Opsonin

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Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. [1] Thus, opsonins act as tags to label things in the body that should be phagocytosed (i.e. eaten) by phagocytes (cells that specialise in phagocytosis, i.e. cellular eating). [1] Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens (such as bacteria), cancer cells, aged cells, dead or dying cells (such as apoptotic cells), excess synapses, or protein aggregates (such as amyloid plaques). Opsonins help clear pathogens, as well as dead, dying and diseased cells. [2]

Contents

Opsonins were discovered and named "opsonins" in 1904 by Wright and Douglas, who found that incubating bacteria with blood plasma enabled phagocytes to phagocytose (and thereby destroy) the bacteria. They concluded that: “We have here conclusive proof that the blood fluids modify the bacteria in a manner which renders them a ready prey to the phagocytes. We may speak of this as an “opsonic” effect (opsono - I cater for; I prepare victuals for), and we may employ the term “opsonins” to designate the elements in the blood fluids which produce this effect.” [3]

Subsequent research found two main types of opsonin in blood that opsonised bacteria: complement proteins [4] and antibodies. [5] However, there are now known to be at least 50 proteins that act as opsonins for pathogens or other targets. [2]

Mechanisms

Opsonins induce phagocytosis of targets by binding the targets (e.g. bacteria) and then also binding phagocytic receptors on phagocytes. Thus, opsonins act as bridging molecules between the target and the phagocyte, bringing them into contact, and then usually activating the phagocytic receptor to induce engulfment of the target by the phagocyte. [2]

All cell membranes have negative charges (zeta potential) which makes it difficult for two cells to come close together. When opsonins bind to their targets they boost the kinetics of phagocytosis by favoring interaction between the opsonin and cell surface receptors on immune cells. [6] This overrides the negative charges from cell membranes.

It is important that opsonins do not tag healthy, non-pathogenic cells for phagocytosis, as phagocytosis results in digestion and thus destruction of targets. Therefore, Some opsonins (including some complement proteins) have evolved to bind Pathogen-associated molecular patterns, molecules only found on the surface of pathogens, enabling phagocytosis of these pathogens, and thus innate immunity. Antibodies bind to antigens on the pathogen surface, enabling adaptive immunity. Opsonins that opsonise host body cells (e.g. GAS6 that opsonises apoptotic cells) bind to "eat-me" signals (such as phosphatidylserine) exposed by dead, dying or stressed cells. [2]

Types

Opsonins are related to the two types of immune systems: the adaptive immune system and the innate immune system.

Adaptive

Antibody-mediated opsonization. FcR on phagocytic cells recognize the Fc region of the antibody. IgG.Opsonization.png
Antibody-mediated opsonization. FcR on phagocytic cells recognize the Fc region of the antibody.

Antibodies are synthesized by B cells and are secreted in response to recognition of specific antigenic epitopes, and bind only to specific epitopes (regions) on an antigen. [5] They comprise the adaptive opsonization pathway, and are composed of two fragments: antigen binding region (Fab region) and the fragment crystallizable region (Fc region). [5] The Fab region is able to bind to a specific epitope on an antigen, such as a specific region of a bacterial surface protein. [5] The Fc region of IgG is recognized by the Fc Receptor (FcR) on natural killer cells and other effector cells; the binding of IgG to antigen causes a conformational change that allows FcR to bind the Fc region and initiate attack on the pathogen through the release of lytic products. [5] Antibody may also tag tumor cells or virally infected cells, with NK cells responding via the FcR; this process is known as antibody-dependent cellular cytotoxicity (ADCC). [5]

Both IgM and IgG undergo conformational change upon binding antigen that allows complement protein C1q to associate with the Fc region of the antibody. [4] C1q association eventually leads to the recruitment of complement C4b and C3b, both of which are recognized by complement receptor 1, 3, and 4 (CR1, CR3, CR4), which are present on most phagocytes. [4] In this way, the complement system participates in the adaptive immune response.

