File Name: innate and adaptive immunity .zip
- Innate and Adaptive Immunity
- Research Area
- Complement and its role in innate and adaptive immune responses
Clinical and Basic Immunodermatology pp Cite as. The skin immune system is the complex network of cells that are able to mount an immune response in the skin. The immune response can be divided into innate and adaptive arms.
As mentioned in Unit 5, the body has two immune systems: innate immunity and adaptive immunity. Unit 5 dealt with innate immunity. In Unit 6 we will cover adaptive immunity. Let's first again briefly compare acquired and innate immunity.
Innate and Adaptive Immunity
More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges.
As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense. The mammalian immune system is a remarkable complex of biochemical processes enabling efficient detection and prosecution of pathogens that threaten host viability.
The incredible complexity of mammalian immune systems is required to provide adequate defense in spite of the impressive number of pathogens and host processes that cause disease. Immune processes have traditionally been divided into two broad, but interconnected, subsystems on the basis of their functions in host defense. The adaptive immune system is organized around two classes of specialized lymphocytes, T and B cells, which display an extremely diverse repertoire of antigen-specific recognition receptors that enable specific identification and elimination of pathogens, as well as adaptive immune measures that ensure tailored immune responses, as well as long-lived immunological memory against reinfection.
In contrast, the innate arm of immunity is composed of those immunological effectors that provide robust, immediate, and nonspecific immune responses. These include evolutionarily primitive humoral, cellular, and mechanical processes that nevertheless play a vital role in the protection of the host from pathogenic challenge.
The complement system comprises a far-reaching and vital component of innate immunity and represents one of the major effector mechanisms of the innate immune system. Discovered in by Bordet as a heat-labile component of serum, it was so named for its ability to 'complement' the antibacterial properties of antibody in the heat-stabile fraction of serum. It is now appreciated that complement is a complex network of plasma and membrane-associated serum proteins which can elicit highly efficient and tightly regulated inflammatory and cytolytic immune responses to infectious organisms bacteria, viruses, parasites , tissue damaged by physical, chemical, or neoplastic insults, and other surfaces identified as 'nonself'.
For many years after its discovery, the role of complement in immunity was thought to be confined to innate immune responses with no impact on adaptive immune responses, in much the same way as innate immunity, in general, was relegated to those functions of immunity that involved prevention and confinement of infection while adaptive immunity provided effectors required to clear the infection.
The ability to separate the functions of the two arms of immunity was called into question as early as the s, and since then the body of knowledge illustrating the interplay between the adaptive and innate wings of immunity has grown dramatically. Similarly, the ability of complement to not only affect robust innate immune responses but also to interface with and influence T- and B-cell biology and adaptive responses has become increasingly appreciated.
This review attempts to summarize the roles that complement biology plays in the immune response, both in the innate detection and elimination of pathogenic infections and in the modulation of adaptive immune responses.
This array of proteins is organized into a hierarchy of proteolytic cascades that start with the identification of pathogenic surfaces and lead to the generation of potent proinflammatory mediators anaphylatoxins , opsonization 'coating' of the pathogenic surface through various complement opsonins e.
Complement represents an evolutionarily ancient component of host defense, and the evolutionary survival value of complement serves to accentuate the important roles it plays in host defense. Originally, it was thought to be a unique vertebrate feature, showing high degrees of homology in structure and function among the higher vertebrates as phylogentically ancient as the nurse shark 4.
However, genomic and functional studies on complement effector molecules have discovered complement analogs in even more ancient phyla, including Cephalochordata lancelets , Urochordata tunicates , and Echinodermata sea urchins 5 , 6 , 7. More recently, functional C3 was identified in horseshoe crab Carcinoscorpius rotundicauda and cnidarian anthrozoans Nematostella vectensis [starlet sea anemone] , demonstrating that the complement system is ancient 8 , 9.
Adaptive immunity is, by contrast, much younger and is generally considered restricted to jawed vertebrates Furthermore, adaptive immune processes are rooted in the earlier innate immune processes, providing logical evidence for why complement and innate immunity in general would integrate with mechanisms of the adaptive immune response to infection. The complement system can be activated through three major pathways: classical, lectin, and alternative Figure 1 1 , 2 , Initiation of the classical pathway occurs when C1q, in complex with C1r and C1s serine proteases the C1 complex , binds to the Fc region of complement-fixing antibodies generally IgG 1 and IgM attached to pathogenic surfaces.
