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Frontiers in Immunology 2019Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular... (Review)
Review
Antibodies are essential components of an adaptive immune response. Immunoglobulin G (IgG) is the most common type of antibody found in circulation and extracellular fluids. Although IgG alone can directly protect the body from infection through the activities of its antigen binding region, the majority of IgG immune functions are mediated via proteins and receptors expressed by specialized cell subsets that bind to the fragment crystallizable (Fc) region of IgG. Fc gamma (γ) receptors (FcγR) belong to a broad family of proteins that presently include classical membrane-bound surface receptors as well as atypical intracellular receptors and cytoplasmic glycoproteins. Among the atypical FcγRs, the neonatal Fc receptor (FcRn) has increasingly gained notoriety given its intimate influence on IgG biology and its ability to also bind to albumin. FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers. More recently, it has been appreciated that FcRn acts as an immune receptor by interacting with and facilitating antigen presentation of peptides derived from IgG immune complexes (IC). Here we review FcRn biology and focus on newer advances including how emerging FcRn-targeted therapies may affect the immune responses to IgG and IgG IC.
Topics: Animals; Antigen-Antibody Complex; Female; Histocompatibility Antigens Class I; Humans; Immune Tolerance; Immunity; Immunoglobulin G; Placenta; Pregnancy; Protein Conformation; Protein Transport; Receptors, Fc
PubMed: 31354709
DOI: 10.3389/fimmu.2019.01540 -
MAbs 2021The occurrence of an immune response against therapeutic proteins poses a major risk for the development of biologics and for successful treatment of patients....
The impact of immunogenicity on therapeutic antibody pharmacokinetics: A preclinical evaluation of the effect of immune complex formation and antibody effector function on clearance.
The occurrence of an immune response against therapeutic proteins poses a major risk for the development of biologics and for successful treatment of patients. Generation of anti-drug antibodies (ADAs) can lead to formation of immune complexes (ICs), consisting of drug and ADAs, with potential impact on safety, efficacy and exposure. Here, we focus on the effects of IC formation, i.e., specific IC sizes, ADA and drug properties, on drug pharmacokinetics. Pre-formed IC preparations of an IgG drug (with wild type or with an ablated effector function at the Fc domain) and different ADA surrogates (directed against the complementarity-determining regions or Fc domain of the drug) were administered to rats and collected serum was analyzed to determine the total drug concentration. A combination of size-exclusion chromatography and ELISA enabled a size-specific evaluation of IC profiles in serum and their changes over time. Within five minutes, total drug concentration decreased by ~20-60% when the drug was complexed. Independent of the ADA surrogate and drug variant used, increasing IC size led to increased clearance. Comparing ICs formed with the same ADA surrogate but different IgG variants, we observed that complexed drug with a wildtype Fc domain showed faster clearance compared to immune effector function modified drug. Data generated in this study indicated that clearance of drug due to ADA generation is driven by size and structure of the formed ICs, but also by the immune effector functions of the Fc domains of IgGs. Ab: antibody, ADA: anti-drug antibody, AUC: area under the curve, Bi: biotin, CDR: complementary-determining region, c: maximal concentration, Dig: digoxigenin, ELISA: enzyme-linked immunosorbent assay, Fc: fragment crystallizable, FcRn: neonatal Fc receptor, HMW: high molecular weight, IC: immune complex, IC-QC: immune complex quality control, IgG: immunoglobulin G, mAb: monoclonal antibody, mADA: monoclonal ADA, pAb: polyclonal antibody, pADA: polyclonal ADA, PD: pharmacodynamics; PK: pharmacokinetic, QC: quality control, SEC: size-exclusion chromatography, WT: wildtype.
Topics: Animals; Antibodies, Monoclonal; Antigen-Antibody Complex; Complementarity Determining Regions; Enzyme-Linked Immunosorbent Assay; Humans; Immunoglobulin G; Rats
PubMed: 34763611
DOI: 10.1080/19420862.2021.1995929 -
Frontiers in Immunology 2022Coronavirus disease 2019 (COVID-19) is a highly prothrombotic viral infection that primarily manifests as an acute respiratory syndrome. However, critically ill COVID-19... (Review)
Review
Coronavirus disease 2019 (COVID-19) is a highly prothrombotic viral infection that primarily manifests as an acute respiratory syndrome. However, critically ill COVID-19 patients will often develop venous thromboembolism with associated increases in morbidity and mortality. The cause for this prothrombotic state is unclear but is likely related to platelet hyperactivation. In this review, we summarize the current evidence surrounding COVID-19 thrombosis and platelet hyperactivation. We highlight the fact that several studies have identified a soluble factor in COVID-19 patient plasma that is capable of altering platelet phenotype . Furthermore, this soluble factor appears to be an immune complex, which may be composed of COVID-19 Spike protein and related antibodies. We suggest that these Spike-specific immune complexes contribute to COVID-19 platelet activation and thrombosis in a manner similar to heparin-induced thrombocytopenia. Understanding this underlying pathobiology will be critical for advancement of future research and therapeutic options.
