bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex and age differences in B cell frequencies and antibody responses following influenza vaccination in highly vaccinated adult populations
Authors: Park Han-Sol , Yin Anna , Kuo Helen , Shapiro Janna , Barranta Caelan , Lee John S , Dhakal Santosh , Shea Patrick , Fenstermacher Katherine , Li Huifen , Ochsner Susan Park , Morgan Rosemary , Gearhart Patricia J , Rothman Richard , Leng Sean X , Pekosz Andrew , Klein Sabra L 
Published: August 2023

Abstract
Annual influenza vaccination is required for healthcare workers (HCWs, 18–49 years of age) at Johns Hopkins and is highly recommended to older adults (75+ years of age) to limit severe outcomes from annual influenza. As a result, vaccination rates and pre-vaccination immunity are high in both populations. We previously reported that sex differences in vaccine-induced antibody responses are not observed in these highly vaccinated populations, but that age-associated reductions in antiviral immunity following vaccination are more pronounced in males than females against both H1N1 and H3N2 viruses. Here, we conducted a clinical study of immune responses to the quadrivalent influenza vaccine to evaluate sex and age differences in influenza A vaccine (IAV) B cell including CD19+ B, plasmablasts (PB, CD3− CD19+ CD38++ CD71+ CD20− IgD− H1+ H3+), memory B cells (MB, CD3− CD19+ CD71− IgD− H1+ H3+), and age-associated B cells (CD3− CD19+ CD21− CD11c− T-bet+ H1+ H3+) following receipt of the seasonal influenza vaccine in 2019–2020 and 2021–2022 seasons among male and female young adult HCWs and older adults. Both young and older females consistently have more total and IAV CD19+ B cells than males, with the greatest percentage being H1. Older adults, however, consistently have greater frequencies of IAV MB cells than young adults. Even with these cellular differences, males and females have equivalent post-vaccination neutralizing antibody titers against H1 and H3 influenza viruses. Whether the transcriptional profiles of B cells differ based on sex and age is currently under investigation. Taken together, these studies may provide mechanistic insights into variability in vaccine outcomes and protection based on the sex and age of the individual.
U54AG062333
Immuno-profiling of Individuals with Opioid Use Disorder : Insights for antibody development and immunological efficacy
Authors: Zhang Yue , Efstathiou Paraskevi Maria Vlachou , Triller Gianna , Luba Rachel , Verdi Joseph , Papavisiliou Nina , Comer Sandra D , Pravetoni Marco 
Published: August 2023

Abstract
Opioid use disorders (OUD) and overdose are a public health emergency in the United States and worldwide. Immunotherapeutics such as vaccines and monoclonal antibodies (mAbs) offer potential solutions in treatment and prevention of OUD and overdose. To accelerate their translation, our work focuses on immunoprofiling of opioid-specific antibodies and B cell repertoires in drug-naive individuals and those with OUD. Using antigen-based enrichment paired with flow cytometry, we found that individuals with OUD display increased frequency of opioid-specific B cells. When the individuals with OUD are compared to the drug-naive individuals, the increased opioid-induced B cell population was not paired with increased opioid-specific IgG polyclonal antibodies, changes in the B cell repertoires were associated with cytokine patterns. Sequencing of the B cell receptor (BCR) revealed that opioids affect the V(D)J rearrangement in B cells, as shown by isolation of a human mid-affinity monoclonal antibody against oxycodone and morphine. Results indicate that immunoprofiling could corroborate diagnosis of OUD, and could provide biomarkers to support testing of novel immunotherapeutics in individuals with OUD.
Supported by grants from NIH U01 DA051658 Antibody-based countermeasures against fentanyl and its analogs and UG3 DA 0477117 Phase 1a/1b clinical trials of multivalent opioid vaccine components.
In silico optimization of prenatal vaccine regimens to promote early-life immunity
Authors: Erdogan Remziye Rachel , Mauldin Ileana S , Dudley Donald J , Dolatshahi Sepideh 
Published: August 2023