The larger fragments associate to form C4bC2a on pathogenic surfaces, and the complex gains the ability to cleave C3 and is termed the C3 convertase. Generation of the C3 convertase, which cleaves C3 into the anaphylatoxin C3a and the opsonin C3b, is the point at which all complement activation cascades converge 2.
When C3 is cleaved into C3b, it exposes an internal thioester bond that allows stable covalent binding of C3b to hydroxyl groups on proximate carbohydrates and proteins. This activity underpins the entire complement system by effectively 'tagging' microorganisms as foreign, leading to further complement activation on and around the opsonized surface and terminating in the production of anaphylatoxins and assembly of the MAC 1 , The complement pathway.
Complement can be activated through three pathways: classical, lectin, and alternative. The classical pathway is activated when C1q binds to antibody attached to antigen, activating C1r and C1s, which cleave C4 and C2.
Properdin facilitates AP activation by stabilizing AP convertases. Anaphylatoxins are potent proinflammatory molecules derived from the cleavage of C4, C3, and C5. The MAC is a terminal assembly of complement components C5b through C9, which can directly lyse targeted surfaces. C3b induces phagocytosis of opsonized targets and also serves to amplify complement activation through the AP. The lectin pathway functions in an analogous, but immunoglobulin-independent, fashion. As opposed to recognizing antigen-antibody immune complexes, the lectin pathway employs germline-encoded pattern-recognition receptors PRRs , such as mannose-binding lectin MBL and ficolins, to conduct nonself recognition 2.
Antigen-recognition receptors e. PRRs, in contrast, focus on a few highly conserved structures present in large groups of microorganisms popularly referred to as pathogen-associated molecular patterns PAMPs MBL is a well-characterized receptor of the collectin family, so termed because of the fusion of a collagenous domain to a calcium-dependant lectin domain, which are synthesized in the liver and secreted into the plasma as a component of the acute-phase response 12 , The AP is mechanistically distinct from the classical and lectin pathways Figure 1.
This C3 convertase forms the basis of an amplification loop in which C3 H 2 O Bb starts to convert C3 into C3b and C3a, in an analogous fashion to the C3 convertase C4bC2a of the classical and lectin pathways.
C3b generated in such a fashion can bind to surfaces in the vicinity and associate with Factor B, which can in turn be activated by Factor D to form C3bBb, the predominant AP C3 convertase 1 , This complex can be further stabilized by properdin Factor P , which helps to amplify AP activation As a consequence of this constitutive activation, and due to the ability to form a feedback amplification pathway, there are a number of complement inhibitory proteins responsible for confining complement activation to appropriate contexts to prevent errant complement activation in the healthy host, which will be discussed below.
Further insight into the formation of C3 convertases of all three pathways has been afforded through structural determinations of key C3 convertase components. Due to the size of C3, determination of its complete structure remained elusive for many years. Solving the structures of the smaller cleavage products of C3, including C3a and C3d discussed below , eventually culminated in the structural determination of intact C3 which afforded extensive insight into C3's activation, regulation, and biological functions 25 , 26 , Insight into the arrangement and activation of the AP C3 convertase has recently been gained as a result of the structural determinations of both Factor B and the AP proconvertase, C3bB 28 , Similarly, the catalytic function of the classical pathway C3 and C5 convertases has been illuminated through the structural determination of C2a, allowing insight into the architecture and biological activities of this pathway Two additional mechanisms for the initiation of complement activation have recently been described, which introduce novel models for complement activation with currently undefined physiological roles.
However, additional evidence has demonstrated that properdin could promote de novo C3 convertase assembly when immobilized to an inert surface and initiate C3 convertase formation on microbial surfaces such as Neisseria gonorrhoeae 31 , The novel role of properdin in AP complement initiation was supported by evidence from a properdin knockout mouse model Additionally, it has been reported that C3 and C5 can be directly cleaved by proteases unrelated to the complement cascade, such as kallikrein and thrombin which are involved in coagulation , leading to an additional source of anaphylatoxins C5a and C3a and establishing a novel and potentially important connection between the complement and coagulation cascades 34 , Due to the destructive potential of complement activation, especially in light of the potent feedback amplification ability of the AP, complement activities need to be confined to appropriate pathogenic surfaces, and generation of potent effectors needs to be tightly regulated to prevent collateral damage to healthy host tissues.
