Complement Flashcards
Complement
Complement proteins are chiefly produced by the Liver and *Continuously circulate in blood and fluids at High Concentrations.
- Complement System is Activated by Infection after Microbes bind to these Proteins.
- Cascade of proteolytic enzyme production generates active components, some of which activate immune responses.
Activated by 3 mechanisms:
–Alternative Pathway: Activated by Microbial Surface Proteins. Part of Innate Immunity.
–Classical Pathway: Activated by Ig bound to Microbes. Part of Humoral Adaptive Immunity.
–Lectin Pathway: Activated by MBL, a plasma protein that attaches to Mannose Terminals on microbial glycoproteins. Part of Innate Immunity.
C3 plays a central role and cleaves early on into fragments of distinct functions:
–C3b Coats Microbes, facilitating *Phagocytosis. Phagocytes have C3b Receptors.
–C3a (and C5a) are *Chemoattractants for Phagocytes and *Trigger Inflammation.
–*Complex C5-9 perforates Microbial cell membrane, killing the microbe.
Alternative Pathway of Complement Activation
Activated by Microbial Surface Proteins.
Part of Innate Immunity.
1) Constant Hydrolysis of C3 –> C3b
2) C3b binds to Microbe and is, thus, stabilized and protected from further degradation.
3) Factor B binds to C3b and is then cleaved –> Bb
4) C3bBb Complex = C3 Convertase
Breaks down more C3. Many more C3b and C3bBb are produced and bind to the microbe.
5) Some C3bBb is bound by another C3b
6) C3bBbC3b Complex = C5 Convertase
Breaks down C5 –> C5b and C5a
7) C5b binds to C6, C7, C8, C9 to form the Membrane Attack Complex (MAC) that perforates Microbial Cell Membranes.
Classical Pathway for Complement Activation
Activated by Ig bound to Microbe.
Part of Humoral Adaptive Immunity.
1) IgM, IgG1, and IgG3 are microbial coating antibodies. Any of them may bind to microbe.
2) The Fc regions of the bound Ig come close together, cross-link, and then bind and activate C1.
3) C1 binds and cleaves C4 and then C2.
4) C4bC2a Complex = C3 Convertase
Breaks down C3 –> C3b, which binds to microbe
5) Some C3b binds to the C4bC2a Complex
6) C4bC2aC3b Complex = C5 Convertase
Breaking down C5 –> C5a and C5b
7) C5b binds to C6, C7, C8, C9 to form the Membrane Attack Complex (MAC) that perforates Microbial Cell Membranes.
Lectin Pathway for Complement Activation
Triggered by binding of MBL to microbes.
Part of Innate Immunity.
(MBL is structurally similar to C1 of the Classical Pathway and serves to activate C4.)
(Subsequent steps are same as in Classical Pathway.)
Regulation of Complement System
**Mammalian cells express Regulatory proteins that inhibit Complement Activation, preventing Host cell damage:
–*Decay-Accelerating Factor (DAF): Blocks Factor B. Thus, it blocks C3 Convertase formation in both Alternative and Classical Pathways
(by blocking binding of Bb to C3b and binding of C4b to C2a).
–*Membrane Cofactor Protein (MCP): Blocks C3b.
(By serving as a Cofactor for C3b proteolysis into inactive fragments)
–*C1 Inhibitor (C1INH): Blocks C1
Thus, blocks Classical Pathway
(By preventing it from becoming proteolytically active)
–*Other protein inhibitors of MAC
*Inherited deficiencies of these inhibitors cause uncontrolled complement activation, such as in Hereditary *Angioneurotic Edema due to C1INH Deficiency.
Angioneurotic Edema
*Inherited deficiencies of these inhibitors cause uncontrolled complement activation, such as in Hereditary *Angioneurotic Edema due to C1INH Deficiency.
–*C1 Inhibitor (C1INH): Blocks C1
Thus, blocks Classical Pathway
(By preventing it from becoming proteolytically active)
Complement Inherited Deficiencies
C3 Deficiency: Results in *Severe Susceptibility to Infections. *Fatal during early life.
C2 and C4 Deficiencies: Don’t cause severe immunodeficiency but do cause increased incidence of *Immune Complex Autoimmune Diseases.
C9 and MAC Deficiencies: Result in increased susceptibility to *Neisseria infections.
Some polymorphisms in MBL gene are associated with increased susceptibility to infections.
Functions of Complement
1) Opsonization of Microbes for Phagocytosis:
- –Binding of C3b to Microbe (Opsonization). (Most important function of complement for defense.)
- –C3b Receptor on Phagocytes recognizes C3b bound to microbe.
- –Phagocytosis and Killing of microbe.
2) Complement-Mediated Cytolysis (MAC-induced lysis)
—Binding of C3b to Microbe.
—Activation of late steps of Complement.
—Formation of Membrane Attack Complex (MAC).
—MAC punched holes in microbial cell membrane.
—Osmotic Lysis of Microbe.
This function is only effective against microbes that have thin cell walls and little or no glycocalyx, such as Neisseria.
3) Stimulation of Inflammation:
- –Chemoattractants *C3a and C5a recruit leukocytes to site of infection
4) Costimulation of B cells:
- –When C3 is activated by Microbe, C3d is recognized by CR2 (Complement Receptor Type 2) on B cells.
5) Complement-Dependent Antigen Display to B cells:
- –Complement proteins bound to Antigen-Antibody Complexes are recognized by Follicular Dendritic Cells @ Germinal Centers.
- –Allowing the antigens to be displayed for further B cell Activation and Selection of High-Affinity B cells.
