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The Journal of Infectious Diseases Nov 2023Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses to zoster vaccine live (ZVL) are correlated with protection, suggesting a potential protective role for antibody. Detailed studies of antibody responses to the recombinant zoster vaccine (RZV) are provided.
METHODS
We compared enzyme-linked immunosorbent assay-measured anti-VZV glycoproteins (anti-gp) and glycoprotein E (anti-gE) antibody levels and avidity in 159 participants randomized to RZV (n = 80) or ZVL (n = 79) recipients over 5 years after vaccination and identified predictors of antibody persistence.
RESULTS
The comparison between vaccine groups showed higher anti-gE and anti-gp antibody levels after RZV than after ZVL over the 5-year study duration. RZV recipients also had higher anti-gE avidity for 5 years and higher anti-gp avidity in the first year after vaccination. Compared with prevaccination levels, RZV recipients maintained higher levels of anti-gE antibodies and avidity for 5 years, whereas ZVL recipients only maintained higher anti-gE avidity. Anti-gp antibody levels and avidity decreased to prevaccination levels or below beyond 1 year after vaccination in both groups. Independent predictors of persistence of antibody levels and avidity included vaccine type, prevaccination and peak antibody levels and avidity, prevaccination and peak cell-mediated immunity, and age. Sex or prior ZVL administration did not affect persistence.
CONCLUSIONS
Antibody responses and avidity were higher and more persistent in RZV than in ZVL recipients. The effect of age on antibody persistence in RZV recipients is novel.
Topics: Humans; Herpes Zoster Vaccine; Antibody Formation; Herpes Zoster; Herpesvirus 3, Human; Glycoproteins; Vaccines, Synthetic
PubMed: 37141390
DOI: 10.1093/infdis/jiad132 -
Nature Communications Dec 2023Overexpression of antibody light chains in small plasma cell clones can lead to misfolding and aggregation. On the other hand, the formation of amyloid fibrils from...
Overexpression of antibody light chains in small plasma cell clones can lead to misfolding and aggregation. On the other hand, the formation of amyloid fibrils from antibody light chains is related to amyloidosis. Although aggregation of antibody light chain is an important issue, atomic-level structural examinations of antibody light chain aggregates are sparse. In this study, we present an antibody light chain that maintains an equilibrium between its monomeric and tetrameric states. According to data from X-ray crystallography, thermodynamic and kinetic measurements, as well as theoretical studies, this antibody light chain engages in 3D domain swapping within its variable region. Here, a pair of domain-swapped dimers creates a tetramer through hydrophobic interactions, facilitating the revelation of the domain-swapped structure. The negative cotton effect linked to the β-sheet structure, observed around 215 nm in the circular dichroism (CD) spectrum of the tetrameric variable region, is more pronounced than that of the monomer. This suggests that the monomer contains less β-sheet structures and exhibits greater flexibility than the tetramer in solution. These findings not only clarify the domain-swapped structure of the antibody light chain but also contribute to controlling antibody quality and advancing the development of future molecular recognition agents and drugs.
Topics: Humans; Immunoglobulin Light Chains; Amyloid; Crystallography, X-Ray; Amyloidosis; Thermodynamics
PubMed: 38065949
DOI: 10.1038/s41467-023-43443-4 -
Cancer Science Oct 2023Carcinoma cells possess high proliferative and invasive potentials and exhibit a resilience against stresses, metabolic disorder, and therapeutic efforts. These...
Carcinoma cells possess high proliferative and invasive potentials and exhibit a resilience against stresses, metabolic disorder, and therapeutic efforts. These properties are mainly acquired by genetic alterations including driver gene mutations. However, the detailed molecular mechanisms have not been fully elucidated. Here, we provide a novel mechanism connecting oncogenic signaling and the tumorigenic properties by a transforming growth factor-β1-stimulated clone 22 (TSC-22) family protein, THG-1 (also called as TSC22D4). THG-1 is localized at the basal layer of normal squamous epithelium and overexpressed in squamous cell carcinomas (SCCs). THG-1 knockdown suppressed SCC cell proliferation, invasiveness, and xenograft tumor formation. In contrast, THG-1 overexpression promoted the EGF-induced proliferation and stratified epithelium formation. Furthermore, THG-1 is phosphorylated by the receptor tyrosine kinase (RTK)-RAS-ERK pathway, which promoted the oncogene-mediated tumorigenesis. Moreover, THG-1 involves in the alternative splicing of CD44 variants, a regulator of invasiveness, stemness, and oxidative stress resistance under the RTK pathway. These findings highlight the pivotal roles of THG-1 as a novel effector of SCC tumorigenesis, and the detection of THG-1 phosphorylation by our established specific antibody could contribute to cancer diagnosis and therapy.