Opsonization by C3b. CR1 recognizes C3b deposited on antigen C3b.Opsonization.png
Opsonization by C3b. CR1 recognizes C3b deposited on antigen

C3d, a cleavage product of C3, recognizes pathogen-associated molecular patterns (PAMPs) and can opsonize molecules to the CR2 receptor on B cells. [4] This lowers the threshold of interaction required for B cell activation via the B cell receptor, and aids in the activation of the adaptive response. [4]

Innate

The complement system, independently of the adaptive immune response, is able to opsonize pathogen before adaptive immunity may even be required. [4] Complement proteins involved in innate opsonization include C4b, C3b and iC3b. [7] In the alternative pathway of complement activation, circulating C3b is deposited directly onto antigens with particular PAMPs, such as lipopolysaccharides on gram-negative bacteria. [7] C3b is recognized by CR1 on phagocytes. iC3b attaches to apoptotic cells and bodies and facilitates clearance of dead cells and remnants without initiating inflammatory pathways, through interaction with CR3 and CR4 on phagocytes. [4]

Mannose-binding lectins, or ficolins, along with pentraxins and collectins are able to recognize certain types of carbohydrates that are expressed on the cell membranes of bacteria, fungi, viruses, and parasites, and can act as opsonin by activating the complement system and phagocytic cells. [4] [7]

Targets

Apoptotic cells

A number of opsonins play a role in marking apoptotic cells for phagocytosis without a pro-inflammatory response. [8]

Members of the pentraxin family can bind to apoptotic cell membrane components like phosphatidylcholine (PC) and phosphatidylethanolamine (PE). IgM antibodies also bind to PC. Collectin molecules such as mannose-binding lectin (MBL), surfactant protein A (SP-A), and SP-D interact with unknown ligands on apoptotic cell membranes. When bound to the appropriate ligand these molecules interact with phagocyte receptors, enhancing phagocytosis of the marked cell. [6]

C1q is capable of binding directly to apoptotic cells. It can also indirectly bind to apoptotic cells via intermediates like IgM autoantibodies, MBL, and pentraxins. In both cases C1q activates complement, resulting in the cells being marked for phagocytosis by C3b and C4b. C1q is an important contributor to the clearance of apoptotic cells and debris. This process usually occurs in late apoptotic cells. [6]

Opsonization of apoptotic cells occurs by different mechanisms in a tissue-dependent pattern. For example, while C1q is necessary for proper apoptotic cell clearance in the peritoneal cavity, it is not important in the lungs where SP-D plays an important role. [6]

Pathogens

As part of the late stage adaptive immune response, pathogens and other particles are marked by IgG antibodies. These antibodies interact with Fc receptors on macrophages and neutrophils resulting in phagocytosis. [9] The C1 complement complex can also interact with the Fc region of IgG and IgM immune complexes activating the classical complement pathway and marking the antigen with C3b. C3b can spontaneously bind to pathogen surfaces through the alternative complement pathway. Furthermore, pentraxins can directly bind to C1q from the C1 complex. [10]

SP-A opsonizes a number of bacterial and viral pathogens for clearance by lung alveolar macrophages. [8]

See also

Related Research Articles

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">Phagocytosis</span> Process by which a cell uses its plasma membrane to engulf a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

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 – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. 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.

<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<span class="mw-page-title-main">Complement system</span> Part of the immune system that enhances the ability of antibodies and phagocytic cells

The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific 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.

<span class="mw-page-title-main">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

<span class="mw-page-title-main">Antibody opsonization</span> Immune system process

Antibody opsonization is a process by which a pathogen is marked for phagocytosis.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">Immune complex</span> Molecule formed binding antigens to antibodies

An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases. Red blood cells carrying CR1-receptors on their surface may bind C3b-coated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return to the general circulation.

<span class="mw-page-title-main">Protein A</span>

Protein A is a 42 kDa surface protein originally found in the cell wall of the bacteria Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, and a two-component system called ArlS-ArlR. It has found use in biochemical research because of its ability to bind immunoglobulins. It is composed of five homologous Ig-binding domains that fold into a three-helix bundle. Each domain is able to bind proteins from many mammalian species, most notably IgGs. It binds the heavy chain within the Fc region of most immunoglobulins and also within the Fab region in the case of the human VH3 family. Through these interactions in serum, where IgG molecules are bound in the wrong orientation, the bacteria disrupts opsonization and phagocytosis.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca2+-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to oligosaccharide structure or lipids that are on the surface of microorganisms. Like other PRRs they bind pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) of oligosaccharide origin. Binding of collectins to microorganisms may trigger elimination of microorganisms by aggregation, complement activation, opsonization, activation of phagocytosis, or inhibition of microbial growth. Other functions of collectins are modulation of inflammatory, allergic responses, adaptive immune system and clearance of apoptotic cells.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

Macrophage-1 antigen is a complement receptor ("CR3") consisting of CD11b and CD18.

