Complement System
Session 48 Complement System
Total Session Time: 120 minutes
Pre-requisites
Students Learning Tasks
By the end of this session students are expected to be able to:
Resources Needed:
SESSION OVERVIEW
|Step |Time |Activity/ |Content |
| | |Method | |
|1 |5 minutes |Presentation |Introduction, Learning Tasks |
|2 |20 minutes |Presentation |Characteristics of complement |
| | | |system |
|3 |25 minutes |Presentation |Biological effect of complement |
| | | |system |
|4 |30 minutes |Presentation |Regulation of compliment system |
|5 |5 minutes |Presentation |Key Points |
|6 |5 minutes |Presentation |Evaluation |
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing
STEP 2: Characteristics of complement system(20minutes)
(complements) the ability of antibodies and phagocytic cells to clear
microbes and damaged cells from an organism, promotes inflammation,
and attacks the pathogen's cell membrane
participate in both innate and adaptive immunity
proteolytic cascades
hepatocytes.
circulating normally in human body in inactive forms (called as
zymogens or proenzymes)
the antigen
interstitial area of the infected tissue through dilated blood
vessels, which are then activated by proteolytic cleavage; this
exposes the active site of the complements.
like, C1, C2, C3, and so on. Some have only alphabet, like, B, D. Some
are simply represented by names, like, homologous restriction factor.
(except C2a, which is larger than C2b)
•
o C3b, bound to immune complex or coated on the surface of pathogen,
activate phagocytic cells
o These proteins bind to specific receptors on the phagocytic cells
to get engulfed.
o Membrane attack complex formed by C5b6789 components ruptures the
microbial cell surface which kills the cell.
o Complement fragments attract neutrophils and macrophages to the
area where the antigen is present
o These cell surfaces have receptors for complements, like C5a, C3a,
thus, run towards the site of inflammation, i.e. chemotaxis.
(Anaphylatoxins)
o The proteolytic complement fragments, C5a, C4a, and C3a induce
acute inflammation by activating mast cells and neutrophils. All
three peptides bind to mast cells and induce degranulation, with
the release of vasoactive mediators such as histamine. These
peptides are also called anaphylatoxins because the mast cell
reactions they trigger are characteristic of anaphylaxis. Binding
to specific complement receptors on cells of the immune system,
they trigger specific cell functions, inflammation, and secretion
of immunoregulatory molecules.
o B cells have receptor for C3b. When C3b binds to B-cell, it
secretes more antibodies
o Thus C3b is also an antibody producing amplifiers which converts
it into an effective defence mechanism to destroy invading
microorganism.
o The complement system removes immune complexes from the
circulation and deposits them in the spleen and liver
o Thus it acts as anti-inflammatory function. Complement proteins
promote the solubilization of these complexes and their clearance
by phagocytes.
o Classical pathway
o Alternative pathway
o Mannose binding Lectin (MBL) pathway
on microbes.
o The classical pathway begins with the formation of antigen-
antibody complex (immune complex)
o When an antigen enters the body, the antibody (IgM/IgG) binds to
it
o This induces conformational changes in the Fc portion of the
antibody which exposes a binding site for C1 protein
o Hence, the antibody activates the complement system only when
bound to an antigen.
o C1 is a large, multimeric, protein complex composed of one
molecule of C1q and two molecules each of C1r and C1s subunits
o C1q binds to the antigen bound antibody (Fc portion). C1r and C1s
are proteases which help to cleave C4 and C2
o The immune complex bound to C1 calls another protein C4 which is
cleaved into C4a and C4b
o C4a goes away whereas activated C4b attaches to the target surface
near C1q
o Now, C4b attracts C2 which is also cleaved into C2a and C2b. C2a
binds C4b forming the C4b2a complex whereas C2b goes away
o 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
o One molecule of C4b2a can cleave a large number of C3 molecules.
C3b binds to the microbial surface or to the convertase itself
o C3b when binds to C3 convertase forms C4bC2aC3b (C5 convertase)
which activates C5
o C5 convertase cleaves C5 into C5a and C5b. C5a diffuses away but
C5b is stabilized by binding C6
o Then C5bC6 binds to C7. C5bC6C7 complex is then inserted into the
phospholipid bilayer of the cell membrane which further binds C8
o These all (C5b678) activate C9 to form a macromolecular structure
called the membrane attack complex (MAC)
o This makes hole in the bacterium, as a result, the intracellular
contents leak out and unwanted substances get in
o Thus, the cell cannot maintain its osmotic stability and the lysis
occurs by an influx of water and loss of electrolytes
o 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
o Some of the C3b molecules do not associate with C4b2a; instead
these molecules coat immune complexes or microbial cell surfaces
and work as opsonins
o This process is called opsonization in which opsonin molecule
binds one side to the particulate matter i.e. in bacteria, tumoUr
cell, RBC and on the other side they bind to the receptor of
phagocytic cell (like, neutrophils and macrophages) which enhance
the process of phagocytosis
o Smaller complement subunits diffuse from the site and can initiate
localized inflammatory responses by binding to specific receptors
o The alternative pathway does not require Ag-Ab complex for the
initiation of complement pathway
o It is initiated by cell surface constituents that are foreign to
the host
o These surface molecules may be lipopolysaccharide etc.