Abstract
Newborn children are vulnerable to infection due to their dampened humoral immune response. Maternal immunoglobulin G (IgG) transferred across the placenta provides passive immunity to newborns, and prenatal vaccination to boost pathogen-specific IgG transfer successfully reduced the incidence of neonatal tetanus, diphtheria, and acellular pertussis (Tdap) infections. Despite this, higher rates of infection among premature neonates signifies a deficiency in current immunization programs. To identify regulators of IgG transfer and refine prenatal vaccine regimens, we used a novel in silico approach. To disentangle the role of placental Fc gamma receptors (FcγRs) in IgG transfer, we conducted multiplexed immunofluorescence (mIF) to measure FcγR expression in paraffin-embedded placental tissue. A mechanistic model of placental IgG transfer informed by single cell RNA sequencing and the mIF data revealed FcγRIIb as a key driver of dynamic subclass-specific IgG transcytosis in placental endothelial cells (ECs). In model simulations and experiments in vitro with human umbilical vein ECs, we found the maternal IgG profile fine-tunes antigen- and subclass-specific IgG transfer dynamics. To identify immunization windows of opportunity for maximum IgG transfer, we simulated maternal vaccination by integrating a model of B cell activation and antibody production into the mechanistic model. This revealed first trimester vaccination as a potential strategy to maximize Tdap-induced IgG transport to premature newborns. We conclude that optimal prenatal vaccine regimens depend on gestational length and that novel prenatal vaccines can leverage these determinants of IgG transport to maximize neonatal immune protection.
Supported by grants from NIH (T32 GM145443) the Jeffress Trust Awards Program.
Baseline HMGB-1 Concentrations Are Predictive of Neutralization Efficacy after SARS-CoV-2 mRNA Vaccination
Authors: Umeda Lesley K , Kunihiro Braden P , Rubas Noelle C , Wells Riley K , Phankitnirundorn Krit , Peres-David Rafael Aniu , Maunakea Alika K 
Published: August 2023

Abstract
Determining vaccine efficacy in individuals is a concern when managing the spread of a virus. In this study pre-vaccination levels of a panel of inflammation factors were measured in order to predict the efficacy of the SARS-CoV-2 mRNA vaccines by measuring neutralization percentages, SARS-CoV-2 antibody concentrations, and inflammation factors over the course of ten weeks after the initial dose of the mRNA vaccine. Blood and stool samples were collected at a time point before administration of the vaccine (pre-vaccination) and in 2-week intervals after the administration of the first dose (post-vaccination). A cohort of 12 adults (n=12) were separated into two groups, high neutralization ability (n=6) and low neutralization ability (n=6), based on the neutralization percentages measured from samples provided ten weeks post-vaccination. Bivariate correlation analysis was performed to measure correlation between the panel of inflammation factors measured from pre-vaccination samples and neutralization ability at ten weeks post-vaccination. Correlation analysis indicates a significant (P=0.0321) inverse relationship (R =−0.5269) between HMGB-1 concentrations and neutralization ability at time points ten weeks post-vaccination. Unpaired t-test between the high and low neutralization groups and HMGB-1 concentrations taken pre-vaccination are also significantly different (P&lt;0.001). Preliminary results indicate that HMGB-1 is a promising biomarker in predicting SARS-CoV-2 mRNA vaccine efficacy.
This study was supported in part by funding provided by Hawaii Community Foundation under award 20HCF-101573. The comments expressed in this report are the sole responsibility of the authors and do not represent the official view of the Hawaii Community Foundation.
Intranasal vaccination with a live-attenuated SARS-CoV-2 vaccine candidate confers potent mucosal and systemic immunity and protection
Authors: Adam Awadalkareem , Kalveram Birte K , Zou Jing , Rodriguez Leslie , Singh Ankita , Chen John Yun-Chung , Xie Xuping , Shi Pei-Yong , Wang Tian 
Published: August 2023

