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    the classical, alternative and ____________ pathways all lead to the cleavage of complement c3 into c3a and c3b.

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    The complement system and innate immunity

    Complement was discovered many years ago as a heat-labile component of normal plasma that augments the opsonization of bacteria by antibodies and allows antibodies to kill some bacteria. This activity was said to ‘complement’ the antibacterial activity of antibody, hence the name. Although first discovered as an effector arm of the antibody response, complement can also be activated early in infection in the absence of antibodies. Indeed, it now seems clear that complement first evolved as part of the innate immune system, where it still plays an important role.

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    Immunobiology: The Immune System in Health and Disease. 5th edition.

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    The complement system and innate immunity

    Complement was discovered many years ago as a heat-labile component of normal plasma that augments the opsonization of bacteria by antibodies and allows antibodies to kill some bacteria. This activity was said to ‘complement’ the antibacterial activity of antibody, hence the name. Although first discovered as an effector arm of the antibody response, complement can also be activated early in infection in the absence of antibodies. Indeed, it now seems clear that complement first evolved as part of the innate immune system, where it still plays an important role.

    The complement system is made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection. A number of complement proteins are proteases that are themselves activated by proteolytic cleavage. Such enzymes are called zymogens and were first found in the gut. The digestive enzyme pepsin, for example, is stored inside cells and secreted as an inactive precursor enzyme, pepsinogen, which is only cleaved to pepsin in the acid environment of the stomach. The advantage to the host of not being autodigested is obvious.

    In the case of the complement system, the precursor zymogens are widely distributed throughout body fluids and tissues without adverse effect. At sites of infection, however, they are activated locally and trigger a series of potent inflammatory events. The complement system activates through a triggered-enzyme cascade. In such a cascade, an active complement enzyme generated by cleavage of its zymogen precursor then cleaves its substrate, another complement zymogen, to its active enzymatic form. This in turn cleaves and activates the next zymogen in the complement pathway. In this way, the activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. As might be expected, there are many regulatory mechanisms to prevent uncontrolled complement activation. The blood coagulation system is another example of a triggered-enzyme cascade. In this case, a small injury to a blood vessel wall can lead to the development of a large thrombus.

    There are three distinct pathways through which complement can be activated on pathogen surfaces. These pathways depend on different molecules for their initiation, but they converge to generate the same set of effector molecules (Fig. 2.7). There are three ways in which the complement system protects against infection. First, it generates large numbers of activated complement proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing receptors for complement. Second, the small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Third, the terminal complement components damage certain bacteria by creating pores in the bacterial membrane.

    Figure 2.7

    Schematic overview of the complement cascade. There are three pathways of complement activation: the classical pathway, which is triggered by antibody or by direct binding of complement component C1q to the pathogen surface; the MB-lectin pathway, which (more...)

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    2-5. Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes

    In the early phases of an infection, the complement cascade can be activated on the surface of a pathogen through any one, or more, of the three pathways shown in Fig. 2.8. The classical pathway can be initiated by the binding of C1q, the first protein in the complement cascade, directly to the pathogen surface. It can also be activated during an adaptive immune response by the binding of C1q to antibody:antigen complexes, and is thus a key link between the effector mechanisms of innate and adaptive immunity. The mannan-binding lectin pathway (MB-lectin pathway) is initiated by binding of the mannan-binding lectin, a serum protein, to mannose-containing carbohydrates on bacteria or viruses. Finally, the alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen. Each pathway follows a sequence of reactions to generate a protease called a C3 convertase. These reactions are known as the ‘early’ events of complement activation, and consist of triggered-enzyme cascades in which inactive complement zymogens are successively cleaved to yield two fragments, the larger of which is an active serine protease. The active protease is retained at the pathogen surface, and this ensures that the next complement zymogen in the pathway is also cleaved and activated at the pathogen surface. By contrast, the small peptide fragment is released from the site of the reaction and can act as a soluble mediator.

    Source : www.ncbi.nlm.nih.gov

    Frontiers

    Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins and the membrane attack complex. We will also discuss the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome. Lastly we will discuss the development and benefits of therapies using complement inhibitors.

