The Complement System Andrew e thompson md frcpc

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The Complement System

  • Andrew E Thompson MD FRCPC

  • Fellow in Rheumatology

  • University of British Columbia


  • The complement system is part of the innate immune system (vs adaptive)

  • It is named “complement system” because it was first identified as a heat-labile component of serum that “complemented” antibodies in the killing of bacteria

  • It is now known that it consists of over 30 proteins and contributes 3 g/L to overall serum protein quantities

“Classical” Pathway

  • Begins with antibody binding to a cell surface and ends with the lysis of the cell

  • The proteins in this pathway are named C1-C9 (the order they were discovered and not the order of the reaction)

  • When complement is activated it is split into two parts

    • a – smaller of the two
    • B – larger part and usually the active part (except with factor 2)
  • Remember 3 Key Words

    • ATTACK

“Classical Pathway”


    • C1q portion of C1 attaches to the Fc portion of an antibody
    • Only IgG and IgM can activate complement
    • Once activated C1s is eventually cleaved which activates C4 and C2
    • C4b & C2a come together to form the C4b2a which is the C3 convertase
    • C3 convertase activates C3 to C3a and C3b

“Classical Pathway”


    • C3a binds to receptors on basophils and mast cells triggering them to release there vasoactive compounds (enhances vasodilation and vasopermeability)
    • C3a is called an anaphylatoxin
    • C3b serves as an opsonin which facilitates immune complex clearance

“Classical Pathway”


    • Each C1s creates many C4b and C2b fragments
    • Each C4bC2a creates many C3b (activated C3)
    • Each C3b goes on to create many Membrane Attack Complexes
    • Example
      • 1 C1S makes 100 C4bC2b
      • 100 C4bC2b makes 10,000 C3b
      • 10,000 C3b makes 1,000,000 MAC

“Classical Pathway”


    • Most C3b serves an opsonin function
    • Some C3b binds to C4bC2a to form the C5 convertase C4bC2aC3b
    • C5 convertase cleaves C5 leading to the formation of the Membrane attack Complex (C5-C6-C7-C8-C9)
    • The MAC “punches holes” in cell walls resulting in lysis

“Alternative Pathway”

  • Requires no specific recognition of antigen in order to cause activation

“Alternative Pathway”


    • Spontaneous conversion from C3 to C3b occurs in body
    • Normally, C3b is very short lived and quickly inactivated by proteins on the surface of the body’s own cell walls
    • However, bacteria or other foreign material may lack these surface proteins allowing C3b to bind and stay active

“Alternative Pathway”


    • Factor B binds to C3b
    • Factor B is then cleaved by factor D into Ba and Bb
    • C3bBb remains which acts as a C3 convertase (C3  C3a and C3b)
    • C3bBbC3b is formed which acts as a C5 convertase

“Alternative Pathway”


    • C5 is cleaved to C5a and C5b
    • C5b then starts the assembly of the Membrane Attack Complex

Summary - Activation

  • Complement can be activated by the binding of antibody (Classical) or by the adherance of C3b to foreign material (Alternative)

  • The two pathways converge at the formation of the C5 convertase (C4b2a3b or C3bBbC3b)

  • The final common pathway is the formation of the membrane attack complex

Summary - Function

  • Opsonization – C3b

  • Chemotaxis – C5a (attracts neutrophils)

  • Increases vasodilation & permeability of capillary beds via mast cell and basophil activation – C3a & C5a (Anaphylatoxins)

  • Cellular Lysis via the MAC

Laboratory Measures

  • C3 – Quantitative measure (nephelometry)

  • C4 – Quantitative measure (nephelometry)

  • CH50

    • Functional assay of entire Classical Pathway
    • Measures the ability of the patients serum to lyse 50% of a standard suspension of sheep erythrocytes coated with rabbit antibody
    • A low CH50 suggests either
  • AH50

The Role of Complement in the Rheumatic Diseases

  • The Double Edged Sword!

  • Needed for proper handling of immune complexes

  • Also mediates tissue damage, especially in the setting of autoantibodies and excessive immune complex formation

  • Just as the complement system can destroy a microbe, it can lyse and erythrocyte, phagocytose a platelet, or disrupt a basement membrane

Autoimmunity and Inherited Complement Deficiencies

  • Inherited deficiencies of complement components can result in autoimmunity, especially SLE

    • C1q deficiency – 90% have SLE
    • C4 deficiency – 75-80% have SLE
    • C2 deficiency – 10-40% have SLE
  • Early age of onset, prominent cutaneous manifestations, and presence of anti-Ro antibodies are features suggestive of a complement deficiency

Autoimmunity and Inherited Complement Deficiencies

  • How does SLE form with complement deficiencies?

    • Failure to clear autoantigens (apoptotic cells)
    • Immature dendritic cells uptake the antigen in the presence of inflammatory cytokines causing them to mature into antigen presenting dendritic cells – Presents to T-Cell
    • Autoreactive B-Cells take up antigen from apoptotic cells and (with the help CD4+ Th2-Cells) transform into plasma cells that secrete autoantibody

Indirect Laboratory uses of Complement – Detection of Immune Complexes

  • C1q binding Assay

    • Normally C1q has a very weak affinity for monomeric IgG and IgM
    • When IgG or IgM are part of an immune complex the Fc portion undergoes a conformational change
    • This results in a much higher affinity for C1q
    • This test is an ELISA which looks for immune complexes in a patients serum capable of binding C1q

Indirect Laboratory uses of Complement – Detection of Immune Complexes

  • Raji Cell Preparation

    • Raji cells are a human lymphoblastoid cell derived from a patient with Burkitt’s lymphoma
    • They are unique because
      • They have surface receptors for C1q, C3b, C3bi, and C3d
      • Lack of surface immunoglobulin
      • Surface IgG receptors are low in number and avidity
    • Therefore, immune complexes containing complement can bind to surface receptors on Raji Cells!
    • This can then help to detect immune complexes capable of binding complement
    • Sensitive test, however, warm reactive anti-lymphocyte antibodies and anti-ds-DNA antibodies may cause false positive results

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