Opsonins are extracellular proteins that, when bound to substances or cells, inducephagocytes 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 inphagocytosis, i.e. cellular eating).[1] Different types of things ("targets") can be tagged by opsonins forphagocytosis, including: pathogens (such as bacteria), cancer cells, aged cells, dead or dying cells (such as apoptotic cells), excesssynapses, or protein aggregates (such asamyloid plaques). Opsonins help clear pathogens, as well as dead, dying and diseased cells.[2]
Opsonins were discovered and named "opsonins" in 1904 by Wright and Douglas, who found that incubating bacteria with blood plasma enabledphagocytes 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] andantibodies.[5] However, there are now known to be at least 50 proteins that act as opsonins for pathogens or other targets.[2]
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 bindPathogen-associated molecular patterns, molecules only found on the surface of pathogens, enabling phagocytosis of these pathogens, and thus innate immunity. Antibodies bind toantigens 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 asphosphatidylserine) exposed by dead, dying or stressed cells.[2]
Opsonins are related to the two types ofimmune systems: theadaptive immune system and theinnate immune system.
Antibodies are synthesized byB cells and are secreted in response to recognition of specific antigenicepitopes, 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 thefragment 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 ofIgG is recognized by theFc Receptor (FcR) onnatural killer cells and othereffector cells; the binding of IgG to antigen causes aconformational change that allows FcR to bind the Fc region and initiate attack on the pathogen through the release of lytic products.[5] Antibodies may also tag tumor cells or virally infected cells, with NK cells responding via the FcR; this process is known asantibody-dependent cellular cytotoxicity (ADCC).[5]
BothIgM and IgG undergo conformational change upon binding antigen that allows complement proteinC1q to associate with the Fc region of the antibody.[4] C1q association eventually leads to the recruitment of complementC4b andC3b, both of which are recognized bycomplement 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.
C3d, a cleavage product of C3, recognizes pathogen-associated molecular patterns (PAMPs) and can opsonize molecules to theCR2 receptor on B cells.[4] This lowers the threshold of interaction required for B cell activation via theB cell receptor, and aids in the activation of the adaptive response.[4]
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 andiC3b.[7] In the alternative pathway of complement activation, circulating C3b is deposited directly onto antigens with particular PAMPs, such aslipopolysaccharides ongram-negative bacteria.[7] C3b is recognized by CR1 on phagocytes. iC3b attaches toapoptotic cells and bodies and facilitates clearance of dead cells and remnants without initiatinginflammatory pathways, through interaction with CR3 and CR4 on phagocytes.[4]
Mannose-binding lectins, or ficolins, along withpentraxins andcollectins are able to recognize certain types ofcarbohydrates that are expressed on the cell membranes ofbacteria,fungi,viruses, andparasites, and can act as opsonin by activating the complement system and phagocytic cells.[4][7]
A number of opsonins play a role in marking apoptotic cells for phagocytosis without a pro-inflammatory response.[8]
Members of thepentraxin family can bind to apoptotic cell membrane components likephosphatidylcholine (PC) andphosphatidylethanolamine (PE).IgM antibodies also bind to PC.Collectin molecules such asmannose-binding lectin (MBL),surfactant protein A (SP-A), andSP-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 byC3b andC4b. 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]
As part of the late stage adaptive immune response, pathogens and other particles are marked byIgG antibodies. These antibodies interact withFc receptors on macrophages and neutrophils resulting in phagocytosis.[9] TheC1 complement complex can also interact with theFc 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]
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