Complement System
• Functions
• Components
• Activation
Overview of the Complement System
• Meaning – to Help or to make Complete
• A primary part of the Innate immune response
• Group of 30 different proteins
• Designation
• Numerals (C1-C9)
• Letter symbols (factor D)
• Cleavage Products
• a and b
Functions of Complement
• 30 soluble and cell-bound proteins
1. Lysis of cells, bacteria and viruses
2. Opsonization
3. Triggers specific cell functions, inflammation and secretion
of immunoregulatory molecules
4. Immune clearance : removal of immune complexes and
deposition in the spleen and liver
Components
• Proteins and glycoproteins synthesized
mainly by liver hepatocytes
• Most circulate in the serum functionally
inactive forms as proenzymes or zymogens
• PRODUCES A CASCADE PHENOMENON
WHERE THE PRODUCT OF ONE REACTION IS
THE ENZYMATIC CATALYST OF THE NEXT
• Heat Labile: destroyed when heated at 56oC
for 30 mins
BIOLOGICAL FUNCTIONS
Function Main Complement Component Comment
involved
1. Anaphylatoxins C3a They bind to receptors on mast cells and
basophils
C4a
C5a Induce degranulation and release of influx
mediators including histamine
2. Increase Role of C2b Can lead to edema if complement is not
controlled
capillary fragment
permeability
3.Chemotaxis C5a Attract cells and play important role in
recruitment of cells to an influx site
4. Virus C4 Enhances neutralization of viruses by
homologous antibodies
neutralization
5 Opsonization C3b C3b on particles such as bacteria or an Ab-Ab
complex promotes the attachment and ultimate
ingestion of the particles
3 pathways
CLASSICAL ALTERNATE/ LECTIN
ALTERNATIVE/
PROPERDIN
1ST to be studied Initiated by: Initiated by: With
1.Aggregates of IgA mannose and other
Initiated by 2.Yeast cell or zymogen similar sugars in the cell
Ag-Ab complex 3.CVF: Cobra Venom wall (Ab independent)
Factor
4.LPS
3 Phases
INTITIATION • Recognition event which will
initiate complement cascade
PHASE • Classical and Alternate pathway
differ at this phase
AMPLIFICATION/ • Activation of early components
culminate in activation of C3,
ACTIVATION which is the critical component
PHASE • Classical and Alternate pathway
differ at this phase
MEMBRANE • Culminates in target cell lysis
• Classical and Alternate pathway
ATTACK PHASE is the same at this phase
Pathways of complement
activation
CLASSICAL LECTIN ALTERNATIVE
PATHWAY PATHWAY PATHWAY
Antibody Antibody
dependent independent
Activation of C3 and
generation of C5 convertase
Activation of C5
LYTIC ATTACK
PATHWAY
9
Components of the
alternative pathway
C3
JMCervantes 10
Classical pathway
• Begins with the formation of soluble antigen-antibody complexes
or with binding of antibody to antigen on a suitable target such as a
bacterial cell
• IgM or IgG
• Ag-Ab-IgM : conformational change in Fc : exposing a binding site
for C1
Alternative pathway
• Antibody is not required
• Innate immunity
• 4 serum proteins : C3, factor B, factor D and properdin
• Initiated by cell-surface constituents that are foreign to the host
(gram + and gram – bacterial cell walls)
Lectin pathway
• Lectins : proteins that recognize and bind to specific carbohydrate targets
• After initiation proceeds thru action of C4 and C2 to produce C5 convertase
• Activated by binding of mannose-binding lectin to mannose residues on
glycoproteins or carbohydrates on the surface of microorganisms such as
Salmonella, Listeria, Neisseria, Cryptococcus and Candida
Membrane Attack Complex
• 3 pathways : active C5 convertase to cleave C5 --- C5a and C5b
(initiates the final steps to form MAC)
• Forms a large channel through the membrane of the target cell
enabling ions and small molecules to diffuse freely across the
membrane
REGULATORS OF THE COMPLEMENT PATHWAY
SERUM PROTEIN FUNCTION
REGULATORS OF THE COMPLEMENT PATHWAY
• CR1
• Molecular weight: 165,000 to 280,000
• Location: It is found mainly on peripheral blood cells, including neutrophils,
monocytes, macrophages, erythrocytes, eosinophils, B lymphocytes, some T
lymphocytes, and follicular dendritic cells.
• Function: It binds C3b and C4b but has the greatest affinity for C3b
REGULATORS OF THE COMPLEMENT PATHWAY
• Membrane Cofactor Protein
• Molecular weight: 50,000 to 70,000
• Location: found on virtually all epithelial and endothelial cells except
erythrocytes.
• Function: MCP is the most efficient cofactor for factor I–mediated cleavage of
C3b.
REGULATORS OF THE COMPLEMENT PATHWAY
• Decay-accelerating factor (DAF)
• Molecular weight: 70,000
• Location: It is found on peripheral blood cells, on endothelial cells and
fibroblasts, and on numerous types of epithelial cells.
• Function: capable of dissociating both classical and alternative pathway C3
convertases
REGULATORS OF THE COMPLEMENT PATHWAY
• Membrane inhibitor of reactive lysis (MIRL)
• Location: widely distributed on the cell membranes of all circulating blood
cells, including red blood cells, and on endothelial, epithelial, and many other
types of cell
• Function: bind to C8 and prevent insertion of C9 into host cell membranes
REGULATORS OF THE COMPLEMENT PATHWAY
INCREASED COMPLEMENT LEVELS
• associated with inflammatory conditions, trauma, or acute
illness
• Limited clinical significance
DECREASED COMPLEMENT LEVELS
• Low levels of complement suggest one of the following
biological effects:
• Complement has been excessively activated recently.
• Complement is currently being consumed.
• A single complement component is absent because of a
genetic defec
HYPOCOMPLEMENTEMIA
• result from the complexing of IgG or IgM antibodies capable
of activating complement
• associated with diseases that give rise to circulating immune
complexes.
Clinical Significance of
Complement
DEFICIENT COMPONENT ASSOCIATED DISEASE