Abstract
Development of effective SARS-CoV-2 vaccines to induce potent and long-lasting immunity and to provide cross-reactive protection against emerging variants remains a high priority. We recently reported a live-attenuated SARS-CoV-2 vaccine candidate with re-engineered viral transcription regulator sequences and deleted open-reading-frames (ORF) 3, 6, 7, and 8 (Δ3678) is highly attenuated in mice and hamsters and vaccination with Δ3678 SARS-CoV-2 protect hamsters from wild-type virus challenge and transmission. Here we report that a single dose intranasal vaccination with the Δ3678 SARS-CoV-2 live attenuated vaccine candidate induced strong SARS-CoV-2-specific systemic and mucosal humoral and T cell-mediated immune responses at one-month post-vaccination and day 4 post wild-type virus challenge, which are at similar levels to those infected with wild-type virus. High titer of SARS-CoV-2-specific IgG and IgA were detected in sera and BAL of vaccinated mice respectively. Furthermore, mice vaccinated with the Δ3678 vaccine showed markedly diminished viral loads and tissue inflammation in the lung following wild-type SARS-CoV-2 challenge. In summary, our results suggest that the Δ3678 SARS-CoV-2 live attenuated vaccine protects mice from wild-type SARS-CoV-2 infection by induction of protective mucosal and systemic cell-mediated and humoral responses.
Molecular fate-mapping of serum antibodies reveals the effects of antigenic imprinting on repeated immunization
Authors: Schiepers Arien , Victora Gabriel 
Published: August 2023

Abstract
The ability of serum antibody to protect against pathogens arises from the interplay of antigen-specific B cell clones of different affinities and fine specificities. These cellular dynamics are ultimately responsible for serum-level phenomena such as antibody imprinting or “Original Antigenic Sin” (OAS), a proposed propensity of the immune system to rely repeatedly on the first cohort of B cells that responded to a stimulus upon exposure to related antigens. Imprinting/OAS is thought to pose a barrier to vaccination against rapidly evolving viruses such as influenza and SARS-CoV-2. Precise measurement of the extent to which imprinting/OAS inhibits the recruitment of new B cell clones by boosting is challenging because cellular and temporal origins cannot readily be assigned to antibodies in circulation. Thus, the extent to which imprinting/OAS impacts the induction of new responses in various settings remains unclear. To address this, we developed a “molecular fate-mapping” approach in which serum antibodies derived from specific cohorts of B cells can be differentially detected. We show that, upon sequential homologous boosting, the serum antibody response strongly favors reuse of the first cohort of B cell clones over the recruitment of new, naÏve-derived B cells. This “primary addiction” decreases as a function of antigenic distance, allowing secondary immunization with divergent influenza virus or SARS-CoV-2 glycoproteins to overcome imprinting/OAS by targeting novel epitopes absent from the priming variant. Our findings have implications for the understanding of imprinting/OAS, and for the design and testing of vaccines aimed at eliciting antibodies to evolving antigens.
This study was funded by NIH/NIAID grants R01AI119006 and R01AI139117 to Gabriel Victora. Work in the Victora laboratory is additionally supported by NIH grant DP1AI144248 (Pioneer award) and the Robertson Foundation. Ariën Schiepers was supported by a Boehringer-Ingelheim Fonds PhD fellowship.
Regulatory maturation of lung cDC1 is required for resolution of Influenza infection
Authors: Wang Xinran 
Published: August 2023

Abstract
Pulmonary infection with Influenza A virus (IAV) is responsible for 20,000–30,000 deaths in the US yearly. During the acute stage of infection, pattern recognition receptors (PRRs)-dependent recognition of the virus leads to DC maturation and subsequent expansion of virus-specific effector T cells in the lung-draining lymph node. Recruitment of cytotoxic T cells into the lungs is crucial for the control of IAV infection, however unchecked effector T cell activation often leads to lung immunopathology even after the virus has been cleared. Reducing the availability of IL-2 by CD25+ regulatory T cells is thought to be the principal mechanism limiting the expansion and differentiation of effector CD8 T cells. Recently, efferocytotic maturation of cDC1 (mregDC) has been implicated in impairing CD8 T cells responses, however mregDC has not been studied in the context of IAV infection. Here we described expression of maturation markers, CCR7, PD-L1, and CD40 of lung cDC subsets. PD-L1+ CCR7+ CD40+ cDC1 differentiates in the lungs several days after the virus has been cleared (12–16 days post-infection, dpi). The accumulation of mature cDC1 coincides with increased frequency of Caspase 3+ cells and recovery of disease. At 8dpi, mature cDC1 produce IL-12p70 and induce IFNg+ CD8 T cells, in contrast, at 16dpi mature cDC1 only produce IL-12p40 and fail to induce IFNg+ CD8 T cells. In conclusion, our data suggest that mature DC1 play a role in limiting CD8 T cells mediated immunopathology after IAV infection.
Mechanisms of lung resident memory B cell activation during secondary influenza infection
Authors: Canter Hannah , Allie Rameeza , Silva-Sanchez Aaron , Mudunuru Uma , Randall Troy D 
Published: August 2023