Topics: Humans; Carcinogenesis; Carcinoma, Squamous Cell; Cell Line, Tumor; MAP Kinase Signaling System; Oncogenes; Phosphorylation; Transcription Factors; Animals
PubMed: 37607779
DOI: 10.1111/cas.15934 -
JCI Insight Aug 2023The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by...
The inactivated vaccine CoronaVac is one of the most widely used COVID-19 vaccines globally. However, the longitudinal evolution of the immune response induced by CoronaVac remains elusive compared with other vaccine platforms. Here, we recruited 88 healthy individuals who received 3 doses of CoronaVac vaccine. We longitudinally evaluated their polyclonal and antigen-specific CD4+ T cells and neutralizing antibody response after receiving each dose of vaccine for over 300 days. Both the second and third doses of vaccine induced robust spike-specific neutralizing antibodies, with a third vaccine further increasing the overall magnitude of antibody response and neutralization against Omicron sublineages B.1.1.529, BA.2, BA.4/BA.5, and BA.2.75.2. Spike-specific CD4+ T cells and circulating T follicular helper (cTfh) cells were markedly increased by the second and third dose of CoronaVac vaccine, accompanied by altered composition of functional cTfh cell subsets with distinct effector and memory potential. Additionally, cTfh cells were positively correlated with neutralizing antibody titers. Our results suggest that CoronaVac vaccine-induced spike-specific T cells are capable of supporting humoral immunity for long-term immune protection.
Topics: Humans; COVID-19 Vaccines; Antibody Formation; T Follicular Helper Cells; COVID-19; Vaccination; Antibodies, Neutralizing
PubMed: 37384407
DOI: 10.1172/jci.insight.168437 -
Current Medicinal Chemistry Jul 2023Alzheimer's disease (AD) is a complex neurological disorder that results in cognitive decline. The incidence rates of AD have been increasing, particularly among...
Alzheimer's disease (AD) is a complex neurological disorder that results in cognitive decline. The incidence rates of AD have been increasing, particularly among individuals 60 years of age or older. In June 2021, the US FDA approved aducanumab, the first humanized monoclonal antibody, as a potential therapeutic option for AD. Clinical trials have shown this drug to effectively target the accumulation of Aβ (beta-amyloid) plaques in the brain, and its effectiveness is dependent on the dosage and duration of treatment. Additionally, aducanumab has been associated with improvements in cognitive function. Biogen, the pharmaceutical company responsible for developing and marketing aducanumab, has positioned it as a potential breakthrough for treating cerebral damage in AD. However, the drug has raised concerns due to its high cost, limitations, and potential side effects. AD is a progressive neurological condition that affects memory, cognitive function, and behaviour. It significantly impacts the quality of life of patients and caregivers and strains healthcare systems. Ongoing research focuses on developing disease-modifying therapies that can halt or slow down AD progression. The pathogenesis of AD involves various molecular cascades and signaling pathways. However, the formation of extracellular amyloid plaques is considered a critical mechanism driving the development and progression of the disease. Aducanumab, as a monoclonal antibody, has shown promising results in inhibiting amyloid plaque formation, which is the primary pathological feature of AD. This review explores the signaling pathways and molecular mechanisms through which aducanumab effectively prevents disease pathogenesis in AD.
PubMed: 37497712
DOI: 10.2174/0929867331666230727103553 -
Scientific Reports Aug 2023The humoral response after the fourth dose of a mRNA vaccine against COVID-19 has not been adequately described in elderly recipients, particularly those not exposed...
The humoral response after the fourth dose of a mRNA vaccine against COVID-19 has not been adequately described in elderly recipients, particularly those not exposed previously to SARS-CoV-2. Serum anti-RBD IgG levels (Abbott SARS-CoV-2 IgG II Quant assay) and neutralizing capacities (spike SARS-CoV-2 pseudovirus Wuhan and Omicron BA.1 variant) were measured after the third and fourth doses of a COVID-19 mRNA vaccine among 46 elderly residents (median age 85 years [IQR 81; 89]) of an assisted living facility. Among participants never infected by SARS-CoV-2, the mean serum IgG levels against RBD (2025 BAU/ml), 99 days after the fourth vaccine, was as high as 76 days after the third vaccine (1987 BAU/ml), and significantly higher (p = 0.030) when the latter were corrected for elapsed time. Neutralizing antibody levels against the historical Wuhan strain were significantly higher (Mean 1046 vs 1573; p = 0.002) and broader (against Omicron) (Mean 170 vs 375; p = 0.018), following the fourth vaccine. The six individuals with an Omicron breakthrough infection mounted strong immune responses for anti-RBD and neutralizing antibodies against the Omicron variant indicating that the fourth vaccine dose did not prevent a specific adaptation of the immune response. These findings point out the value of continued vaccine boosting in the elderly population.