Topics: Antigen-Antibody Complex; COVID-19; Humans; Platelet Activation; Platelet Factor 4; SARS-CoV-2; Thrombosis
PubMed: 35371058
DOI: 10.3389/fimmu.2022.807934 -
EMBO Molecular Medicine Oct 2016Clinical and experimental preparations of IgG/soluble antigen complexes, as well as those formed following antibody therapy in vivo, are multifaceted immune regulators.... (Review)
Review
Clinical and experimental preparations of IgG/soluble antigen complexes, as well as those formed following antibody therapy in vivo, are multifaceted immune regulators. These immune complexes (ICs) have been tested in humans and animal models, mostly in forms of experimental or clinical vaccination, for at least a century. With intensified research on Fcγ receptor-mediated immune modulation, as well as with immune complex-directed antigen processing, presentation, and inflammatory responses, there are renewed interests of using ICs in vaccines and immunotherapies. Currently, IC-based immune therapy has been broadly experimented in HBV and HIV viral infection control and antitumor treatments. However, mechanistic insights of IC-based treatments are relatively recent subjects of study; strong efforts are needed to establish links to connect laboratory findings with clinical practices. This review covers the history, mechanisms, and in vivo outcomes of this safe and effective therapeutic tool, with a clear aim to bridge laboratory findings with evolving clinical applications.
Topics: Animals; Antigen-Antibody Complex; Disease Models, Animal; Drug Evaluation, Preclinical; HIV Infections; Hepatitis B, Chronic; Humans; Immunologic Factors; Immunotherapy; Neoplasms
PubMed: 27572622
DOI: 10.15252/emmm.201606593 -
Molecular Plant Pathology Nov 2022Being sessile in soil, plant cells rely on cell-surface receptors to sense and transduce environmental stimulus signals into intracellular responses. FERONIA (FER), a... (Review)
Review
Being sessile in soil, plant cells rely on cell-surface receptors to sense and transduce environmental stimulus signals into intracellular responses. FERONIA (FER), a Catharanthus roseus receptor-like kinase 1-like protein, has emerged as a versatile regulator of plant growth, development, and stress responses. In recent years, accumulating studies have witnessed rapid advances in dissecting the mechanisms underlying the interaction between FER and its partners in response to pathogen invasion, particularly regulation of immune complex formation and signalling. Moreover, hormonal signalling, rhizosphere microbiota and other constituents are also extensively involved in these processes.
Topics: Antigen-Antibody Complex; Arabidopsis Proteins; Phosphotransferases; Signal Transduction; Soil
PubMed: 35951729
DOI: 10.1111/mpp.13256 -
MAbs 2011The development of an immune response to a protein therapeutic may nullify its beneficial activity or result in adverse events. Immunogenicity is, therefore, a major...
The development of an immune response to a protein therapeutic may nullify its beneficial activity or result in adverse events. Immunogenicity is, therefore, a major concern for clinicians, regulatory authorities and the biopharmaceutical industry. These concerns are particularly acute for the treatment of chronic diseases, as opposed to cancer, that may require repeated exposure to therapeutic over extended cycles of remission/relapse. There are many parameters that may be contributory to immunogenicity; however, the "bête noire," for the past decade has been aggregation. ( 1-3).
Topics: Animals; Antibodies, Monoclonal; Antigen-Antibody Complex; Humans; Immunity; Immunoglobulin G; Mice
PubMed: 22123066
DOI: 10.4161/mabs.3.6.17611 -
International Journal of Hyperthermia :... Nov 2019Fever is a complex physiological response to pathogen infection and injury. One of the beneficial effects of febrile temperatures is stimulation of immune cell... (Review)
Review
Fever is a complex physiological response to pathogen infection and injury. One of the beneficial effects of febrile temperatures is stimulation of immune cell trafficking to the lymphoid organs and inflamed tissues, thereby enhancing immune surveillance during infection and inflammation. This trafficking process consists of a highly ordered adhesion cascade that includes tethering and rolling of immune cells along the vessel walls, chemokine-induced activation, firm arrest and diapedesis. In this review, we summarize the current findings of how febrile temperatures regulate the immune cell trafficking process. Febrile temperatures play multiple roles in the functional regulation of critical biomolecules involved in each step of the ordered adhesion cascade that includes L-selectin, chemokines, and α4 and β2 integrins. A better understanding of febrile temperature-induced regulation of immune cell trafficking will shed light on modulating the immunity to fight against infection and inflammation.