Therefore, many steps involved in complement activation are checked by inhibitors so that the final system represents an intricate, homeostatic balance between the efficient detection and destruction of pathogens and the minimization of bystander tissue damage. Complement regulation occurs predominantly at two steps within the cascades, at the level of the convertases, both in their assembly and in their enzymatic activity, and during assembly of the MAC Figure 2 Upon generation of C4b and C3b fragments through upstream complement activation and their covalent linkage to cellular surfaces, they experience one of the two fates.
The first, which prevents these molecules from forming active convertases, is the catabolism of C3b and C4b via the constitutively active serine protease Factor I which can cleave C3b and C4b into inactive fragments, such as iC3b, C3c, and C3dg Figure 2A To prevent nonspecific C3b degradation, for instance in the case of proper complement activation, Factor I requires cofactors for its proteolytic activity.
These cofactors include membrane cofactor protein MCP; CD46 , complement receptor 1 CR1 , and Factor H which are either intrinsic membrane proteins on host cells or have various mechanisms to ensure preferential cofactor activity on host surfaces, and thereby limit complement activation in these contexts and prevent bystander tissue damage 38 , 39 , Complement activity must be regulated to prevent bystander damage to the host.
A Factor I-mediated cleavage of C3b and C4b prevents them from forming active convertases and requires cofactor activity, so that complement can be activated in appropriate contexts. B C3 convertases are regulated by proteins containing decay-accelerating activity, which serve to inhibit assembly of new C3 convertases and shorten the half-life of the preformed convertases, limiting their ability to participate in complement activation. C The MAC is the lytic complex of complement and its assembly can be inhibited by the membrane-bound CD59 and the fluid-phase vitronectin and S protein.
D Anaphylatoxins are very potent proinflammatory molecules and their activity is limited by removal of their N-terminal arginine residue by serum carboxypeptidases, including carboxypeptidase N, B, and R. Formation of the 'des-Arg' forms of C5a and C3a limits their ability to interact with their cognate receptors, C5aR and C3aR, respectively.
A primary example of this category of complement inhibitors is decay-accelerating factor DAF; CD55 , which serves to inhibit assembly of new C3 convertases and shorten the half-life of preformed convertases, thereby limiting their ability to participate in further complement activation 36 , New structural advances have helped to elucidate the mechanistic basis of convertase regulation.
A recent study has solved the structure of the first four domains of Factor H in complex with C3b, suggesting that Factor H destabilizes the AP C3 convertase through competition and also provides a binding platform for Factor I-mediated proteolysis of C3b, thereby limiting the AP Host-specific protection is generally achieved by ensuring host-specific expression patterns of complement regulators. While many of the complement regulators are intrinsic membrane proteins in host cells, the fluid-phase inhibitor Factor H achieves host-specific protection by binding polyanions, such as sialic acid and heparin, which make up an essential component of eukaryotic, but not prokaryotic, cell surfaces 38 , The functional consequence of this mechanism is that Factor H is preferentially targeted to host surfaces, where it exerts cofactor and decay-accelerating activities to prevent C3 convertase formation and leads to the catabolism of C3b to its degradation products e.
The final level of complement control, necessary in situations in which there is rampant complement activation, is to inhibit the assembly of the lytic MAC via of membrane-bound CD59 or fluid-phase vitronectin, S protein inhibitors Figure 2C 38 , Thus, the array of complement inhibitory proteins serves to check complement activation in the healthy host and upon complement activation as a response to infection, helping to confine the destructive activities of complement to appropriate surfaces to minimize bystander tissue damage.
Complement activation, regardless of the pathway, converges on the generation of three broad effector pathways that serve to enable the complement to fulfill its physiological imperatives in host defense: 1 direct lysis of targeted surfaces by way of the MAC assembly, 2 alerting and priming the immune system by way of the generation of potent proinflammatory anaphylatoxins, and 3 opsonization and clearance of target surfaces by way of the complement opsonins C4b, C3b, C3bi and engagement of CRs on phagocytic cells, such as macrophages and neutrophils Figure 3 1 , 2 , C5 convertases are the staging points for the terminal complement activation and cleave C5 into anaphylatoxins C5a and C5b.