Topics: Humans; Aged; Aged, 80 and over; COVID-19 Vaccines; Antibody Formation; COVID-19; SARS-CoV-2; Antibodies, Neutralizing; Immunoglobulin G; RNA, Messenger
PubMed: 37644113
DOI: 10.1038/s41598-023-41399-5 -
Immunity Apr 2024The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of...
The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals. It remains unclear if exposures to antigenically distant SARS-CoV-2 variants can overcome memory B cell biases established by initial SARS-CoV-2 encounters. We determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that targeted epitopes conserved between the BA.5 and ancestral spike. XBB exposures also elicited antibody responses that primarily targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low frequencies of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses.
Topics: Humans; SARS-CoV-2; Antibody Formation; COVID-19; Antibodies; Epitopes; Antibodies, Neutralizing; Antibodies, Viral
PubMed: 38490198
DOI: 10.1016/j.immuni.2024.02.017 -
Beilstein Journal of Nanotechnology 2023Nanotechnology provides effective methods for precisely delivering chemotherapeutics to cancer cells, thereby improving efficacy and reducing off-target side effects.... (Review)
Review
Nanotechnology provides effective methods for precisely delivering chemotherapeutics to cancer cells, thereby improving efficacy and reducing off-target side effects. The targeted delivery of nanoscale chemotherapeutics is accomplished by two different approaches, namely the exploitation of leaky tumor vasculature (EPR effect) and the surface modification of nanoparticles (NPs) with various tumor-homing peptides, aptamers, oligonucleotides, and monoclonal antibodies (mAbs). Because of higher binding affinity and specificity, mAbs have received a lot of attention for the detection of selective cancer biomarkers and also for the treatment of various types of cancer. Antibody-conjugated nanoparticles (ACNPs) are an effective targeted therapy for the efficient delivery of chemotherapeutics specifically to the targeted cancer cells. ACNPs combine the benefits of NPs and mAbs to provide high drug loads at the tumor site with better selectivity and delivery efficiency. The mAbs on the NP surfaces recognize their specific receptors expressed on the target cells and release the chemotherapeutic agent in a controlled manner. Appropriately designed and synthesized ACNPs are essential to fully realize their therapeutic benefits. In blood stream, ACNPs instantly interact with biological molecules, and a protein corona is formed. Protein corona formation triggers an immune response and affects the targeting ability of the nanoformulation. In this review, we provide recent findings to highlight several antibody conjugation methods such as adsorption, covalent conjugation, and biotin-avidin interaction. This review also provides an overview of the many effects of the protein corona and the theranostic applications of ACNPs for the treatment of cancer.
PubMed: 37701520
DOI: 10.3762/bjnano.14.75 -
JCI Insight Aug 2023BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the...
BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).
Topics: Humans; Aged; Antibody Formation; SARS-CoV-2; BNT162 Vaccine; COVID-19; Vaccination; Antibodies, Monoclonal; Antilymphocyte Serum; RNA, Messenger
PubMed: 37606046
DOI: 10.1172/jci.insight.168102 -
Current Opinion in Pulmonary Medicine Sep 2023Interstitial lung disease (ILD) is now recognized as a common complication of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), especially... (Review)
Review
PURPOSE OF REVIEW
Interstitial lung disease (ILD) is now recognized as a common complication of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), especially myeloperoxidase (MPO)-ANCA-positive AAV and microscopic polyangiitis (MPA). This review focuses on current concepts pertaining to the pathogenesis, clinical assessment, and management of AAV-ILD.
RECENT FINDINGS
ILD is typically identified before or at the onset of systemic AAV, and usual interstitial pneumonia (UIP) is the most common CT pattern. MPO-ANCA production, neutrophil extracellular traps formation, reactive oxidative species production, complement activation, environmental exposures, and genetic background might play a role in the pathogenesis of AAV-ILD. Recent research has identified promising biomarkers as potential diagnostic and prognostic tools in AAV-ILD. The optimal treatment for AAV-ILD is not well defined but might rely on a combination of immunosuppression and antifibrotics, especially in patients with progressive lung fibrosis. Despite the effectiveness of current therapies for AAV, the outcome of patients with AAV-ILD remains poor.
SUMMARY
ANCA screening should be considered in patients with newly diagnosed ILD. Management of AAV-ILD should be overviewed by a collaborative team comprising vasculitis experts and respirologists.
VIDEO ABSTRACT
http://links.lww.com/COPM/A33.
Topics: Humans; Antibodies, Antineutrophil Cytoplasmic; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Lung Diseases, Interstitial; Biomarkers; Cytoplasm
PubMed: 37395510
DOI: 10.1097/MCP.0000000000000979