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Frontiers in Immunology 2023Cancer is one of the leading causes of death worldwide. Treatment outcome is largely dictated by the tumor type, disease stage, and treatment success rates, but also by...
Cancer is one of the leading causes of death worldwide. Treatment outcome is largely dictated by the tumor type, disease stage, and treatment success rates, but also by the variation among patients in endogenous anti-tumor responses. Studies indicate that the presence of neutrophils in the tumor microenvironment is associated with a worse patient outcome due to their ability to suppress local anti-tumor T cell activity. Our previous studies investigated the mechanisms by which neutrophils suppress and damage T cells to become smaller in size (small T cells), debilitating their effector activities. Several studies indicate a role for tumor-associated macrophages in scavenging damaged or dead cells. We hypothesized that the observed lack of small T cells in the TME by confocal microscopy is due to immediate uptake by macrophages. In this study, we confirmed that indeed only the smaller, damaged T cells are taken up by macrophages, once serum-opsonized. Damaged T cells opsonized with complement factor C3 fragments were phagocytosed by macrophages, resulting in almost instantaneous and highly efficient uptake of these small T cells. Inhibition of the complement receptors CR1, CR3 and CR4 expressed by macrophages completely blocked phagocytosis. By contrast, actively proliferating T cells (large T cells) were neither impaired in neutrophil-MDSC activity nor opsonized for phagocytosis by macrophages. Rapid removal of damaged T cells suggests a role of complement and macrophages within the tumor microenvironment to clear suppressed T cells in cancer patients.
Topics: Humans; Receptors, Complement 3b; T-Lymphocytes; Macrophages; Receptors, Complement; Complement C3
PubMed: 37261342
DOI: 10.3389/fimmu.2023.1183180 -
Frontiers in Immunology 2023Syphilis, a sexually transmitted infection caused by the spirochete (), is resurging globally. 's repertoire of outer membrane proteins (OMPs) includes BamA (β-barrel...
INTRODUCTION
Syphilis, a sexually transmitted infection caused by the spirochete (), is resurging globally. 's repertoire of outer membrane proteins (OMPs) includes BamA (β-barrel assembly machinery subunit A/TP0326), a bipartite protein consisting of a 16-stranded β-barrel with nine extracellular loops (ECLs) and five periplasmic POTRA (polypeptide transport-associated) domains. BamA ECL4 antisera promotes internalization of by rabbit peritoneal macrophages.
METHODS
Three overlapping BamA ECL4 peptides and a two-stage, phage display strategy, termed "Epivolve" (for epitope evolution) were employed to generate single-chain variable fragments (scFvs). Additionally, antisera generated by immunizing mice and rabbits with BamA ECL4 displayed by a thioredoxin scaffold (Trx). MAbs and antisera reactivities were evaluated by immunoblotting and ELISA. A comparison of murine and rabbit opsonophagocytosis assays was conducted to evaluate the functional ability of the Abs (, opsonization) and validate the mouse assay. Sera from -infected mice (MSS) and rabbits (IRS) were evaluated for ECL4-specific Abs using Trx and overlapping ECL4 peptides in immunoblotting and ELISA assays.
RESULTS
Each of the five mAbs demonstrated reactivity by immunoblotting and ELISA to nanogram amounts of Trx. One mAb, containing a unique amino acid sequence in both the light and heavy chains, showed activity in the murine opsonophagocytosis assay. Mice and rabbits hyperimmunized with Trx produced opsonic antisera that strongly recognized the ECL presented in a heterologous scaffold and overlapping ECL4 peptides, including S2. In contrast, Abs generated during infection of mice and rabbits poorly recognized the peptides, indicating that S2 contains a subdominant epitope.
DISCUSSION
Epivolve produced mAbs target subdominant opsonic epitopes in BamA ECL4, a top syphilis vaccine candidate. The murine opsonophagocytosis assay can serve as an alternative model to investigate the opsonic potential of vaccinogens. Detailed characterization of BamA ECL4-specific Abs provided a means to dissect Ab responses elicited by infection.
Topics: Mice; Animals; Rabbits; Treponema pallidum; Antibodies, Monoclonal; Syphilis; Immune Sera; Bacteriophages; Epitopes
PubMed: 37675118
DOI: 10.3389/fimmu.2023.1222267 -
Irish Journal of Medical Science Apr 2022COVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a... (Review)
Review
COVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.