<span class="mw-page-title-main">C3a (complement)</span>

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

Apoptotic-cell associated molecular patterns (ACAMPs) are molecular markers present on cells which are going through apoptosis, i.e. programmed cell death. The term was used for the first time by C. D. Gregory in 2000. Recognition of these patterns by the pattern recognition receptors (PRRs) of phagocytes then leads to phagocytosis of the apoptotic cell. These patterns include eat-me signals on the apoptotic cells, loss of don’t-eat-me signals on viable cells and come-get-me signals ) secreted by the apoptotic cells in order to attract phagocytes. Thanks to these markers, apoptotic cells, unlike necrotic cells, do not trigger the unwanted immune response.

Phagoptosis is a type of cell death caused by the cell being phagocytosed by another cell, and therefore this form of cell death is prevented by blocking phagocytosis.

References

  1. 1 2 Punt J, Stranford SA, Jones PP, Owen JA (2019). Kuby immunology (Eighth ed.). New York. ISBN   978-1-4641-8978-4. OCLC   1002672752.{{cite book}}: CS1 maint: location missing publisher (link)
  2. 1 2 3 4 Cockram, Tom O. J.; Dundee, Jacob M.; Popescu, Alma S.; Brown, Guy C. (2021). "The Phagocytic Code Regulating Phagocytosis of Mammalian Cells". Frontiers in Immunology. 12: 629979. doi: 10.3389/fimmu.2021.629979 . PMC   8220072 . PMID   34177884.
  3. Wright, A. E.; Douglas, S. R.; Sanderson, J. B. (September 1989). "An experimental investigation of the rôle of the blood fluids in connection with phagocytosis. 1903". Reviews of Infectious Diseases. 11 (5): 827–834. doi:10.1093/clinids/11.5.827. PMID   2682954.
  4. 1 2 3 4 5 6 7 8 Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT (2015). "Complement System Part II: Role in Immunity". Frontiers in Immunology. 6: 257. doi: 10.3389/fimmu.2015.00257 . PMC   4443744 . PMID   26074922.
  5. 1 2 3 4 5 6 Chiu ML, Goulet DR, Teplyakov A, Gilliland GL (December 2019). "Antibody Structure and Function: The Basis for Engineering Therapeutics". Antibodies. 8 (4): 55. doi: 10.3390/antib8040055 . PMC   6963682 . PMID   31816964.
  6. 1 2 3 4 Roos A, Xu W, Castellano G, Nauta AJ, Garred P, Daha MR, van Kooten C (April 2004). "Mini-review: A pivotal role for innate immunity in the clearance of apoptotic cells". European Journal of Immunology. 34 (4): 921–9. doi: 10.1002/eji.200424904 . PMID   15048702. S2CID   22966937.
  7. 1 2 3 Ricklin D, Hajishengallis G, Yang K, Lambris JD (September 2010). "Complement: a key system for immune surveillance and homeostasis". Nature Immunology. 11 (9): 785–97. doi:10.1038/ni.1923. PMC   2924908 . PMID   20720586.
  8. 1 2 Litvack ML, Palaniyar N (June 2010). "Review: Soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components: implications on exacerbating or resolving inflammation". Innate Immunity. 16 (3): 191–200. doi:10.1177/1753425910369271. PMID   20529971. S2CID   8344490.
  9. Zhang Y, Hoppe AD, Swanson JA (November 2010). "Coordination of Fc receptor signaling regulates cellular commitment to phagocytosis". Proceedings of the National Academy of Sciences of the United States of America. 107 (45): 19332–7. Bibcode:2010PNAS..10719332Z. doi: 10.1073/pnas.1008248107 . PMC   2984174 . PMID   20974965.
  10. Sarma JV, Ward PA (January 2011). "The complement system". Cell and Tissue Research. 343 (1): 227–35. doi:10.1007/s00441-010-1034-0. PMC   3097465 . PMID   20838815.