Abstract
B cells and the antibodies they produce are essential components of immunity to respiratory viruses, including influenza virus (IAV) and SARS-CoV-2. B cells responding to viral infection can differentiate into antibody secreting cells (ASCs), or resting memory B cells, some of which are tissue-resident (BRM cells). ASCs provide protection by secreting virus-specific antibodies, whereas BRM cells rapidly differentiate into ASCs after secondary infection. We previously published that IAV-specific BRM cells are retained in the lungs and do not recirculate. We now show that many lung-resident BRM cells reside in the airways and can be collected by bronchoalveolar lavage (BAL). BRM cells in the BAL are phenotypically and functionally different than those in the lung tissue and lymph nodes and express markers at various levels that possibly effect function. There is also a distinction in the role of the ASCs between the lungs and the BAL that will secrete certain antibodies at different time points during the IAV challenge. To understand BRM cell homing, differentiation, and function, we are using single cell approaches to define the transcriptional and epigenetic programs of airway-resident BRM cells at resting memory and during the response to IAV challenge. We are also using this technique to identify the changes among the entire immune system during a secondary IAV challenge to gain an understanding of how the entire immune system plays a role in protection. By understanding the programs that regulate BRM placement in the lung and their response to challenge infection, we expect to identify ways to improve vaccines against respiratory viruses and ameliorate B cell-dependent lung pathology in the context of autoimmunity or allergy.
Supported by grants from NIH (R01 AI152476)
Survivors of Ebola virus disease exhibit elevated levels of autoantibodies
Authors: Velazquez Jalene V , Bond Nell G , Schieffelin John S , Gunn Bronwyn M 
Published: August 2023

Abstract
Survivors of Ebola virus disease (EVD) report a wide range of symptoms following recovery from acute viral infection, but underlying mechanisms are unclear. Many of these symptoms, collectively termed Post-Ebola Syndrome (PES), occur in the absence of detectable virus and resemble symptoms associated with autoimmune disease, such as arthralgia and myalgia, suggesting that EVD survivors may be experiencing a virus-induced autoimmune response. Studies in mice have shown that mice develop autoantibodies (autoAb) against HSP-60 and double stranded (ds) DNA that can bind to host tissues following Ebola virus (EBOV) infection. To determine if human EVD survivors also develop autoAb that may be associated with PES development, we profiled the humoral immune response of 354 survivors and 195 household contacts (HHC) from the 2014–2016 outbreak in Sierra Leone. Using Systems Serology, we measured the levels of antibodies against common autoantigens and found that EVD survivors had elevated levels of autoAb against dsDNA, HSP-60, IFNα, and citrullinated histone compared to HHC. As a subset of HHC were seropositive for EBOV glycoprotein (GP)-specific antibodies, separation of HHC into GP-seropositive and seronegative groups showed that the levels of autoAb in GP-seropositive HHC were elevated compared to GP-seronegative HHC, strongly suggesting that exposure/infection to EBOV tracks with presence of autoAb. As antibodies can activate innate immune cells via the antibody Fc domain, current studies are focused on analyzing the innate effector response mediated by these autoAb in EVD survivors and seropositive HHC. Together, our study highlights the potential role of autoAb in long-term sequelae associated with survival from EVD.
Notch2 amplification of B cell division and differentiation fates
Authors: Londregan Jennifer , Gaudette Brian T , Allman David 
Published: August 2023

