Neutralizing antibody
Properties | |
---|---|
Protein Type | Immunoglobin |
Function | Neutralization of antigens |
Production | B cells[1][2] |
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.[3][4] 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.
Mechanism
In order to enter cells, pathogens, such as circulating viral particles or extracellular bacteria, use molecules on their surfaces to interact with the
Neutralizing antibodies are also important in neutralizing the toxic effects of bacterial toxins. An example of a neutralizing antibody is
Difference between neutralizing antibodies and binding antibodies
Not all antibodies that bind to a pathogenic particle are neutralizing. Non-neutralizing antibodies, or binding antibodies, bind specifically to the pathogen, but do not interfere with their infectivity. That might be because they do not bind to the right region. Non-neutralizing antibodies can be important to flag the particle for
Production
Antibodies are produced and secreted by B cells. When B cells are produced in the bone marrow, the genes that encode the antibodies undergo random genetic recombination (V(D)J recombination), which results in every mature B cell producing antibodies that differ in their amino acid sequence in the antigen-binding region. Therefore, every B cell produces antibodies that bind specifically to different antigens.[12] A strong diversity in the antibody repertoire allows the immune system to recognize a plethora of pathogens which can come in all different forms and sizes. During an infection only antibodies that bind to the pathogenic antigen with high affinity are produced. This is achieved by clonal selection of a single B cell clone: B cells are recruited to the site of infection by sensing interferons that are released by the infected cells as part of the innate immune response. B cells display B-cell receptors on their cell surface, which is just the antibody anchored to the cell membrane. When the B-cell receptor binds to its cognate antigen with high affinity, an intracellular signalling cascade is triggered. In addition to binding to an antigen, B cells need to be stimulated by cytokines produced by T helper cells as part of the cellular response of the immune system against the pathogen. Once a B cell is fully activated, it rapidly proliferates and differentiates into plasma cells. Plasma cells then secrete the antigen-specific antibody in large quantities.[13] After a first encounter of the antigen by vaccination or natural infection, immunological memory allows for a more rapid production of neutralizing antibodies following the next exposure to the virus.
Virus evasion of neutralizing antibodies
Viruses use a variety of mechanisms to evade neutralizing antibodies.[14] Viral genomes mutate at a high rate. Mutations that allow viruses to evade a neutralizing antibody will be selected for, and hence prevail. Conversely, antibodies also simultaneously evolve by affinity maturation during the course of an immune response, thereby improving recognition of viral particles. Conserved parts of viral proteins that play a central role in viral function are less likely to evolve over time, and therefore are more vulnerable to antibody binding. However, viruses have evolved certain mechanisms to hinder steric access of an antibody to these regions, making binding difficult.[14] Viruses with a low density of surface structural proteins are more difficult for antibodies to bind to.[14] Some viral glycoproteins are heavily glycosylated by N- and O- linked glycans, creating a so-called glycan shield, which may decrease antibody binding affinity and facilitate evasion of neutralizing antibodies.[14] HIV-1, the cause of human AIDS, uses both of these mechanisms.[15][16]
Medical uses of neutralizing antibodies
Neutralizing antibodies are used for
For a more specific and robust treatment, purified
Neutralizing antibodies also play a role in active immunisation by vaccination. By understanding the binding sites and structure of neutralizing antibodies in a natural immune response a vaccine can be rationally designed such that it stimulates the immune system to produce neutralizing antibodies and not binding antibodies.[29][30] Introducing a weakened form of a virus through vaccination allows for the production of neutralizing antibodies by B cells. After a second exposure, the neutralizing antibody response is more rapid due to the existence of memory B cells that produce antibodies specific to the virus.[31] An effective vaccine induces the production of antibodies that are able to neutralize the majority of variants of a virus, although virus mutation resulting in antibody evasion may require vaccines to be updated in response.[31] Some viruses evolve faster than others, which can require the need for vaccines to be updated in response. A well known example is the vaccine for the influenza virus, which must be updated annually to account for the recent circulating strains of the virus.[14]
Neutralizing antibodies may also assist the treatment of
Methods for detection and quantification of neutralizing antibodies
Neutralization assays are capable of being performed and measured in different ways, including the use of techniques such as
Broadly neutralizing antibodies
Most of the neutralizing antibodies produced by the immune system are very specific for a single virus strain due to affinity maturation by B cells.[13] Some pathogens with high genetic variability, such as HIV, constantly change their surface structure such that neutralizing antibodies with high specificity to the old strain can no longer bind to the new virus strain. This immune evasion strategy prevents the immune system from developing immunological memory against the pathogen.[33] Broadly neutralizing antibodies (bNAbs), on the other hand, have the special ability to bind and neutralize multiple strains of a virus species.[34]
bNAbs have been initially found in HIV patients.
Additionally, bNAbs have been found for other viruses including influenza,
Research
Preliminary research is conducted to identify and test bNAbs against HIV-1.[43] bNAbs are used in research to rationally design vaccines to stimulate production of bNAbs and immunity against viruses. No antigen that triggers bNAb production in animal models or humans is known.[34]
See also
References
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