The complement system is a defence mechanism of our immune system against foreign pathogens as well as hyper immune responses.

1. THE
COMPLEMENT
SYSTEM
ALIYA FIRDOUS
M.Sc. Biotechnology
II Semester

2. CONTENTS
• Introduction
• History
• Proteins involved
• Activation pathways
-Classical pathway
-Alternate pathway
-Lectin pathway
-Terminal pathway
• Functions
• Regulation
• Significance of regulation
• Complement deficiencies
• References

3. INTRODUCTION
• The term complement refers to a set of serum proteins
that cooperates with both the innate and the adaptive
immune systems to eliminate blood and tissue
pathogens and interacts with one another in catalytic
cascades.
• The complement system constitute approximately 15%
of the globulin protein fraction in the blood plasma.
• It is named Complement system because it was first
identified as a heat-labile component of serum that
‘complemented’ antibodies in the killing of bacteria.

4. HISTORY
• Research on complement started in 1890s when Jules
Bordet at the Institute Pasteur in Paris conducted
experiment using sheep antiserum and the bacterium
Vibrio cholerae.
• His experiment lead to the conclusion that bacteriolysis
required two different substances: the heat-stable
specific antibodies that bound to the bacterial surface,
and a second, heat-labile (sensitive) component
responsible for the lytic activity
• Paul Ehrlich coined the term complement, defining it
as “the activity of blood serum that completes the action
of antibody.”

5. PROTEINS INVOLVED
1. Initiators: C1q, MBL, Ficolins
2. Enzymatic mediators: C1r, C1s, MASP2
3. Convertase activators: C3, C5 convertase
4. Opsonins: C3b, C4b
5. Anaphylatoxins: C3a, C5a
6. Membrane attack complex: C5b, C6, C7
7. Complement receptors: CR1, C5aR
8. Regulatory proteins: factor I, Protectin

6. ACTIVATION
PATHWAYS
Complement activation occurs by three
pathways:
The classical pathway
The lectin pathway and
The alternate pathway
Although the initiating event of each of the
three pathways of complement activation
is different, they all converge in the
generation of an enzyme complex leading
to membrane lysis.

7. THE CLASSICAL PATHWAY
This pathway involves complement components:
C1,C2 and C4.
Classical pathway is triggered by antibody-antigen
complex binding to C1 which itself has 3 components i.e.,
C1q, C1r and C1s. The Ag-Ab complex bind to C1q which
activates C1r which further cleaves C1s.
This activates the serine protease that leads to cleaving of
C4 and C2, leading to the formation of C4b2a (C3
convertase). This in turn cleaves C3 into C3a and C3b.
C3a activates mast cells (inflammation) and C3b binds with
the C4b2a complex to form C5 convertase (C2b2a3b).

8. THE ALTERNATE PATHWAY
This pathway involves various factors like: factor B, factor
D, H and I.
C3 activation takes place when C3b binds to factor B and
is then cleaved by factor D.
The enzymatic action of factor D acts as the rate limiting
step of the alternative pathway and cleaves factor B, the
larger fragments of which remains bound to C3b to form
the alternate pathway C3 convertase- C3bBb.
C3b is able to create new C3 convertase in the presence
of factor B and D, thus acting as an amplification loop
for other pathways

9. THE LECTIN PATHWAY
The initial molecules of this pathway are MBL (Mannose
Binding Lectin) and ficolins.
The MBL binds to mannose residues on the pathogen
surface, this in turn activates the MBL-associated serine
proteases MASP1 and MASP2.
MASP2 cleaves C4 and C2 to form C3 convertase (C4b2a),
while MASP1 may cleave C3 directly, bypassing the C4b2a
complex but at a very slow rate.
The ficolins activate the lectin pathway by forming active
complexes with MASP.

10. THE TERMINAL PATHWAY
• The end result of the three initiation pathways is the formation of a C5 convertase. For the
classical and lectin pathways, the C5 convertase (C4b2a3b); for the alternative pathway, the
C5 convertase (C3bBbC3b).
• However, the end result of all types of C5 convertase activity is the same: the cleavage of the
C5 molecule into two fragments, C5a and C5b. The large C5b fragment is generated on the
surface of the target cell or immune complex and provides a binding site for the subsequent
components of the MAC.
• The addition of C6, C7, C8, and C9 components to the C5b component forms the Membrane
Attack Complex (MAC).
• These MAC when inserted into the membrane of some bacteria or pathogen, lead to loss of
membrane integrity resulting irreversibly to cell death.

