Intracellular antibody-mediated degradation (IAMD) is a neutralization mechanism of intracellular antibody-mediated immunity whereby an effector protein, TRIM21, directs antibody bound virions to the proteasome where they are degraded. As yet, it has only been observed to act against the adenovirus [1] but is likely to also be effective against other non-enveloped viruses.
In IAMD, the neutralization of the pathogen follows a non-cytotoxic mechanism. [1] That is, the infected cell is not attacked as in Antibody-dependent cell-mediated cytotoxicity, instead the virions are rapidly destroyed and the cell may be relieved of infection.
There are a number of reasons why IAMD is so resistant to evasion by mutants through evolution:
In immunology, an antigen (Ag) is a molecule or molecular structure, that may be present on the outside of a pathogen, that can be bound by an antigen-specific antibody or B-cell antigen receptor. The presence of antigens in the body normally triggers an immune response. The Ag abbreviation stands for an antibody generator.
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence onto the cells of an immunized species.
CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.
Humoral immunity is the aspect of immunity that is mediated by macromolecules found in extracellular fluids such as secreted antibodies, complement proteins, and certain antimicrobial peptides. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.
Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.
Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.
Tripartite motif-containing protein 5 also known as RING finger protein 88 is a protein that in humans is encoded by the TRIM5 gene. The alpha isoform of this protein, TRIM5α, is a retrovirus restriction factor, which mediates species-specific, early block to retrovirus infection.
Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins helps clear pathogens, as well as dead, dying and diseased cells.
The adaptive immune system, also referred as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.
A Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.
Tripartite motif-containing protein 21, also known as E3 ubiquitin-protein ligase TRIM21, is a protein that in humans is encoded by the TRIM21 gene. Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. It is expressed in most human tissues.
Intrinsic immunity refers to a set of recently discovered cellular-based anti-viral defense mechanisms, notably genetically encoded proteins which specifically target eukaryotic retroviruses. Unlike adaptive and innate immunity effectors, intrinsic immune proteins are usually expressed at a constant level, allowing a viral infection to be halted quickly. Intrinsic antiviral immunity refers to a form of innate immunity that directly restricts viral replication and assembly, thereby rendering a cell non-permissive to a specific class or species of viruses. Intrinsic immunity is conferred by restriction factors preexisting in certain cell types, although these factors can be further induced by virus infection. Intrinsic viral restriction factors recognize specific viral components, but unlike other pattern recognition receptors that inhibit viral infection indirectly by inducing interferons and other antiviral molecules, intrinsic antiviral factors block viral replication immediately and directly.
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy. Immunity due to neutralizing antibodies is also known as sterilizing immunity, as the immune system eliminates the infectious particle before any infection takes place.
Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the STING1 gene.
Mitogen-activated protein kinase (MAPK) networks are the pathways and signaling of MAPK, which is a protein kinase that consists of amino acids serine and threonine. MAPK pathways have both a positive and negative regulation in plants. A positive regulation of MAPK networks is to help in assisting with stresses from the environment. A negative regulation of MAPK networks is pertaining to a high quantity of reactive oxygen species (ROS) in the plant.
Alfred “Fred” Goldberg, Ph.D., is an American cell biologist-biochemist and professor at Harvard University. His major discoveries have concerned the mechanisms and physiological importance of protein degradation in cells. Of wide impact have been his lab's demonstration that all cells contain a pathway for selectively eliminating misfolded proteins, his discoveries about the role of proteasomes in this process and of the enzyme systems catalyzing protein breakdown in bacteria, his elucidating the mechanisms for muscle atrophy and the role of proteasomes in antigen presentation to the immune system, and his introduction of proteasome inhibitors now widely used as research tools and in the treatment of blood cancers.