cellular & molecular immunology...
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Cellular & Molecular Cellular & Molecular ImmunologyImmunology
20092009
ComplementComplement
Nicholas M. Ponzio, Ph.D.Nicholas M. Ponzio, Ph.D.Department of Pathology & Laboratory MedicineDepartment of Pathology & Laboratory Medicine
March 4, 2009March 4, 2009
Innate and adaptive immunity
FAMOUS BELGIANS
Jules Jean Baptiste Vincent BORDET(1870-1961)
Lysis of Vibrio cholera by immune serumExperiment #1
Since antibodies are heat stable, Bordet concluded that a heat labile substancewas needed in addition to antibodies to cause lysis
Fresh normal serum no lysisFresh immune serum lysisHeated immune serum no lysis
Lysis of Vibrio cholera by immune serumExperiment #2
Conclusion: A heat labile substance in normal serum “complements” the ability of antibodies in immune serum to lysetargets
Proof of Principle:Heated immune serum
+ fresh normal serum LYSIS
What is Complement ?• C is a complex series of proteins in the blood
• These proteins are sequentially activated (aka, fixed), and they non-specifically “complement” the action of antibodies
• In the process of being activated, the C proteins are cleaved into a major fragment and a minor fragment (aka, split product)
• These fragments are responsible for the observed biological functions of C
Biological Functions of C• Opsonization and Phagocytosis
Microbes coated with C componentsare ingested more efficiently
• Stimulation of InflammationC products can induce acute inflammation
• CytolysisC can cause lysis of microbes
• C activation involves the sequential proteolysis of proteins to generate enzymes with proteolytic activity
• C products attach to microbial surfaces or to antibodies that are bound to microbes
• C activation is inhibited by regulatory proteins present on host cells, but absent from microbes
To perform these functions:
Fig. 12-8 Pathways of Complement Activation
Structure of Complement Component C1
Classical pathway of complement activation
C2b
C2b
C4b2b
C4b2b
C5a
Structure of Complement Component C1
The C1 component of complement
Activation of complement by IgM and IgG antibodies
Fig. 12-8 Pathways of Complement Activation
Thioester bond of C3
Alternative pathway of complement activation
C5a
Late steps of complement activation:Formation of the membrane attack complex (MAC)
Electron micrographs of Membrane Attack Complex inserted into the cell membrane
MHC IMHC II
MHC I
MHC II
Table 14-6 Receptors for Fragments of C3
Co-receptor for B cell activation; Trapping of antigens in germinal centers; Receptor for EBV
B Cells, Follicular Dendritic Cells,
Type 2 (CR2, CD21)
Phagocytosis; Clearance of immune complexes; Promotes dissociation of C3 convertasesby acting as cofactor for cleavage of C3b, C4b
Mononuclear phagocytes, neutrophils, B and T cells, RBCs, FDCseosinophils,
Type 1 (CR1, CD35)
FunctionDistributionReceptor
Table 14-6 Receptors for Fragments of C3
Phagocytosis; Leukocyte adhesion
Mononuclear phagocytes, neutrophils, NK cells
Type 4 (CR4, CD11c/18)
Phagocytosis; Leukocyte adhesion to endothelium (via ICAM-1)
Mononuclear phagocytes, neutrophils, NK cells
Type 3 (CR3, CD11b/18)
FunctionDistributionReceptor
Regulation of complement activation by C1 inhibitor
Classical pathway of complement activation
Cleavage of C3b by Factor I
Inhibition of the membrane attack complex
Functions of the Complement
System
Functions of the Complement
System
Functions of the
Complement System
C3a & C5a = Anaphylatoxins
Functions of the Complement
System
Additional functions of the complement system:
• Trapping of IC in germinal centers – C receptors on Follicular Dendritic Cells bind IC and present antigen to B cells during humoral immune responses.
• B cell activation – C3d (cleavage product of C3b) binds to C receptors on B cells, providing a signal to initiate B cell activation during humoral immune responses.
9-5
• Classical Pathway:C1q, C1r, C4, C2, C3 (C2 most common)C2 & C4 -- autoimmune diseases
(e.g., SLE)C3 -- gram+ bacterial infections
• Alternative Pathway:Properdin & Factor D -- gram+ infections
• Membrane Attack Complex (MAC):C5 - 9 -- Neisseria bacterial infections
Complement Deficiencies