details about complement pathway system.

1. SEMINAR
TOPICS-
 COMPLEMENT SYSTEM
 Inflammation
SNEHASISH

2.  Introduction-
The complement system is a part of the immune system that enhances the ability of antibodies
and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation,
and attack the pathogen's cell membrane. It is part of the innate immune system. The complement
system can recruited and brought into action by antibodies generated by the adaptive immune
system.
The complement system consists of a number of small proteins that are synthesized by the liver,
and circulate in the blood as inactive precursors. When stimulated by one of several triggers,
proteases in the system cleave specific proteins to release cytokines and initiate an amplifying
cascade of further cleavages. The end result of this complement activation or complement fixation
cascade is stimulation of phagocytes to clear foreign and damaged material, inflammation to attract
additional phagocytes, and activation of the cell-killing membrane attack complex.
 Definition-
The complement system is a part of the immune system, consists of a series of proteins that
interact with one another in a highly regulated manner, in order to eliminate pathogens. It helps
antibodies and phagocytic cells to clear pathogens and damaged cells; promote inflammation and
attack pathogen’s plasma membrane.

3.  Features of the complement pathway-
• Complements are soluble proteins and glycoproteins mostly produced by hepatocytes.
• More than 20 types of complements are present in serum, found circulating normally in human body in
inactive forms (called as zymogens or proenzymes).
• Thus the complement system works in both innate and acquired immunity.
• Complements are activated only during inflammatory reactions. During the inflammation, more amount of
complements reaches to the interstitial area of the infected tissue through dilated blood vessels, which are
then activated by proteolytic cleavage.
• Complements are mainly denoted by the capital letter C with numbers; like, C1, C2, C3, and so on. Some
have only alphabet, like, B, D. Some are simply represented by names, like, homologous restriction factor.
• C1 has three sub-units; C1q, C1r and C1s. C2-C5 have two components, a and b. Larger subunits are denoted
by b whereas the smaller are denoted by a (except C2a, which is larger than C2b).
 Complement Activation and cell lysis-
The complement activation occurs via three pathways; which are:
1. Classical pathway
2. Alternative pathway
3. Lectin pathway (or mannose binding lectin pathway)

4. 1. Classical Pathway-
The classical pathway begins with the formation of antigen-antibody complex (immune complex). When an
antigen enters the body, the antibody (IgM/IgG) binds to it. This induces conformational changes in the Fc
portion of the antibody which exposes a binding site for C1 protein. Hence, the antibody activates the
complement system only when bound to an antigen.
 Unlike classical pathway, alternative pathway, does not require Ag-Ab complex for the initiation of
complement pathway. It is initiated by cell surface constituents that are foreign to the host. These surface
molecules may be lipopolysaccharide etcC1 is a large, multimeric, protein complex composed of one
molecule of C1q and two molecules each of C1r and C1s subunits. C1q binds to the antigen bound antibody
(Fc portion). C1r and C1s are proteases which help to cleave C4 and C2.
a) The immune complex bound to C1 calls another protein C4 which is cleaved into C4a and C4b. C4a goes
away whereas activated C4b attaches to the target surface near C1q.
b) Now, C4b attracts C2 which is also cleaved into C2a and C2b. C2a binds C4b forming the C4b2a complex
whereas C2b goes away.
c) The active C4bC2a activates C3. The C4b2a complex is also known as C3 convertase as this converts C3 into
an active form by separating C3a and C3b. One molecule of C4b2a can cleave a large number of C3
molecules. C3b binds to the microbial surface or to the convertase itself.
d) C3b when binds to C3 convertase forms C4bC2aC3b (C5 convertase) which activates C5

5. f) C5 convertase cleaves C5 into C5a and C5b. C5a diffuses away but C5b is stabilized by binding C6.
g) Then C5bC6 binds to C7. C5bC6C7 complex is then inserted into the phospholipid bilayer of the cell
membrane which further binds C8.
h) These all (C5b678) activate C9 to form a macromolecular structure called the membrane attack complex
(MAC).
 Importance of Classical pathway-
a) This makes hole in the bacterium, as a result, the intracellular contents leak out and unwanted substances
get in. Thus, the cell cannot maintain its osmotic stability and the lysis occurs by an influx of water and loss
of electrolytes.
b) This is more effective in Gram negative bacteria than in Gram positive bacteria because MAC formation is
easy in the outer membrane in Gram negatives whereas it is difficult in the rigid thick layer of peptidoglycan
in Gram positives

6.  Classical Pathway-
C1q r2s2 C1qr2s2 ( C )
C4 C4a
C2 C2b
C4b2a ( C3 convertase )
C3 C3a
C4b2a3b ( C5 convertase )
C5 C5a
C4b2a3b5b
C6 C6a
C4b2a3b5b6b
C7 C7a
C4b2a3b5b6b7b C4b2a3b5b6b7b8b9b MAC
C8 C8a C9 C9a
C4b2a3b5b6b7b8b

7. 2. Alternative Pathway-
Unlike classical pathway, alternative pathway, does not require Ag-Ab complex for the initiation of complement
pathway. It is initiated by cell surface constituents that are foreign to the host. These surface molecules may be
lipopolysaccharide etc.
 Process to formation of Alternative pathway-
a) When a bacterium enters the host body, as a result of inflammation, complements reach towards the site,
where C3 molecules directly touch antigen and become active.
b) In this pathway, serum C3 containing an unstable thioester bond undergoes slow spontaneous hydrolysis to
yield C3a and C3b. C3b binds the surface of foreign cell and then binds to another serum protein called
factor B.
c) Now the factor B exposes the site which serves as the substrate for enzymatically active serum protein D.
d) Then factor D cleaves B into Ba and Bb forming C3 convertase (C3bBb). C3 convertase then forms C5
convertase which ultimately forms a MAC as in classical pathway.