Topics: COVID-19; Humans; Mucosal-Associated Invariant T Cells; Natural Killer T-Cells; Pandemics; SARS-CoV-2
PubMed: 34050887
DOI: 10.1007/s11845-021-02653-9 -
Annals of Anatomy = Anatomischer... Nov 2016Surfactant and its components have multiple functions. The so called collectins are surfactant proteins which opsonize bacteria and improve pulmonary host defense via... (Review)
Review
Surfactant and its components have multiple functions. The so called collectins are surfactant proteins which opsonize bacteria and improve pulmonary host defense via the phagocytosis and clearance of microorganisms and particles. In this special issue of the Annals of Anatomy a new surfactant protein, Surfactant Associated 3, is highlighted. As outlined in this mini review Surfactant Associated 3 is regarded as an enhancer of phagocytosis. In addition, the role played by SP-A is updated and open research questions raised.
Topics: Humans; Immunity, Innate; Lung; Macrophages; Models, Immunological; Phagocytosis; Pulmonary Surfactant-Associated Proteins
PubMed: 27498043
DOI: 10.1016/j.aanat.2016.07.005 -
Frontiers in Immunology 2018Intravenous immunoglobulins (IVIg) are used in the treatment of different autoimmune and inflammatory diseases, such as immune thrombocytopenia and hemolytic anemia. One...
Intravenous immunoglobulins (IVIg) are used in the treatment of different autoimmune and inflammatory diseases, such as immune thrombocytopenia and hemolytic anemia. One of the modes of action of IVIg is preventing phagocytosis of autoantibody-opsonized blood cells by saturation of the Fc-gamma receptors of macrophages in spleen and liver. IgG contains a fixed glycan, which is in most cases biantennary, at the asparagine residue at position 297 in the Fc tail. This glycan consists of a core structure of N-acetyl glucosamine (GlcNAc) and mannose groups, variably extended with core fucose, bisecting GlcNAc as well as terminal galactose and sialic acid. This structural glycan influences the binding affinity of IgG to Fc-gamma receptors. By glyco-engineering, we generated monoclonal IgG antibodies with different Fc-tail glycans and tested both their opsonizing and blocking capacity in a phagocytosis assay of IgG-opsonized erythrocytes with human monocyte-derived macrophages. In contrast to a lack of effect in opsono-phagocytosis, these IgG glycovariants differentially inhibited the uptake of opsonized erythrocytes. The level of bisecting GlcNAc and galactosylation had unexpectedly larger impact than core fucosylation, and suggest that targeted modifications different from the core fucose may well improve the immunomodulating efficacy of IVIg treatment.
Topics: Acetylglucosamine; Anemia, Hemolytic; Antibody Affinity; Autoantibodies; Cells, Cultured; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Macrophages; Phagocytosis; Protein Binding; Protein Engineering; Purpura, Thrombocytopenic, Idiopathic; Receptors, IgG; Structure-Activity Relationship
PubMed: 30405631
DOI: 10.3389/fimmu.2018.02442 -
Brain and Nerve = Shinkei Kenkyu No... Jun 2019Complements are deposited in senile plaques, neurofibrillary tangles, and blood vessels. Microglia is activated around these structures and induce chronic inflammation... (Review)
Review
Complements are deposited in senile plaques, neurofibrillary tangles, and blood vessels. Microglia is activated around these structures and induce chronic inflammation through a cross talk between microglia and astroglia. Complements activated by amyloidβ (Aβ) bind to complement receptor (CR3) and help phagocytosis of the aggregated Aβ via opsonization of the aggregated Aβ. Inflammation in capillary cerebral amyloid angiopathy (CAA) may suppress Aβclearance and trigger a vicious cycle aggravating CAA.
Topics: Alzheimer Disease; Cerebral Amyloid Angiopathy; Complement System Proteins; Humans; Neurofibrillary Tangles; Plaque, Amyloid
PubMed: 31171756
DOI: 10.11477/mf.1416201321 -
Journal of Bacteriology Aug 2023Pseudomonas aeruginosa is an opportunistic pathogen heavily implicated in chronic diseases. Immunocompromised patients that become infected with P. aeruginosa usually... (Review)
Review
Pseudomonas aeruginosa is an opportunistic pathogen heavily implicated in chronic diseases. Immunocompromised patients that become infected with P. aeruginosa usually are afflicted with a lifelong chronic infection, leading to worsened patient outcomes. The complement system is an integral piece of the first line of defense against invading microorganisms. Gram-negative bacteria are thought to be generally susceptible to attack from complement; however, P. aeruginosa can be an exception, with certain strains being serum resistant. Various molecular mechanisms have been described that confer P. aeruginosa unique resistance to numerous aspects of the complement response. In this review, we summarize the current published literature regarding the interactions of P. aeruginosa and complement, as well as the mechanisms used by P. aeruginosa to exploit various complement deficiencies and the strategies used to disrupt or hijack normal complement activities.
