accumulation of Neutrophil Phagocytic Antibody Features Tracks With Naturally Acquired Immunity Against Malaria in Children
    (Oxford University Press, 2023) Nziza, Nadege; Tran, Tuan M.; DeRiso, Elizabeth A.; Dolatshahi, Sepideh; Herman, Jonathan D.; de Lacerda, Luna; Junqueira, Caroline; Lieberman, Judy; Ongoiba, Aissata; Doumbo, Safiatou; Kayentao, Kassoum; Traore, Boubacar; Crompton, Peter D.; Alter, Galit; Medicine, School of Medicine
    Background: Studies have demonstrated the protective role of antibodies against malaria. Young children are known to be particularly vulnerable to malaria, pointing to the evolution of naturally acquired clinical immunity over time. However, whether changes in antibody functionality track with the acquisition of naturally acquired malaria immunity remains incompletely understood. Methods: Using systems serology, we characterized sporozoite- and merozoite-specific antibody profiles of uninfected Malian children before the malaria season who differed in their ability to control parasitemia and fever following Plasmodium falciparum (Pf) infection. We then assessed the contributions of individual traits to overall clinical outcomes, focusing on the immunodominant sporozoite CSP and merozoite AMA1 and MSP1 antigens. Results: Humoral immunity evolved with age, with an expansion of both magnitude and functional quality, particularly within blood-stage phagocytic antibody activity. Moreover, concerning clinical outcomes postinfection, protected children had higher antibody-dependent neutrophil activity along with higher levels of MSP1-specific IgG3 and IgA and CSP-specific IgG3 and IgG4 prior to the malaria season. Conclusions: These data point to the natural evolution of functional humoral immunity to Pf with age and highlight particular antibody Fc-effector profiles associated with the control of malaria in children, providing clues for the design of next-generation vaccines or therapeutics.
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    Author Correction: Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C
    (Springer Nature, 2022-08-12) Tang, Juanjie; Novak, Tanya; Hecker, Julian; Grubbs, Gabrielle; Zahra, Fatema Tuz; Bellusci, Lorenza; Pourhashemi, Sara; Chou, Janet; Moffitt, Kristin; Halasa, Natasha B.; Schwartz, Stephanie P.; Walker, Tracie C.; Tarquinio, Keiko M.; Zinter, Matt S.; Staat, Mary A.; Gertz, Shira J.; Cvijanovich, Natalie Z.; Schuster, Jennifer E.; Loftis, Laura L.; Coates, Bria M.; Mack, Elizabeth H.; Irby, Katherine; Fitzgerald, Julie C.; Rowan, Courtney M.; Kong, Michele; Flori, Heidi R.; Maddux, Aline B.; Shein, Steven L.; Crandall, Hillary; Hume, Janet R.; Hobbs, Charlotte V.; Tremoulet, Adriana H.; Shimizu, Chisato; Burns, Jane C.; Chen, Sabrina R.; Moon, Hye Kyung; Lange, Christoph; Randolph, Adrienne G.; Khurana, Surender; Pediatrics, School of Medicine
    Correction to: Nature Communications 10.1038/s41467-022-30649-1, published online 27 May 2022
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    B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes
    (MDPI, 2021-01-06) Felton, Jamie L.; Conway, Holly; Bonami, Rachel H.; Pediatrics, School of Medicine
    Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.
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    Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette
    (Elsevier, 2021-08-26) Kumar, Sandeep R. P.; Xie, Jun; Hu, Shilang; Ko, Jihye; Huang, Qifeng; Brown, Harrison C.; Srivastava, Alok; Markusic, David M.; Doering, Christopher B.; Spencer, H. Trent; Srivastava, Arun; Gao, Guangping; Herzog, Roland W.; Pediatrics, School of Medicine
    Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 × 1011 vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8+ T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans.