8.  Alternative pathway- C3 C3a
C3b
Factor-D and Factor-B
C3bBb ( C3 convertase )
C3 C3A
C3bBb3B ( C5 convertase )
C5 C5a
C3bBb3B5b
C6 C6a
C3bBb3B5b6b C3bBb3B5b6b7b8b9b (MAC )
C7 C7a C9 C9a
C3bBb3B5b6b7b C3bBb3B5b6b7b8b
C8 C8a

9. 3. Mannose binding Lectin (MBL) Pathway-
• Some bacteria can activate complement system without having antibody and endotoxin. This occurs
through MBL pathway which is activated when circulating lectin (MBL) binds to mannose residues on
glycoproteins or carbohydrates on the surface of microorganisms.
• Microorganisms inducing MBL pathway are bacteria, such as Salmonella, Listeria, and Neisseria strains,
some fungi and some viruses including HIV-1.
• MBL is an acute phase protein and its concentration increases during inflammation. The lectin recognizes
and binds the carbohydrate of the target cell which then activates complements.
 Process to formation of Lectin pathway-
a) MBL pathway resembles classical pathway as it proceeds through the action of C4 and C2 to produce
activated proteins of the complement system. MBL works same as C1q which it resembles in structure.
b) After the MBL binds to carbohydrate residues on the surface of a cell or pathogen, two components,
MASP-1 and MASP-2 bind to MBL. MASP stands for MBL-associated serine proteases.
c) Two proteases form a tetrameric complex similar to the one formed by C1r and C1s and cleaves C4 and C2
forming C3 convertase. The process now continues to form of C5 convertase and the MAC as in classical
pathway.

10.  Lectin pathway- MBL
MASP-1 (r2) and MASP-2 (S2)
C4b2a (C1qr2s2) C3-convertase
C3 C3a
C4b2a3b C5-convertase
C5 C5a
C4b2a3b5b
C6 C6a
C4b2a3b5b6b
C7 C7a
C3bBb3B5b6b7b C3bBb3B5b6b7b8b (MAC)
C8 C8a C9 C9a
C3bBb3B5b6b7b8b

11.  Functions of Complements-
 Opsonization and phagocytosis
C3b, bound to immune complex or coated on the surface of pathogen, activate phagocytic cells. These
proteins bind to specific receptors on the phagocytic cells to get engulfed.
 Cell lysis
Membrane attack complex formed by C5b6789 components ruptures the microbial cell surface which kills
the cell.
 Chemotaxis
Complement fragments attract neutrophils and macrophages to the area where the antigen is present. These
cell surfaces have receptors for complements, like C5a, C3a, thus, run towards the site of inflammation, i.e.
chemotaxis
 Production of antibodies
B cells have receptor for C3b. When C3b binds to B-cell, it secretes more antibodies. Thus C3b is also an antibody
producing amplifiers which converts it into an effective defense mechanism to destroy invading microorganism
 Immune clearance
The complement system removes immune complexes from the circulation and deposits them in the spleen
and liver. Thus it acts as anti-inflammatory function. Complement proteins promote the solubilization of these
complexes and their clearance by phagocytes

12. INFLAMMATION
 INTRODUCTION
When something harmful or irritating affects a part of our body, there is a
biological response to try to remove it. The signs and symptoms of inflammation can be
uncomfortable but are a show that the body is trying to heal itself.
 DEFINATION
Inflammation is part of the body's immune response.
It can be beneficial when, for example, your knee sustains a blow and tissues need care and
protection. However, sometimes, inflammation can persist longer than necessary, causing more harm
than benefit.
 FACTS ON INFLAMMATION
a) Inflammation is the body's attempt at self-protection to remove harmful stimuli and begin the
healing process.
b) Inflammation is part of the body's immune response.

13. c) Infections, wounds, and any damage to tissue would not be able to heal without an inflammatory
response.
d) Chronic inflammation can eventually cause several diseases and conditions, including some
cancers and rheumatoid arthritis.
 SYMPTOMS
Symptoms of inflammation vary depending on whether the reaction is acute or
chronic.
The effects of acute inflammation can be summed up by the acronym PRISH. They include:
o Pain: The inflamed area is likely to be painful, especially during and after touching. Chemicals that
stimulate nerve endings are released, making the area more sensitive.
o Redness: This occurs because the capillaries in the area are filled with more blood than usual.
o Immobility: There may be some loss of function in the region of the inflammation.
o Swelling: This is caused by a buildup of fluid.
o Heat: More blood flows to the affected area, and this makes it feel warm to the touch.