11. FUNCTIONS
1. Opsonization: Increases phagocytosis by opsonins (C4b and
C3b) binding to foreign organisms.
2. Chemotaxis: Attracts macrophages and neutrophils via
inflammation by inflammatory mediators; C5a, and to a
lesser extent C3a and C4a.
3. Cell lysis: Ruptures membranes due to formation of a
membrane attack complex (MAC).
4. Agglutination: Causes clustering and binding of pathogens.
5. Immune clearance: Removes immune complexes from the
circulation and deposits them in the spleen and liver.
6. Binding to specific complement receptors on cells of the
immune system, triggering specific cell functions,
inflammation, and secretion of immunoregulatory molecules.

12. Fig. Functions of complement system

13. REGULATION
Complement activation leads to a variety of
outcomes that can either benefit or harm the host.
Thus, complement regulation is a complex
physiological process.
• The C1 inhibitor, C1lNH promotes dissociation of
C1 components. It inhibits both C3b and
MASP2.
• Decay accelerating factors promote decay of C3
convertases.
• Factor I is an active serine protease that can
cleave C3b and C4b into inactive fragments.
• A host cell surface protein protectin inhibits the
MAC attack thereby preventing cell lysis.
• Carboxypeptidases regulate the anaphylatoxin
activity of C3a and C5a by cleaving their C-
terminal arginine residues.

14. SIGNIFICANCE OF REGULATION
• The complement regulators allow intact host cells to protect their
surfaces from complement activation.
• Complement activation is necessary for the removal of damaged or
modified self-cells such as apoptotic particles and necrotic cells.
• The complement is activated to distinguish the surface of invading
micro-organisms and remove cellular debris in a tightly regulated
manner.
Considering the importance of complement regulation, it is not surprising
that complement dysregulation can contribute to the pathology of various
diseases.
• Complement dysregulation can result in damage to the surfaces of intact
host cells.
• Deficient complement regulators can fail to effectively tag modified self-
cells, thus interfering with the removal of damaged or modified self-cells.
Some pathogens successfully evade complement by co-opting host
regulators, thus leading to the establishment of an infection. Therefore, it
is imperative that the complement system maintains the appropriate
balance between activation on pathogens and modified self-cells and
inhibition on intact host cells.

15. COMPLEMENT DEFICIENCIES
• The diseases that accompany uncontrolled activation or inadequate performance of
complement’s functions are often the result of inherited deficiency or subtle
impairment of one or more of the components.
• Clinical indications for possible complement deficiencies include recurrent mild or
serious bacterial infections, autoimmune disease, or episodes of angioedema (a
painless, but often dramatic, swelling under the skin, or swelling in the intestines).
• The list of potential complement-related problems includes renal disease, vasculitis
(blood vessel inflammation) and age-related macular degeneration.
• Therapeutics specific for complement deficiencies are still in the developmental
stage for most components, but in some cases, such as C1-Inh deficiency, there are
currently several drugs available (tranexamic acid or danazol, icatibant etc.).
• For uncontrolled complement, there are a few drugs available to treat acute
episodes or to prevent recurrence (Eculizumab, Berinert). Therapeutics for
complement-derived diseases is in its infancy at this time, but more treatments
should become available in the near future.

16. • Homozygous deficiencies in any of the early components of the classical pathway (C1q, C1r,
C1s, C4, and C2) result in similar symptoms, in immune-complex diseases such as SLE,
glomerulonephritis, and vasculitis.
• Individuals with deficiencies in the early complement components may also suffer from
recurrent infections by pyogenic (pus-forming) bacteria such as streptococci and
staphylococci.
• A deficiency in MBL, the first component of the lectin pathway, has been shown to be
relatively common, and results in serious pyrogenic (fever-inducing) infections in babies and
children. Children with MBL deficiency suffer from respiratory tract infections.
• Deficiencies in factor D and properdin (alternative pathway) appear to be associated with
Neisseria infections but not with immune-complex disease.
• People with C3 deficiencies display the most severe clinical manifestations of any of the
complement deficiency patients, reflecting the central role of C3 in opsonization and in the
formation of the MAC.
• Deficiencies of complement regulatory proteins have also been reported. Patients with C1INH
deficiency suffer from a complex disorder that includes excessive production of vasoactive
mediators (molecules that control blood vessel diameter and integrity), which in turn leads to
tissue swelling and extracellular fluid accumulation. The resultant clinical condition is
referred to as hereditary angioedema.

17. REFERENCES
• Kuby immunology (7th ed)
• http://www.ncbi.nlm.nih.gov
• Immunobiology: The immune system and innate
immunity
• http://www.immunology.org
• The complement cascade: Journal of neurochemistry
• http://www.nature.com

18. THANK
YOU