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    Frontiers in Immunology

    Frontiers in Immunology Molecular Innate Immunity

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    Front. Immunol., 02 June 2015 | https://doi.org/10.3389/fimmu.2015.00262

    Complement system part I – molecular mechanisms of activation and regulation

    Nicolas S. Merle1,2,3, Sarah Elizabeth Church2,3,4, Veronique Fremeaux-Bacchi1,2,3,5 and Lubka T. Roumenina1,2,3*

    1UMR_S 1138, Cordeliers Research Center, Complement and Diseases Team, INSERM, Paris, France

    2UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Paris Cité, Université Paris Descartes, Paris, France

    3UMR_S 1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Université Pierre et Marie Curie-Paris, Paris, France

    4UMR_S 1138, Cordeliers Research Center, Integrative Cancer Immunology Team, INSERM, Paris, France

    5Service d’Immunologie Biologique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France

    Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure–function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.

    Introduction

    Complement is a central part of the innate immunity that serves as a first line of defense against foreign and altered host cells (1). The complement system is composed of plasma proteins produced mainly by the liver or membrane proteins expressed on cell surface. Complement operates in plasma, in tissues, or within cells (2). Complement proteins collaborate as a cascade to opsonize pathogens and induce a series of inflammatory responses helping immune cells to fight infection and maintain homeostasis. The complement system can be initiated depending on the context by three distinct pathways – classical (CP), lectin (LP), and alternative (AP), each leading to a common terminal pathway. In a healthy individual, the AP is permanently active at low levels to survey for presence of pathogens (Figure 1A). Healthy host cells are protected against complement attack and are resistant to persistent low-grade activation. The three pathways are activated on the surface of apoptotic cells, which are constantly generated within the body during normal cellular homeostasis (Figure 1B). This complement activation is tightly regulated to eliminate dying cells without further activation of other innate or adaptive immune components. Complement is only fully activated in cases of pathogen infection. During an infection, complement leads to inflammation, opsonization, phagocytosis, and destruction of the pathogen and ultimately results in activation of the adaptive immune response (Figure 2). Both inefficient and over stimulation of complement can be detrimental for the host and are associated with increased susceptibility to infections or non-infectious diseases, including autoimmunity, chronic inflammation, thrombotic microangiopathy, graft rejection, and cancer.

    FIGURE 1

    Figure 1. Complement activation in physiological conditions. (A) The alternative pathway is permanently active due to spontaneous transformation of bio-inactive molecule C3 to bioactive C3(H2O). This allows generation of C3b, which is rapidly inactivated by FH and FI in fluid phase or is covalently bound to the surface and then inactivated on host cells. (B) Classical and lectin pathway recognition molecules bind to apoptotic cells and together with C3b from the alternative pathway induce a low level of complement activation. Apoptotic cells are not lysed, but rapidly cleared by phagocytes in an immunologically silent manner. Host cells and plasma contain multiple regulatory proteins to assure that complement activation will be limited in physiological conditions.

    FIGURE 2

    Figure 2. Complement during infection with a pathogen. The permanent activity of the alternative pathway allows it to immediately identify pathogens that are not specifically protected against complement. Danger-associated molecular patterns on its surface of pathogens are recognized by C1q, MBL, and ficolins allowing classical and lectin pathway activation, C3 convertase, C4b2a generation, and C3 cleavage. Opsonization due to covalent binding of C3b to the target is accelerated by the amplification loop of the complement pathways. The effector functions resulting from this complement activation are: pathogen lysis by C5b-9 membrane attack complex, opsonization and phagocytosis of the pathogen, activation of host immune and non-immune cells by complement anaphylatoxins, inflammation, stimulation of an adaptive immune response, and antibody generation. Secreted antibodies will bind to the pathogen and create immune complexes that will be recognized by C1q and will activate the classical pathway. Altogether these mechanisms contribute to pathogen elimination.

    Source : www.frontiersin.org

    Connect Questions for Ch. 21 Flashcards

    Start studying Connect Questions for Ch. 21. Learn vocabulary, terms, and more with flashcards, games, and other study tools.

    Connect Questions for Ch. 21

    Lymphatic vessel ____ cells are different from blood vessel cells.

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    endothelial

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    Lymphatic endothelial cells ____ have tight junctions and they do not have a continual basal lamina.