Topics: Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Complement System Proteins
PubMed: 37436150
DOI: 10.1128/jb.00018-23 -
Frontiers in Molecular Neuroscience 2022Animal models of multiple sclerosis (MS) have been extensively used to characterize the disease mechanisms in MS, as well as to identify potential pharmacologic targets... (Review)
Review
Animal models of multiple sclerosis (MS) have been extensively used to characterize the disease mechanisms in MS, as well as to identify potential pharmacologic targets for this condition. In recent years, the immune complement system has gained increased attention as an important effector in the pathogenesis of MS. Evidence from histological, serum, and CSF studies of patients supports an involvement of complement in both relapsing-remitting and progressive MS. In this review, we discuss the history and advances made on the use of MS animal models to profile the effects of the complement system in this condition. The first studies that explored the complement system in the context of MS used cobra venom factor (CVF) as a complement depleting agent in experimental autoimmune encephalomyelitis (EAE) Lewis rats. Since then, multiple mice and rat models of MS have revealed a role of C3 and the alternative complement cascade in the opsonization and phagocytosis of myelin by microglia and myeloid cells. Studies using viral vectors, genetic knockouts and pharmacologic complement inhibitors have also shown an effect of complement in synaptic loss. Antibody-mediated EAE models have revealed an involvement of the C1 complex and the classical complement as an effector of the humoral response in this disease. C1q itself may also be involved in modulating microglia activation and oligodendrocyte differentiation in these animals. In addition, animal and models have revealed that multiple complement factors may act as modulators of both the innate and adaptive immune responses. Finally, evidence gathered from mice models suggests that the membrane attack complex (MAC) may even exert protective roles in the chronic stages of EAE. Overall, this review summarizes the importance of MS animal models to better characterize the role of the complement system and guide future therapeutic approaches in this condition.
PubMed: 36311030
DOI: 10.3389/fnmol.2022.1017484 -
Microbiology and Molecular Biology... Feb 2021The complement system is an evolutionarily ancient defense mechanism against foreign substances. Consisting of three proteolytic activation pathways, complement... (Review)
Review
The complement system is an evolutionarily ancient defense mechanism against foreign substances. Consisting of three proteolytic activation pathways, complement converges on a common effector cascade terminating in the formation of a lytic pore on the target surface. The classical and lectin pathways are initiated by pattern recognition molecules binding to specific ligands, while the alternative pathway is constitutively active at low levels in circulation. Complement-mediated killing is essential for defense against many Gram-negative bacterial pathogens, and genetic deficiencies in complement can render individuals highly susceptible to infection, for example, invasive meningococcal disease. In contrast, Gram-positive bacteria are inherently resistant to the direct bactericidal activity of complement due to their thick layer of cell wall peptidoglycan. However, complement also serves diverse roles in immune defense against all bacteria by flagging them for opsonization and killing by professional phagocytes, synergizing with neutrophils, modulating inflammatory responses, regulating T cell development, and cross talk with coagulation cascades. In this review, we discuss newly appreciated roles for complement beyond direct membrane lysis, incorporate nonlytic roles of complement into immunological paradigms of host-pathogen interactions, and identify bacterial strategies for complement evasion.
Topics: Complement System Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Host-Pathogen Interactions; Humans; Neutrophils; Phagocytosis; Receptors, Complement; Signal Transduction
PubMed: 33504655
DOI: 10.1128/MMBR.00177-20 -
Advanced Healthcare Materials Apr 2022Numerous human disorders can benefit from targeted, intravenous (IV) drug delivery. Polymeric nanoparticles have been designed to undergo systemic circulation and... (Review)
Review
Numerous human disorders can benefit from targeted, intravenous (IV) drug delivery. Polymeric nanoparticles have been designed to undergo systemic circulation and deliver their therapeutic cargo to target sites in a controlled manner. Poly(lactic-co-glycolic) acid (PLGA) is a particularly promising biomaterial for designing intravenous drug carriers due to its biocompatibility, biodegradability, and history of clinical success across other routes of administration. Despite these merits, PLGA remains markedly absent in clinically approved IV drug delivery formulations. A prominent factor in PLGA particles' inability to succeed intravenously may lie in the hydrophobic character of the polyester, leading to the adsorption of serum proteins (i.e., opsonization) and a cascade of events that end in their premature clearance from the bloodstream. PEGylation, or surface-attached polyethylene glycol chains, is a common strategy for shielding particles from opsonization. Polyethylene glycol (PEG) continues to be regarded as the ultimate "stealth" solution despite the lack of clinical progress of PEGylated PLGA carriers. This review reflects on some of the reasons for the clinical failure of PLGA, particularly the drawbacks of PEGylation, and highlights alternative surface coatings on PLGA particles. Ultimately, a new approach will be needed to harness the potential of PLGA nanoparticles and allow their widespread clinical adoption.
Topics: Drug Carriers; Drug Delivery Systems; Humans; Nanoparticles; Polyethylene Glycols; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers
PubMed: 35032406
DOI: 10.1002/adhm.202101536