Abstract
The efficiency with which B cells respond to activation signals varies depending on the subset. Whereas marginal zone (MZ) B cells exhibit rapid activation kinetics following stimulation, follicular (FO) B cells adopt delayed effector programs. The development and maintenance of MZ B cells uniquely requires signaling through transmembrane receptor family member Notch2, but whether this signal underlies distinctive response patterns among B cell subsets is not known. To examine the functional consequences of Notch2 signals on B cells with no Notch requirement, we cultured FO B cells on Notch2-ligand expressing OP9 stromal cells and subsequently stimulated them. Notch2-experienced FO B cells displayed a marked enhancement of several aspects of proliferation, including two-fold more rounds of division. Further, sensitivity to BCR cross-linking was enhanced by this signal, enabling cell cycle entry earlier and in response to lower concentrations of anti-BCR. Additionally, Notch2 signals modified responses to TLR stimuli Poly(I:C) and LPS by amplifying the time to first division and the propensity to become a plasma cell. Intriguingly, TLR3 responsiveness appeared to be an entirely Notch2-dependant mechanism. Employing a published mathematical model for dividing lymphocytes, we found Notch2 amplified the division destiny of both graded and quantal patterns of B cell responses. We next examined the timing and magnitude of Myc induction, a mitotic regulator and known Notch target. Remarkably, Myc levels prior to the first division appeared to be a direct predictor of division destiny. Together these observations highlight a novel role for Notch2 in modifying two distinct response patterns and their respective outcomes for B cells.
Supported by grants from NIH (T32-AI00763,R01 AI139123,T R01 AI154932)
Dietary L-tryptophan determines the number of colonic regulatory T-cells and susceptibility to colitis via GPR15
Authors: Kim Sangwon V , Van Nguyen T , Zhang Karen , Wigmore Rachel M , Kennedy Anne I , DaSilva Carolina R , Huang Jialing , Ambelil Manju , Vilagomez Jose H , O’Connor Gerald J , Platten Michael , Kasenty Gerard , Sigal Luis J , Prendergast George C 
Published: August 2023

Abstract
Environmental factors play a prominent role in the onset of immunological disorders such as ulcerative colitis, but the mechanisms are unclear. Diet is a major environmental factor, mostly known to influence the gut microbiota, which in turn affects the host immune system. Here, we demonstrated the microbiota-independent effect of the ubiquitous dietary component, L-tryptophan (L-Trp) on mucosal immune responses. We discovered that the amount of ingested L-Trp determines the number of colonic CD4+ T-cells through the aryl hydrocarbon receptor (AhR), which triggers the direct transcriptional activation of the colon T-cell homing receptor, GPR15. However, the default pathway connecting L-Trp, AhR, GPR15, and T-cells is microbiota-independent and involves host IDO1 and IDO2 enzymes, selectively increasing GPR15+ Tregs. Consequently, two weeks of L-Trp supplementation nearly doubled the colonic GPR15+ Tregs and significantly decreased the future risk of colitis. Our extensive, in vitro screening of AhR ligands suggests that AhR ligand-specific variations in target gene expression may account for the Treg-selective response to L-Trp. We also identified benzo[a]pyrene, a compound enriched in cigarette smoke and grilled meat, as an AHR agonist that strongly promotes GPR15+FOXP3+ Treg generation. Thus, our findings uncover mechanisms by which routine dietary and behavioral practices have a significant impact on colonic Treg responses, suggesting a potential non- invasive therapeutic approach for colitis.
Supported by grant from NIH (R01AI141787, R21AI142318, T32 AI134646, 5P30CA056036-22) Supported by grant from CCFA (Career Development Award 329388)
Investigating the Interaction of Inflammation-Associated Fibroblasts (IAFs) with Colon Epithelial Cells in Inflammatory Bowel Disease (IBD)
Authors: Dong Yi , Johnson Blake , Chiu Ian , Larman Tatianna , Li Rong 
Published: August 2023

Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease that affects the epithelial lining of the gastrointestinal tract. Recent single cell RNA-sequencing (scRNA-seq) studies suggested that inflammation-associated fibroblasts (IAFs) play important roles in the disease pathogenesis and drug resistance. To elucidate IAF’s role in IBD, we isolated fibroblasts from patients with IBD and profiled their responses to a panel of pro-inflammatory cytokines. We found a cocktail of the cytokines can induce IAF marker genes in the patient-derived fibroblasts. These cytokine-stimulated fibroblasts recapitulate many characteristics of IAFs, including increased ECM and chemokine secretion. Furthermore, when co-cultured with colon organoids, the cytokine-stimulated fibroblasts secrete prostaglandin E2 (PGE2) to induce organoid swelling through EP4-cAMP-PKA-CFTR signaling, which mimics diarrhea and crypt distortion of IBD. Furthermore, rapid swelling increases the chance of mitosis error and activates p53 pathway, which increases the risk of tumorigenesis. Thus, we are reporting novel mechanisms of fibroblasts that regulates the pathogenesis of IBD.
This study was funded by Takeda Development Center Americas, Inc.