C5b liberation exposes a binding site for C6, and the subsequent C5bC6 binds reversibly to the targeted surfaces and forms the molecular foundation for the MAC Figure 3A This C5b-9 complex is the fully formed MAC, and is effective in inducing cell lysis in a variety of targets through a multi-hit process. Whether cell death is apoptotic or necrotic seems to be a function of C5b-9 quantity, and fragmentation of DNA has been detected in as little as 30 min after treatment with a lytic dosage of complement, illustrating the destructive potential of the terminal pathway of complement activation 45 , Effectors of the complement system.
A Complement activation and the generation of C5 convertases lead to the liberation of the C5 product, C5b. C5b forms the basis of the MAC assembly. C5b first associates with C6, C7, and the targeted surface. C8 associates with this complex and is partially inserted into the membrane.
Formation of the pore leads to the targeted lysis of the surface upon which it is assembled, accompanied with a dysregulation of ion concentrations across the membrane and loss of mitochondrial polarity.
B Anaphylatoxins are potent proinflammatory molecules generated from the cleavage of C4, C3, and C5 into C4a, C3a, and C5a C4a not shown , respectively. Binding of anaphylatoxins to the N-terminal region of their cognate receptors, C3aR and C5aR, allows conformational changes to the intracellular domains to induce G-protein coupling and downstream signaling.
The effects of this binding depend on the cell type on which the anaphylatoxin receptor is expressed; and some of the most important cell types and effects in the innate immune response are summarized.
C Generation of the C3b fragments by C3 convertases of all three activation pathways initiates the opsonization pathway of complement, an important effector in the 'tagging' and clearance of foreign bodies.
Fc receptors bind to the Fc region of antibody.
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 the other being the innate immune system. Like the innate system, the adaptive immune system includes both humoral immunity components and cell-mediated immunity components and destroys invading pathogens. Unlike the innate immune system , which is pre-programmed to react to common broad categories of pathogen, the adaptive immune system is highly specific to each particular pathogen the body has encountered. Adaptive immunity creates immunological memory after an initial response to a specific pathogen, and leads to an enhanced response to future encounters with that pathogen. Antibodies are a critical part of the adaptive immune system. Adaptive immunity can provide long-lasting protection, sometimes for the person's entire lifetime.
Complement and its role in innate and adaptive immune responses
The immune system is typically divided into two categories--innate and adaptive--although these distinctions are not mutually exclusive. Introduction to Immunology Tutorial Innate vs. Adaptive Immunity The immune system is typically divided into two categories--innate and adaptive--although these distinctions are not mutually exclusive. Innate immunity Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body.
NCBI Bookshelf. New York: Garland Science; The macrophages and neutrophils of the innate immune system provide a first line of defense against many common microorganisms and are essential for the control of common bacterial infections.
Clin Sci Lond 31 July ; 14 : — Recent advancements on the molecular and cellular levels have shaken the traditional view of adaptive and innate immunity. Innate immune cells are able to recognize large number of pathogen- or danger- associated molecular patterns PAMPs and DAMPs to behave in a highly specific manner and regulate adaptive immune responses. On the other hand, T and B lymphocytes exhibit functional properties traditionally attributed to innate immunity such as phagocytosis or production of tissue remodeling growth factors.
In Silico Immunology pp Cite as. Innate immune responses recognise generic targets on pathogens using germline encoded receptors, whereas adaptive immune responses recognise specific targets using randomly generated receptors which have an essentially unlimited recognition repertoire. Interactions between innate and adaptive forms of immune recognition are increasingly being recognised as essential for the effective functioning of the immune response. Examples given here demonstrate the advantages of integrating pre-programmed recognition rapid response using widely distributed receptors with random repertoire recognition open repertoire for specific recognition of novel targets, with memory. The interactions between innate and adaptive immunity are many, complex, and bidirectional, with innate mechanisms being instrumental in the initiation of adaptive responses, and controlling the type of adaptive response induced; innate effector mechanisms are also recruited in the effector phase of adaptive responses.
Она вздохнула, надеясь, что ей не придется раскаиваться в том, чем она собиралась заняться. - Если все пойдет хорошо, то результат будет примерно через полчаса.