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    don't

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    Terms in this set (29)

    Lymphatic vessel ____ cells are different from blood vessel cells.

    endothelial

    Lymphatic endothelial cells ____ have tight junctions and they do not have a continual basal lamina.

    don't

    There are large gaps between the endothelial cells so ____ and large molecules can pass between them.

    lymphocytes

    The overlapping endothelial cells make ____ that can open and close.

    valves

    They will open and close due to the ____ of the lymph fluid flowing through the vessel.

    pressure

    The classical, alternative and ____ pathways all lead to the cleavage of complement C3 into C3a and C3b.

    lectin

    Those two fragments activate processes that lead to ____ inflammation, immune clearance and phagocytosis.

    enhanced

    Inflammation activates and attracts ____ and macrophages, two key cellular agents of pathogen destruction.

    neutrophils

    Immune clearance will clear foreign antigens from the ____.

    bloodstream

    During phagocytosis, ____ occurs which is the coating of microbial cells.

    opsonization

    Cytotoxic T cells produce

    -self proteins.

    -perforin, which makes holes in cell membrane of infected cells.

    -antibodies, which make holes in cell membrane of infected cells.

    -class II MHCs.

    perforin, which makes holes in cell membrane of infected cells.

    Cytotoxic T cells attack

    -viruses. -bacteria.

    -cells that display foreign proteins on their surface.

    -cells that display normal proteins on their surface.

    -The first and second choices are both correct answers.

    cells that display foreign proteins on their surface.

    Cytotoxic T cells produce _______ which creates holes in the cell membranes of target cells.

    -perforin -cytokinin -complement -lysozyme -antibody perforin

    Skin lesions due to hypersensitivity appear

    -48-72 hours after first exposure to antigen.

    -3 weeks after second exposure to antigen.

    -24 hours after second exposure to antigen.

    -24 hours after first exposure to antigen

    24 hours after second exposure to antigen.

    In IgE mediated hypersensitivity, all of the following are needed except

    -antigen presenting cells.

    -mast cells. -IgE antibodies. -B cells. -neutrophils. neutrophils.

    Histamine released by mast cells leads to all of the following symptoms except

    -capillary dilation.

    -high fever. -mucus secretion. -itching.

    -airway constriction.

    high fever

    A hypersensitivity reaction occurs

    -only in individuals with asthma.

    -in individuals with diseases of the immune system.

    -during the first exposure to an antigen.

    -during a second or subsequent exposure to an antigen.

    -only in children.

    during a second or subsequent exposure to an antigen.

    Immune complexes consist of

    -antigen plus complement.

    -antigen plus antibody.

    -antibody plus complement.

    -basophil plus complement.

    antigen plus antibody.

    In the presence of activated complement, neutrophils

    -are repelled.

    -degranulate and release enzymes that cause tissue damage.

    -cause vasodilation.

    -produce histamine.

    degranulate and release enzymes that cause tissue damage.

    Which of the following terms describes the migration of neutrophils from blood vessels?

    -degranulation -dilatation -extravasation -neutrophilisation

    -None of these choices are correct answers.

    extravasation

    Which of the following are antigen-presenting cells?

    -macrophages -B cells -cytotoxic T cells

    -All of these choices are correct answers.

    -Only the first and second choices are correct answers.

    Only the first and second choices are correct answers.

    Helper T cells secrete ________ to stimulate the proliferation of B cells.

    -allergens -antigens -agglutinins -antibodies -cytokines cytokines

    An antigen presenting cell presents antigen to a T helper cell

    -on its surface attached to an antibody.

    -on its surface on a class II MHC.

    -on its surface on a class I MHC.

    -inside a vesicle.

    on its surface on a class II MHC

    Interestingly, ____ do not directly attach nor destroy any pathogens. Rather, they bind to pathogens and in doing so render them incapable of causing an immune response.

    antibodies

    Antibodies bind to antigens sites on pathogenic cells and in doing so open binding site and promote ____ ____ resulting in a conversion of complement proteins to fight the pathogen.

    complement fixation

    Antibodies that bind to more than one cell simultaneously can rapidly cause clumping or ____ to occur which prevents the pathogen from contacting and damaging human cells.

    agglutination

    Small pathogenic molecules that are soluble are clumped together by antibodies binding more than one molecule simultaneously, making the molecule insoluble and less mobile. This is an example of ____.

    Source : quizlet.com

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