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    Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C
    (Springer Nature, 2022-05-27) Tang, Juanjie; Novak, Tanya; Hecker, Julian; Grubbs, Gabrielle; Tuz Zahra, Fatema; Bellusci, Lorenza; Pourhashemi, Sara; Chou, Janet; Moffitt, Kristin; Halasa, Natasha B.; Schwartz, Stephanie P.; Walker, Tracie C.; Tarquinio, Keiko M.; Zinter, Matt S.; Staat, Mary A.; Gertz, Shira J.; Cvijanovich, Natalie Z.; Schuster, Jennifer E.; Loftis, Laura L.; Coates, Bria M.; Mack, Elizabeth H.; Irby, Katherine; Fitzgerald, Julie C.; Rowan, Courtney M.; Kong, Michele; Flori, Heidi R.; Maddux, Aline B.; Shein, Steven L.; Crandall, Hillary; Hume, Janet R.; Hobbs, Charlotte V.; Tremoulet, Adriana H.; Shimizu, Chisato; Burns, Jane C.; Chen, Sabrina R.; Moon, Hye Kyung; Lange, Christoph; Randolph, Adrienne G.; Khurana, Surender; Pediatrics, School of Medicine
    Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5-11, 12-21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.
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    CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance
    (Springer Nature, 2019-09-27) Chen, Yuhong; Yu, Mei; Zheng, Yongwei; Fu, Guoping; Xin, Gang; Zhu, Wen; Luo, Lan; Burns, Robert; Li, Quan-Zhen; Dent, Alexander L.; Zhu, Nan; Cui, Weiguo; Malherbe, Laurent; Wen, Renren; Wang, Demin; Microbiology and Immunology, School of Medicine
    Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.
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    Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation
    (National Academy of Sciences, 2017-01-17) McEwan, William A.; Falcon, Benjamin; Vaysburd, Marina; Clift, Dean; Oblak, Adrian L.; Ghetti, Bernardino; Goedert, Michel; James, Leo C.; Pathology and Laboratory Medicine, School of Medicine
    Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubule-associated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.
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    The Detection and Analysis of Pathogen-Reactive Immunoglobulins in the Urine of Men With Nongonococcal Urethritis
    (2023-05) Ryan, John D.; Nelson, David E.; Jordan, Stephen J.; Kaplan, Mark H.; Absalon, Sabrina
    Inflammation of the urethra—urethritis—is commonly diagnosed in men and women who have sexually transmitted infections (STI). Characteristic signs and symptoms of urethritis include urethral discharge and burning pain during urination (dysuria). However, these findings are non-specific and can be elicited by STI for which optimal treatment approaches differ. We wanted to investigate if immunoglobulins (antibodies) in the urine of men with acute urethritis could determine the etiologies of these cases. Previously, we conducted an observational case-control study of biological males to compare the urethral microbiota of participants with unambiguous, laboratory-confirmed urethritis (cases) and participants without urethral inflammation (controls). This revealed that nearly 2 in 5 men with nongonococcal urethritis tested negative for all common STI. We identified atypical urethral pathogens in approximately 1/3 of these STI-negative individuals using shotgun metagenomic sequencing. However, we did not detect microorganisms suspected to be urethral pathogens in the remaining 2/3 of STI-negative participants. We hypothesized that these men with “pathogen-negative” urethritis had persisting inflammation from a recent STI that already cleared spontaneously by the time of testing. We observed that urine IgA antibodies against Chlamydia trachomatis (Ctr) infectious particles were significantly more prevalent among men with pathogen-negative urethritis compared to controls. In contrast, we found that the prevalence of urine anti-Ctr IgA was similar between controls and urethritis cases with atypical infections. However, our efforts to detect antibodies against another common STI, Mycoplasma genitalium (Mgen), were complicated by low abundance in urine and the unexpected prevalence of Mgen-reactive antibodies among controls. Collectively, our results suggest that signs and symptoms of urethritis can continue after the causative STI(s) have been eliminated. Furthermore, male urine represents a practical, non-invasive source of pathogen-reactive antibodies that could be evaluated using point-of-care diagnostic tests to elucidate urethritis etiologies. Importantly, our results also suggest that sexual partners of men with pathogen-negative, nongonococcal urethritis are an unrecognized chlamydia reservoir.
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