Topics: Antigen-Antibody Complex; Chemokines; Fever; Humans; Integrins
PubMed: 31795834
DOI: 10.1080/02656736.2019.1647357 -
The Journal of Investigative Dermatology Aug 1989Hypersensitivity angiitis is a disease in which patients present with palpable purpura dominant on the lower legs. As lesions evolve they become confluent, and sometimes... (Review)
Review
Hypersensitivity angiitis is a disease in which patients present with palpable purpura dominant on the lower legs. As lesions evolve they become confluent, and sometimes hemorrhagic and ulcerate. Other organ systems may be involved, particularly the joints, gastrointestinal tract, and kidneys. Current evidence supports an immune complex pathogenesis in which a variety of antigens including bacteria, viruses, drugs, or chemicals are involved. Therapy consists of identifying the potential offending agent and administration of antiinflammatory drugs.
Topics: Antigen-Antibody Complex; Histamine; Humans; Leg; Purpura; Vasculitis, Leukocytoclastic, Cutaneous
PubMed: 2666526
DOI: 10.1111/1523-1747.ep12581075 -
Blood Purification 2012Plasmapheresis has been used in the management of immunologic renal disease for the last 40 years. The rationale behind this approach is to remove pathogenic immune... (Review)
Review
Plasmapheresis has been used in the management of immunologic renal disease for the last 40 years. The rationale behind this approach is to remove pathogenic immune mediators, such as autoantibodies and immune complexes, from the circulation. There may also be benefit in depleting proinflammatory molecules, such as complement components and coagulation factors. Initial experience was gained in Goodpasture's disease, in which antiglomerular basement membrane antibodies were known to be pathogenic. More recently, a role for autoantibodies has become clear in small-vessel systemic vasculitis and some cases of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Removal of immune complexes is thought to be important in cryoglobulinemia and systemic lupus erythematosus. Plasmapheresis is used in renal transplantation for the treatment of acute antibody-mediated rejection, and for desensitization of patients with preformed anti-HLA antibodies or those receiving an ABO-incompatible transplant. Although many of the early studies were uncontrolled, there has been an increasing number of randomized controlled trials in recent years. The aim of this article is to summarize current indications for the use of plasmapheresis in immunologic renal disease.
Topics: Animals; Antigen-Antibody Complex; Autoantibodies; Equipment Design; Humans; Immune System Diseases; Kidney Diseases; Plasmapheresis
PubMed: 22269818
DOI: 10.1159/000334155 -
Lupus Science & Medicine Jul 2022The role of neutrophils in driving pathogenic B cell responses in SLE is not fully understood. In this study, we explored the link between immune complex (IC)-driven...
OBJECTIVE
The role of neutrophils in driving pathogenic B cell responses in SLE is not fully understood. In this study, we explored the link between immune complex (IC)-driven neutrophil activation, the release of B cell pro-survival factor BAFF and B cell activation using SLE clinical samples.
METHODS
BAFF levels were analysed in serum samples from patients with SLE (n=60) and healthy controls (HCs, n=20) by ELISA and correlated with markers of neutrophil activation and circulating IC levels. Neutrophils were stimulated with RNP/IgG ICs and neutrophil activation, the release of BAFF, and neutrophil-mediated B cell responses were studied in vitro.
RESULTS
Levels of BAFF in patients with SLE were associated with markers of disease activity, including anti-dsDNA antibody titres (r=0.33, p<0.05), serum C3 levels (r=-0.57, p<0.001) and levels of circulating ICs (r=0.39, p<0.05). Stimulation of neutrophils from healthy individuals with RNP-ICs in vitro induced the release of BAFF (p<0.05), concomitant with formation of neutrophil extracellular traps (NETs) (p<0.05). In culture, neutrophils promoted B cell survival (p<0.05), proliferation (p<0.05) and CD27CD38 plasmablast differentiation.
CONCLUSIONS
Our results support a new mechanism by which ICs, on NET formation, induce the release of B cell pro-survival factor BAFF by neutrophils. Furthermore, neutrophils directly promoted B cell activation and cell differentiation. Targeting neutrophil-B cell interactions can be further explored as an approach for inhibiting pathogenic B cell responses in SLE.
Topics: Humans; Antigen-Antibody Complex; Neutrophil Activation; Lupus Erythematosus, Systemic; B-Lymphocytes; Neutrophils
PubMed: 37938805
DOI: 10.1136/lupus-2022-000709