Complement System
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Complement System

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Complement System Complement System Presentation Transcript

  • COMPLEMENT SYSTEM
    Fe A. Bartolome, MD, FPASMAP
    Department of Microbiology
    Our Lady of Fatima University
    • Consists of approx. 20 proteins that are present in normal human serum  synthesized mainly by liver
    • Heat-labile  inactivated by heating serum at 560C for 30 minutes
    • Able to augment the effects of other components of the immune system
    • Important component of innate host defenses
    • Three main effects:
    Lysis of cells (bacteria, allografts, tumor cells)
    Generation of mediators of inflammation
    Opsonization – enhancement of phagocytosis
    • Sequential activation of complement components occurs via one of three pathways:
    Classic pathway
    Lectin pathway
    Alternative or Properdin pathway
    • Lectin and alternative pathways are more important the first time we are infected by microorganisms because antibody required to activate the classic pathway is not yet present
  • Classic Pathway
    • Part of acquired or adaptive immunity
    • Activated by Ag-Ab complexes
    • Immunoglobulins involved: IgM and IgG (except IgG4)
    • Involves activation of C1
    • Composed of C1q, C1r, and C1s  binds to Fc portion of IgG and IgM
    • Requires calcium for activation
  • Classic Pathway
    • Other activators include:
    Viruses – Murine and Retroviruses
    Bacteria – Mycoplasma
    Polyanions, especially bound to cations
    a. PO43- - DNA, lipid A, cardiolipin
    b. SO42- - dextran, heparin, chondroitin
    Arrays of terminal mannan groups
  • Classic Pathway
  • Classic Pathway
  • Classic Pathway
  • Alternative Pathway
    • Also known as the Properdin Pathway
    • Part of innate immunity
    • Bypasses C1, C4, and C2
    • Does not require an antigen-binding protein
    • Does not wait for antibody to be formed for activation
    • Acts synergistically with the classical pathway
  • Alternative Pathway
    • Usually activated by products of micro-organisms like endotoxin
    • Other activators include:
    Complexes containing IgA
    Some virus-infected cells (e.g. EBV)
    Many gram negative and gram positive organisms
    Parasites – Trypanosomes, Leishmania
    Dextran SO4
    Erythrocytes
    Carbohydrates (agarose)
  • Alternative Pathway
  • Alternative Pathway
  • Lectin Pathway
    • Also known as the MBL Pathway
    • Activated by binding of mannose-binding lectin (or mannose-binding protein) to surface of microbes bearing mannan(polymer of the sugar mannose) in a calcium dependent manner
    • Binding causes activation of MASP (MBP- associated serine proteases)  cleave C2 and C4
  • Lectin Pathway
    • All three pathways lead to production of C3b  central molecule of complement cascade
    • Presence of C3b on surface of a microbe marks it as foreign and targets it for destruction
    • C3b with two important functions:
    Combines with other complement components to generate C5 convertase
    Opsonizes bacteria
  • Biologic Effects:
    Opsonization
    • C3b & C1q; enhance phagocytosis
    Chemotaxis
    • C5a and C5,6,7 complex  attract neutrophils
    • C5a – enhance adhesiveness of neutrophils to the endothelium
    Anaphylatoxin (C3a, C4a, C5a)
    • Cause degranulation of mast cells
    • Bind directly to smooth muscles of bronchioles  bronchospasm
  • Biologic Effects:
    Cytolysis (MAC)
    • Disrupt the membrane & the entry of water and electrolytes into the cell
    Enhancement of antibody production
    • Binding of C3b to its receptors on the surface of activated B cells  enhanced antibody production
  • Regulation of Complement System
    C1 inhibitor (C1-INH)
    • Important regulator of classic pathway
    • A serine protease inhibitor (serpin)
    • Irreversibly binds to and inactivates C1r and C1s, as well as MASP in lectin pathway
    Factor H
    • Regulate alternative pathway
    • Reduce amount of C5 convertase available
    • With both cofactor activity for the factor I- mediated C3b cleavage, and decay accelerating activity against C3bBb (C3 convertase)
  • Regulation of Complement System
    Properdin
    • Protects C3b and stabilizes C3 convertase
    Factor I
    • Cleaves cell-bound or fluid phase C3b and C4b  inactivates C3b and C4b
    Decay accelerating factor (DAF)
    • Glycoprotein on surface of human cells
    • Prevents assembly of C3bBb or accelerates disassembly of preformed convertase  no formation of MAC
    • Acts on both classical and alternative
  • Regulation of Complement System
    C4b-binding protein (C4BP)
    • Inhibits the action of C4b in classical pathway
    • Splits C4 convertase and is a cofactor for factor I
    Complement Receptor 1 (CR-1)
    • Co-factor for factor I, together with CD46
    Protectin (CD59) and Vitronectin (S protein)
    • Inhibits formation of MAC by binding C5b678
    • Present on “self” cells to prevent complement from damaging them
  • Clinical Aspects
    Deficiency of C5-C8 & Mannan-binding lectin
    • Predispose to severe Neisseriabacteremia
    Deficiency of C3
    • Severe, recurrent pyogenic sinus & resp. tract infections
    Deficiency of C1 esterase inhibitor
    • Angioedema inc. capillary permeability and edema
    Deficiency of DAF
    • Increased complement-mediated hemolysis  paroxysmal nocturnal hemoglobinuria
  • Clinical Aspects
    Transfusion mismatches
    • Activation of complement  generate large amounts of anaphylatoxins & MAC  red cell hemolysis
    Autoimmune diseases
    • Immune complexes bind complement  low complement levels + activate inflammation  tissue damage
    Severe liver disease
    • Deficient complement proteins  predispose to infection with pyogenic bacteria
  • Clinical Aspects
    Factor I deficiency
    • Low levels of C3 in plasma due to unregulated activation of alternative pathway  recurrent bacterial infections in children
    • Mutations in factor I gene  implicated in development of Hemolytic Uremic Syndrome