complement system

PATHWAYS


CLASSICAL


ALTERNATIVE


LECTIN














CLASSICAL PATHWAY
(ATTACK)
Most C3b serves an opsonin function
Some C3b binds to C4bC2a to form the C5 convertase C4bC2aC3b
C5 convertase cleaves C5 leading to the formation of the Membrane attack Complex (C5-C6-C7-C8-C9)
The MAC "punches holes" in cell walls resulting in lysis

CLASSICAL PATHWAY
(ACTIVATION)
C3a increases the inflammatory response by binding to mast cells and causing them to release histamine
C3a is called an anaphylatoxin
C3b serves as an opsonin which facilitates immune complex clearance

CLASSICAL PATHWAY
(ACTIVATION)
C1 attaches to the Fc portion of an antibody
Only IgG and IgM can activate complement
Once C1 is activated, it activates C4 and C2
C4b & C2a come together to form the C4b2a which is the C3 convertase
C3 convertase activates C3 to C3a and C3b

CLASSICAL PATHWAY
Begins with antibody binding to a cell surface and ends with the lysis of the cell
The proteins in this pathway are named C1-C9
When complement is activated it is split into two parts
a – smaller of the two
B – larger part and usually the active part
Remember 3 Key Words
ACTIVATION
AMPLIFICATION
ATTACK

PATHWAYS
03 biochemical pathways activate the complement system:
Classical complement pathway 
Alternative complement pathway
Lectin pathway
Complement Protein Nomenclature
An in-active complement protein Usually Designated by UPPER Case Letter "C" with number 1,2,3…
for example: C1
An activated complement protein is usually designated by adding LOWER case letter "a"
for example: C1a, C1b
ALTERNATIVE PATHWAY
(ACTIVATION)
Requires no specific recognition of antigen in order to cause activation
Spontaneous conversion from C3 to C3b occurs in body
Normally, C3b is very short lived and quickly inactivated by proteins on the surface of the body's own cell walls
However, bacteria or other foreign material may lack these surface proteins allowing C3b to bind and stay active

ALTERNATIVE PATHWAY
(AMPLIFICATION)
Factor B binds to C3b
Factor B is then cleaved by factor D into Ba and Bb
C3bBb remains which acts as a C3 convertase (C3 C3a and C3b)
C3bBbC3b is formed which acts as a C5 convertase

ALTERNATIVE PATHWAY
(ATTACK)
C5 is cleaved to C5a and C5b
C5a increases inflammation and most power chemotactic factor for leukocyte
C5b then starts the assembly of the Membrane Attack Complex

OVERVIEW
Complement System and Autoimmune Disorders
The Double Edged Sword!
Just as the complement system can destroy a microbe, it can lyse the erythrocyte, phagocytose a platelet, or disrupt a basement membrane
For example: Rheumatic Disease

LACTIN PATHWAY
C4b & C2a bind together to form classical C3-convertase (C4bC2a)
Furthur Amplification and Attack proceed just like Classical Pathway.
LACTIN PATHWAY

Homologous to Classical Pathway
ACTIVATION:
Starts with binding of mannose-binding lectin (MBL) to mannose residues on the pathogenic surface
It activates the MBL-associated serine protease, MASP1 & MASP2
MASP activates C4 & C2 into C4a,C4b & C2a,C2b
FUNCTIONS
Opsonization – enhancing phagocytosis of antigens.
Chemotaxis – attracting macrophages and neutrophils
Cell Lysis – rupturing membranes of foreign cells
Agglutination – clustering and binding of pathogens together (sticking)

CLASSICAL PATHWAY
(AMPLIFICATION)
Each C1 creates many C4b and C2b fragments
Each C4bC2a creates many C3b (activated C3)
Each C3b goes on to create many Membrane Attack Complexes (MAC)
Example
1 C1 makes 100 C4bC2a
100 C4bC2a makes 10,000 C3b
10,000 C3b makes 1,000,000 MAC

HISTORY
Paul Ehrlich introduced the term "Complement" -- late 1890s
Theory of Ehrlich: "the immune system consists of cells that have specific receptors on their surface to recognize antigens. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. These receptors, which we now call "antibodies," were called by Ehrlich "amboceptors". They recognize and bind to a specific antigen, but they also recognize and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich, therefore, named this heat-labile component "complement," because it is something in the blood that "complements" the cells of the immune system. "
COMPLEMENT SYSTEM
PRESENTER:
ABDUL RAUF
(AP402833)
HISTORY
Controversy of Ehrlich & Bordet: Ehrlich believed that each antigen-specific amboceptor has its own specific complement, whereas Bordet believed that there is only one type of complement.
In the early 20th century, this controversy was resolved when it became understood that complement can act in combination with specific antibodies, or on its own in a non-specific way

HISTORY
In the late 19th century, Hans Ernst August Buchner found that blood serum contains a "factor" capable of killing bacteria.
 Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this factor has 02 components:
Heat stable
Heat labile
Heat-labile component is what we now call "complement" earlier known as "alexine"
INTRODUCTION
Part of the innate immune system which complement the ability of antibodies and phagocytic cells to clear pathogens from body
It consists of over 30 small proteins, including serum proteins, serosal proteins & cell membrane receptors & contribute 3g/L of blood serum proteins.
Synthesized by liver & circulated as inactive precursor
Stimulated by some triggers (i.e proteases)
Work as a Cascade
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