14. Symptoms of chronic inflammation present in a different way. These can include:
Fatigue, mouth sores, chest pain,
abdominal pain, fever, rash, joint pain
 Causes
Inflammation is caused by a number of physical reactions triggered by the immune system in
response to a physical injury or an infection.
 Inflammation does not necessarily mean that there is an infection, but an infection can cause
inflammation.
Three main processes occur before and during acute inflammation:
 The small branches of arteries enlarge when supplying blood to the damaged region, resulting in
increased blood flow.
 Capillaries become easier for fluids and proteins to infiltrate, meaning that they can move between
blood and cells.
 The body releases neutrophils. A neutrophil is a type of white blood cell filled with tiny sacs that
contain enzymes and digest microorganisms.

15.  TYPES OF INFLAMMATION
There are two types of inflammation 1. Acute Inflammation and 2. chronic inflammation.
 Acute inflammation
An acute inflammation is one that starts rapidly and becomes severe in a short space of time. Signs
and symptoms are normally only present for a few days but may persist for a few weeks in some cases.
Examples of diseases, conditions, and situations that can result in acute inflammation include:
Acute bronchitis, Infected ingrown toenail
Sore throat from a cold. Scratch or cut on the skin ,
High-intensity exercise, Acute appendicitis,
Dermatitis. Tonsillitis,
Infective meningitis.

16.  Chronic inflammation
This refers to long-term inflammation and can last for several months and even years.
It can result from:
 failure to eliminate whatever was causing an acute inflammation
 an autoimmune disorder that attacks normal healthy tissue, mistaking it for a pathogen that causes
disease
 exposure to a low level of a particular irritant, such as an industrial chemical, over a long period.
Examples of diseases and conditions that include chronic inflammation:
Asthma Chronic peptic ulcer
Tuberculosis Rheumatoid arthritis
Periodontitis Ulcerative colitis and Crohn's disease
Sinusitis Active hepatitis

17.  Although damaged tissue cannot heal without inflammation, chronic inflammation can eventually
cause several diseases and conditions including some cancers, rheumatoid arthritis,
atherosclerosis, periodontitis, and hay fever.
 People will feel pain, stiffness, discomfort, distress, and even agony, depending on the severity of
the inflammation. The type of pain varies. It can be described as constant and steady, throbbing
and pulsating, stabbing, or pinching.
 Inflammation primarily causes pain because the swelling pushes against the sensitive nerve
endings. This sends pain signals to the brain.
 Other biochemical processes also occur during inflammation. They affect how nerves behave, and
this can enhance pain.
 TREATMENTS
1) Non-steroidal anti-inflammatory drugs (NSAIDs) can be taken to alleviate the pain
caused by inflammation.
2) They counteract an enzyme that contributes to inflammation. This either prevents or
reduces pain.
Examples of NSAIDs include naproxen, ibuprofen, and aspirin.

18. 3) avoid the long-term use of NSAIDs unless advised by a doctor. They increase a person's risk
of stomach ulcers, which can result in severe, life-threatening bleeding.
4) NSAIDs may also worsen asthma symptoms, cause kidney damage, and increase the risk of
having a stroke or heart attack.
5) Acetaminophen, such as paracetamol or Tylenol, can reduce pain without affecting the
inflammation. They may be ideal for those wishing to treat just the pain while allowing the healing
factor of the inflammation to run its course.
 Herbs for Inflammation
 Ginger: This has been used for hundreds of years to treat dyspepsia, constipation, colic, and other
gastrointestinal problems, as well as rheumatoid arthritis pain. Ginger may be purchased online in
supplement form.
 Turmeric: Current research is looking into the possible beneficial effects of turmeric in treating
arthritis, Alzheimer's disease, and some other inflammatory conditions. Curcumin, a substance
found in turmeric, is being invested for the treatment of several illnesses and disorders, including
inflammation.
 Cannabis: This contains a cannabinoid, which has been shown to have anti-inflammatory
properties. However, cannabis is not legal in many places.

19.  Inflammation diet
There are several foods that can have been shown to help reduce the risk of inflammation, including:
 olive oil
 tomatoes
 nuts, such as walnuts and almonds
 leafy greens, including spinach and kale
 fatty fish, such as salmon and mackerel
 fruit, including blueberries and oranges.
Avoid eating foods that aggravate inflammation, including:
o fried foods, including French fries
o white bread, pastry, and other foods that contain refined carbohydrates
o soda and sugary drinks
o red meat
o margarine and lard

20. The following table shows the key differences between acute and chronic inflammation:
THANK YOU
Acute Inflammation Chronic Inflammation
Caused by Harmful bacteria or tissue injury Pathogens that the body cannot break down,
including some types of virus, foreign bodies that
remain in the system, or overactive immune
responses
Onset Rapid Slow
Duration A few days From months to year
Outcomes Inflammation improves, turns into an
abscess, or becomes chronic.
Tissue death and the thickening and scarring of
connective tissue.