complement

  1. Open response: 1 of the cascade given (alternative, lectin, classical) and diagram cascade start to finish. What caused recognition of foreign substances to MAC (membrane attack complex). know which ones convert to C3 convertase. Focus on 

  • Classical:

    • Initiated by antibody bound to antigen

      • Activated by IgM and the IgG subclasses, IgG3, IgG1 and IgG2

    • After antibody binds to antigen, a conformational change occurs

      • Reveals a site on the antibody molecule that binds the C1q molecule

  • Formation of C3 convertase by classical pathway

    • C1q structure (6 arms)

    • C1r and C1s wrap around C1q (Ca^2+ required for function)

    • Binds Ab only after it has bound Ag (role in controlling complement cascade)

    • Two globular heads of C1q must bind to antibody that is bound to Ag (2 IgGs close together or two Fc of IgM)

    • Mechanical shift of C1q activates C1r which activates C1s

    • C1 unit then cleaves C4 into C4a and C4b (C4a released into fluid phase, C4b lands on cell surface)

    • C4b forms Mg^2+ dependent complex with C2

    • C2 is cleaved by C1s forming C2a and C2b (C2a lands on surface and complexes with C4b, C2b floats away)

    • C3 convertase of classical pathway C4b2a


  • Alternative:

    • Formation of C3 convertase by alternative pathway

      • C3 is hydrolyzed and called C3w

        • C3w lands on activator surface

        • Factor B binds next to C3w

        • Factor D interacts, does not land and splits factor B into Bb

        • C3wBb is C3 convertase

        • Properdin stabilizes complex

  • Lectin: 

    • Mannose binding lectin or serum ficolin bind to surface carbohydrates

    • MBL-associated serine protease-2 (MASP-2) binds to MBL and cleaves C2 and C4

      • C2b and C4a diffuse, C2aC4b forms C3 convertase

  1. Know what complement helps with in the body 

  • 3 different pathways that involve recognition of different foreign particles 

    • This recognition results in the activation of the pathway components 


  1. Know the sequence of all of the pathways and the order in which they work. 


  1. Know which components act as an opsonin, which ones act anaphylatoxins, which ones are part of the membrane attack complex. Chemotactic activity. 

  • Opsonin:

    • C3b, C4b, iC3b, C1q; increase phagocytosis, bind cellular receptors on phagocytic cells, involved in immune complex clearance

  • Anaphylatoxins:

    • C5a, C3a, C4a; small peptide that causes histamine release from mast cells, leads to smooth muscle contraction and increases in vascular permeability

  • Membrane attack complex: 

    • After C3 convertase, C3 is converted to C3a and C3b

      • C3b lands on the pathogen and next to C3 convertase forming a C5 convertase

    • C5 is split to C5a and C5b

      • C5a floats away, C5b lands on cell surface

    • C6 binds to C5b → C7 binds →C8

    • Once C9 binds then additional C9 binds

    • C9 units polymerize (forms a donut shaped hole in membrane)

    • C5-9 complex is called membrane attack complex

  • Chemotactic activity: 

    • C5a, C3a, C4a

  • I remember him saying this would def be on exam… just not sure what question it answers but imma throw it in here lol


  1.  Know regulators and what they are regulating and what they are stopping

  • Classical:

    • C1 inhibitor (C1INH) inactivates C1

      • Causes C1r and C1s to dissociate from C1q

      • Also regulates lectin pathway (inhibits binding of MBL-MASP-2)

    • Factor 1 inactivates C3b and C4b

      • Requires one of the following to be present: C4b-binding protein (C4BP), decay accelerating factor (DAF), membrane cofactor protein, complement receptor 1 (CR1)

    • CR1: binds to C3b coated immune complexes, CR1 on RBCs and platelets bring the complexes to the liver and spleen, complexes are stripped and RBCs are returned to circulation

    • DAF: on most cells, stops bystander lysis

  • alternati


  1. Know how to interpret CH50 and AH50 results. CH = classical. AH= alternative.

  • CH50 assay:

    • Measures the function of complement initiated through the classical pathway

    • Sheep RBC lysis and subsequent free HgB measurement 

    • Newer test measures neoantigen formation from MAC

  • AH50 assay: 

    • Measures the function of complement initiated through the alternative pathway 

    • Rabbit blood directly activates alternative pathway

    • Mix plasma with Rabbit RBC and detect free Hb

 

  • Both CH50 and AH50 require the complement components C3 and C5-9

    • CH50 requires C1, C2, C4, C1INH

    • AH50 requires factor B, factor D, properdin and Factor H and I

  • High complement levels = acute inflammation can raise levels 

  • Low complement levels 

    • Genetic deficiencies 

    • Chronic infection or inflammation 

    • Incorrectly processed serum samples 


  • Deficiency in C1, C4, and C2 increase risk of

    • Autoimmune connective tissue diseases 

    • Recurrent infections with staph and streptococcus 

  • Deficiency in the lectin pathway 

    • Associated with bacterial infections in infants 

  • Deficiency in C1INH

    • Involved in inhibiting both the classical and lectin pathways 

    • Can cause hereditary angioedema 

  • Deficiency in C3

    • Profound affect all pathways 

    • Decrease phagocytosis, immune complex clearance and class switching 

  • Alternative pathway deficiencies 

    • Related to pus forming infections 

  • Deficient in terminal components 

    • Severe Neisseria meningitidis infections 

    • SLE (lupus)

  • Deficiencies of DAF and CD59

    • PNH (paroxysmal nocturnal hemoglobinuria)

    • Anemia