Immlec finals

• Complement


  A group of blood serum over 30 proteins that "complements" or enhances the activity of antibodies and immune cells in the immune response
• Complement components


  • Most are synthesized in the liver by hepatocytes, some produced by other cell types, including blood monocytes, tissue macrophages, fibroblasts, and epithelial cells of the gastrointestinal and genitourinary tracts
  • They are released into the bloodstream where they exist in their inactive forms
  • Constitute approximately 15% of the globulin protein fraction in plasma, and their combined concentration can be as high as 3 mg/mL
• Complement activation


  Once activated, these proteins interact with one another in a cascade of enzymatic reactions, leading to a variety of immune responses, including opsonization, phagocytosis, secretion of inflammatory mediators, and pathogenic cell lysis
• Complement proteins


  Named with a capital C followed by a number (e.g., C1, C2, C3, etc.), each playing a specific role in the cascade of reactions that lead to the activation of the complement system
• Bordet's finding that bacteriolysis required two different substances: a heat-stable specific antibody that bound to the bacterial surface, and a heat-labile (sensitive) component responsible for the lytic activity
• Complement


  The activity of blood serum that completes the action of antibody
• The action of complement is the result of interactions among a complex group of more than 30 glycoproteins
• Several of the regulatory components of the complement system exist on cell membranes
• Scientists noticed that certain immune reactions were more effective when both antibodies and another, as yet unidentified, factor were present
• This additional factor was found to be a group of proteins in the blood that could enhance the ability of antibodies to clear pathogens from the body
• Bordet showed that sheep antiserum to the bacterium Vibrio cholerae caused lysis (membrane destruction) of the bacteria, and that heating the antiserum destroyed its bacteriolytic activity
• Heating the serum destroyed its bacteriolytic activity, but adding fresh serum that contained no antibacterial antibodies restored the ability to lyse the bacteria
• Initiator Complement Components (Initiators)

  Antigen-recognizing proteins that trigger the initiation of their respective complement cascades by binding to particular soluble or membrane-bound molecules
• Enzymatic mediators


  Proteolytic enzymes that cleave and activate other members of the complement cascade, producing a larger fragment (opsonin) and a smaller fragment (anaphylatoxin)
• Membrane-binding components (Opsonins)


  The larger fragments of cleaved complement proteins that serve as opsonins, enhancing phagocytosis by binding to microbial cells and serving as binding tags for phagocytic cells
• Inflammatory mediators (Anaphylatoxins)


  The smaller fragments of cleaved complement proteins that enhance the blood supply to the area in which they are released, by binding to receptors on endothelial cells and inducing an increase in capillary diameter, and also attract other cells to the site of tissue damage
• Membrane attack proteins


  The proteins of the membrane attack complex (MAC) that insert into the cell membranes of invading microorganisms and punch holes that result in lysis of the pathogen
• Complement receptor proteins


  Receptor molecules on cell surfaces that bind complement proteins and signal specific cell functions, expressed on various immune cells and non-immune cells
• Regulatory complement components


  Proteins that modulate the activity of the complement system to prevent excessive or inappropriate complement activation, protecting host cells from unintended complement-mediated lysis
• The pathways in the complement system are characterized by the series of enzymatic cleavages that result in the formation of smaller complement fragments, with two main products: C3 convertases and C5 convertases
• Zymogens


  Inactive proteins that are activated through proteolytic cleavage
• Classical Pathway


  1. C1 complex containing C1q, C1s and C1r binds to antigen-antibody complexes or bacterial surfaces, activating C1r which then cleaves C1s to cleave C4 and C2, forming the C3 convertase C4b2a

  2. C3 convertase cleaves C3 into C3a and C3b, with C3b combining with C4b2a to form the C5 convertase C4b2a3b
• Lectin Pathway


  Mannose-binding lectin (MBL) binds to pathogens, activating MBL-associated serine proteases (MASPs) which cleave C2 and C4 to generate the C3 convertase as in the classical pathway
• Alternative Pathway


  1. C3 undergoes spontaneous hydrolysis to C3(H2O), which binds factor B and is cleaved by factor D to form the fluid phase C3 convertase C3(H2O)Bb

  2. C3b binds to microbial surfaces and binds factor B, which is cleaved by factor D to form the cell-bound alternative pathway C3 convertase C3bBb, stabilized by Properdin

  3. C5 convertases are formed by the addition of a C3b fragment to each of the C3 convertases
• Complement protein complexes


  The fragments complex together to form enzymes, with the fragment names merged in the order in which they bind (e.g. C4b2a, C4b2a3b)
• Main complement proteins


  • C1, C2, C3, C4, C5, C6, C7, C8, C9
• Complement protein fragments


  • a fragment is the smaller protein, also an anaphylatoxin that diffuses to the system
  • b fragment is the larger protein that interacts and binds to other proteins or the target plasma membrane
• The classical pathway of complement activation is considered part of the adaptive immune response since it begins with the formation of antigen-antibody complexes
• Only complexes formed by IgM or certain subclasses of IgG antibodies are capable of activating the classical complement pathway
• C1 Complex

  Consists of one molecule of C1q, two molecules each of the serine proteases C1r and C1s, held together in a Ca²⁺-stabilized complex
• C1q molecule


  Composed of 18 polypeptide chains that associate to form six collagen-like triple helical arms, with a globular head tip at the end of each arm that associates to the CH2 domain in the Fc region of the antibody attached to an antibody
• At least 2 IgG antibodies are required to activate C1 complex, while only one IgM (attached to the antibody) is needed since it is a pentamer
• Classical Pathway Initiation


  1. C1 complex binds to antigen-antibody complexes, activating C1r which then cleaves C1s to cleave C4 and C2, forming the C3 convertase C4b2a

  2. C3 convertase cleaves C3 into C3a and C3b, with C3b combining with C4b2a to form the C5 convertase C4b2a3b
• C3b


  • Acts as an opsonin on microbial surfaces, tags immune complexes for clearance, and forms part of the C5 convertase
  • Deficiencies of complement components acting prior to C3 cleavage leave the host extremely vulnerable, while deficiencies later in the pathway are generally of lesser consequence
• Complement Activation


  C5 convertase cleaves C5 into C5a (anaphylatoxin) and C5b, which goes on to form the membrane attack complex (MAC) that punches holes in pathogen cell membranes
• C3b


  • Opsonin in microbial surface
  • Clearance of immune complexes
  • Formation of C5 convertase
• Opsonin


  Molecule that binds to a pathogen and marks it for phagocytosis
• C3b binding to microbial surface

  1. Covalent binding

  2. Providing a molecular "tag" for phagocytic cells with C3b receptors to engulf the tagged microbes
• C3b binding to immune complexes

  1. C3b-tagged immune complexes are bound by C3b receptors on phagocytes or red blood cells

  2. Immune complexes are either phagocytosed or conveyed to the liver where they are destroyed
• Formation of C5 convertase


  1. Some molecules of C3b bind the membrane-localized C4b2a enzyme

  2. To form the trimolecular, membrane-bound, C5 convertase complex C4b2a3b