Complement
Activation can be Ab
Heat-labile series of 18 plasma proteins
( most are enzymes)
Major fraction of B1 and B1 globulin
The term complement was coined by
Paul Ehrlich
Function was elucidated by Jules Bordet
Activation pathways:
Classical Pathway
Alternative Pathway
Mannose-binding lectin
Complement System
A. Innate Immunity
Opsonization
Lysis of pathogens
Chemotaxis
Inflammation
Cell activation
B. Disposal System
Clearance of immune complexes
and apoptotic cells
C. Adaptive Immunity
Augmentation of the antibody
response
Promotion of T-cell response
Elimination of self-reactive B cells
Enhancement of immunologic
memory
Properties of Complement Proteins
1. Not all antigens are susceptible to
complement mediated lysis
2. Complement activity can be destroyed
in vitro
3. IgM and IgG are the only antibodies that
activate complement
4. Complement is bound to all Ag-Ab
complexes provided that the antibody is
of proper isotype.
5. Found in all mammalian sera and sera
of most lower animals like birds, fish,
sharks and amphibians
6. Complement one species will usually
react with antibodies of other species
(non-specific)
7. Complement can contribute to
chemotaxis, anaphylaxis, opsonization
and other physiologic functions
8. It can be activated by non Ag-Ab
reaction
9. It is a complex of nine major
components that act synergistically
10.
dependent( classical) or independent
(alternative,MBL)
Complement Proteins
Nine major components
Numbered sequentially (C1-C9 -> order
of discovery)
The individual peptide chains present in
each complement proteins is designated
by a Greek letters
Activated fragments are designated
with lowercase letters
Classical Complement Pathway
Activation of the classical pathway is
often termed as complement cascade
C1-C4-C2-C3-C5-C6-C7-C8-C9 (order
of the activation)
End result: Lysis of cellular
immunogens that triggered its
activation
C1 COMPLEX (C1q, C1r, C1s)
Recognition Unit
First complement component
Tri-molecular protein held by Ca2+
Removal of Ca will cause C1 to
dissociate
C4
First activation unit
Synthesized by macrophage
Activated by C1s thus producing C4a
and C4b
C2
Second activation unit
Binds C4b and then cleaved by C1s to
C2a and C2b
C2a binds C4b in the presence of Mg2+
C4b2a = C3 convertase
C3
Third activation unit
Most abundant complement protein
Secreted by macrophages
Cleaved by C3 convertase to C3a and
C3b
 C4b2a3b=C5 convertase MBL-associated serine protease (MASP)

C5
First MAC unit Anaphylatoxin
Cleaved by C5 convertase to C5a and
Increases vascular permeability by
C5b
binding to basophils and mast cells
which trigger the release of histamine
C3a, C4a, C5a
C6 and C7
Attaches to C5b to form C5b67 (1st MAC)

C8
Inserted to the cell membrane that
initiates cell lysis
C9
Polymerizes in the presence of C5b678
to accelerate cytolysis
End Result = lysis of the targeted cell
Chemotactic factor
Influence the migration of phagocytes
towards the site of immune response
C5a
Opsonin
Complement activation leads to the
production of large amount of C3b

ALTERNATIVE COMPLEMENT PATHWAY COMPLEMENT REGULATION

Activators: (ACP) Under normal conditions, complement is
1. Water regulated by regulatory proteins
2. Zymosan (fungal cells In some disease processes, antigen-
3. LPS antibody complexes persists and so as
4. Aggregates of IgA, IgG2, IgE complement activation
5. CVF
Regulation at several levels
1. Regulation of pathway activation
ALTERNATIVE PATHWAY (classical and lectin)
2. Regulation of C3 convertase on both
Formerly known as the properdin classical and alternative pathway
pathway 3. Regulation of membrane attack complex
Components: C3-C9, Factor B, factor D,
Properdin
Activation is non Ag-Ab complex
C1 Inhibitor
initiated
Inhibits the activation at the first stage
of classical and lectin pathways
MANNOSE-BINDING LECTIN PATHWAY
Inactivates C1 binding to active sites of
Involves non-specific recognition of C1r and C1s
mannose or other related sugars that Inhibits MASP-2
are common constituents of the
Regulation of C3 convertase
bacterial cell wall
MBL is homologous to C1q Occurs in two ways:
Associated with MASP-1, MASP-2, MASP-
3 1. Prevents C3 convertase formation by
When MBL binds to mannose, MASP-2 inactivating proteins that will compose
autoactivates and cleaves C4 and C2 the convertase
 Regulatory Function Remarks restrictio
Protein
n factor
Factor I Inactivates C3b Acts synergistically
and C4b with C4BP, CR1, (HRF)
MCP or DAF
C4b binding Binds C4b, Abundant in plasma
protein making available Complement Deficiency
(C4BP) for degration by
Factor I Protein Associated
Complemen Binds C3band Also known as Disease
t Receptor C4b, making them CD35 C1NH Hereditary
Type 1 available for
Angioneurotic
(CR1) degradation by
Factor I Edema (HANE)
Membrane Most efficient Also known as DAF Paroxysmal
cofactor cofactor of Factor CD46 Nocturnal
protein I- mediated C3b Hemoglobinuria
(MCP) cleavage
MIRL Paroxysmal
2. Dissociation of C3 convertase that have Nocturnal
been formed on cell surfaces Hemoglobinuria
FACTOR H AND Recurrent pyogenic
Regulat Function Remarks FACTOR I infection
ory
protein MBL Pneumococcal
Decay- Dissociated Also known as diseases; sepsis;
accelera C3 CD55 Neisseria Infection
ting convertase Does not inhibit PROPERDIN Neisseria Infections
factor formation of C3 MASP-2 Pneumococcal
(DAF) convertase
Disease
Factor H Binds C3b
and Factor B
Dissociates
C3bBb
complex
Cofactor of I

Radial Immunodiffusion
Sensitive technique when done correctly
Regulation of MAC TAT is at least 24 hours
Can be used for C1q, C4,C3,C5, Factor
Inhibits the formation of membrane
B, Factor H, Factor I and C1NH
attack complex
Nephelometry
Regulato Function Remarks
ry Measurement based on the amount of
Protein scattered light
S-protein Prevents Also known More Ag-Ab complex, more scattered
Binding of as vitronectin light
C5b67 to cell Very accurate and short TAT due to
membrane automation
Membran Binds C8 and Also known
CH50 Assay
e prevents as CD59
inhibitor insertion of C9 Functional assay of classical
of complement pathway
reactive Measures degree of hemolysis (end
lysis product of C activation)
(MIRL)
Homolog
ous
 Determines the amount of patient MBL, MASP- Normal Low Normal
serum required to lyse 50% of 2
sensitized cells B, D, P Normal Normal Low

AH50 Assay C3, C5, C6, Low Low Low

C7, C9, C9
Principle is same as CH50
Uses buffer with MgCl2 and ethylene
glycol tetra acetic acid C1NH Low Low Low

Interpretation of Laboratory Result Factor H Low Low Low

and I
Decreased complement levels can
Improperly Low Low Low
be due to: handed
1. Decreased production
sera
2. Increased consumption
3. In vitro consumption
No. 3 should be ruled out first before
considering the first two
Diagnosis of Complement Abnormalities

C1q, C1r, Low Normal Normal

C1s
C4, C2 Low Low Normal