o 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
o In this pathway, serum C3 containing an unstable thioester bond
undergoes slow spontaneous hydrolysis to yield C3a and C3b
o C3b binds the surface of foreign cell and then binds to another
serum protein called factor B
o Now the factor B exposes the site which serves as the substrate
for enzymatically active serum protein D
o Then factor D cleaves B into Ba and Bb forming C3 convertase
(C3bBb)
o C3 convertase then forms C5 convertase which ultimately forms a
MAC as in classical pathway
o Some bacteria can activate complement system without having
antibody and endotoxin
o 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
o Microorganisms inducing MBL pathway are bacteria, such as
Salmonella, Listeria, and Neisseria strains, some fungi and some
viruses including HIV-1.
o MBL is an acute phase protein and its concentration increases
during inflammation
o The lectin recognizes and binds the carbohydrate of the target
cell which then activates complements
o MBL pathway resembles classical pathway as it proceeds through the
action of C4 and C2 to produce activated proteins of the
complement system
o MBL works same as C1q which it resembles in structure.
o 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
o MASP stands for MBL-associated serine proteases
o Two proteases form a tetrameric complex similar to the one formed
by C1r and C1s and cleaves C4 and C2 forming C3 convertase
o The process now continues to form of C5 convertase and the MAC as
in classical pathway
STEP 4: Regulation of the Complement System (15 minutes)
o The complement system has the potential to be extremely damaging
to host tissues; hence regulatory mechanisms are required to
restrict the complement pathway
o In order to avoid constant complement activation, a regulatory
network exits to terminate complement activity
o Several serum proteins regulate the complement system at different
stages:
protease activity of C1r and C1s, causing them to dissociate
from C1q;
C5 convertase available; (3) factor H enhances the effect of
factor I on C3b;
convertase of the alternative pathway. Regulation is also
provided by proteins that have the ability to accelerate the
decay of the complement proteins, such as decay-accelerating
factor (DAF expressed on blood and endothelial cells) that can
act to accelerate dissociation of the C3 convertases of all
three pathways
Pathways of the Complement System
[pic]
[pic]
Source: https://microbeonline.com/wp-content/uploads/2017/11/Complement-
Pathway.png
STEP 5: Key Points (5 minutes)
(complements) the ability of antibodies and phagocytic cells to clear
microbes and damaged cells from an organism, promotes inflammation,
and attacks the pathogen's cell membrane
that binds to mannose residues on microbes.
STEP 6: Evaluation (5 minutes)
References
Hugo and Russell (2011), Pharmaceutical Microbiology 8th Edition, Willey-
Blackwel publications
Karen C. Carroll et al (2013); Jawetz, Melnick and Adelberg’s Medical
Microbiology 26th Ed. McGraw Hill Co. Inc.
Greenwood et al (2012); Medical Microbiology, 18th edition Churchill
Livingstone
Andrey Kopot, Alex Volve http://www.aklectures.com/lecture/activation-of-
lymphocytes. Accessed 18th September, 2018
Srijana Khanal (2017) Complement Pathways: Types, Functions and Regulation,
https://microbeonline.com/complement-system-pathways-functions-
regulation/
Kindt TJ, Goldsby RA, Osborne BA, Kuby J (2007). Kuby Immunology. 6th W. H.
Freeman, New York. pp. 168-188.
Session 48: Immunization in Tanzania
Total Session Time: 60 minutes
Pre-requisites
Students Learning Tasks
By the end of this session students are expected to be able to:
Resources Needed:
SESSION OVERVIEW
|Step |Time |Activity/ |Content |
| | |Method | |
|1 |5 minutes |Presentation |Introduction, Learning Tasks |
|2 | 10 minutes|Presentation |The Concept of Immunization |
|3 |10 minutes |Buzzing/ |Objectives of Immunization |
| | |Presentation | |
|4 |25 minutes |Presentation |Schedule of Immunization in |
| | | |Tanzania |
|5 |5 minutes |Presentation |Key Points |
|6 |5 minutes |Presentation |Evaluation |
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing
STEP 2: The Concept of Immunization (10 minutes)
resistant to an infectious disease, typically by the administration of
a vaccine
against subsequent infection or disease
in the vaccine
threatening infectious diseases and is estimated to avert between 2
and 3 million deaths each year
strategies that make it accessible to even the most hard-to-reach and
vulnerable populations
through outreach activities; and vaccination does not require any
major lifestyle change
Expanded Programme on Immunization
STEP 3: Objectives of Immunization (10 minutes)
o Prevention of serious diseases and their complications
o Protection of individuals and communities
o Containment of outbreaks
o Elimination of certain diseases, e.g. neonatal tetanus
o Eradication of diseases, e.g. smallpox, polio
STEP 4: Schedule of Immunization in Tanzania (25 minutes)
basis
African countries starts with the Bacille Calmette-Guérin (BCG) for
Tuberculosis and oral polio vaccine (OPV) for poliomyelitis at birth,
followed by diphtheria-tetanus-pertussis (DPT) for diphtheria,
neonatal tetanus and whooping cough, OPV, Haemophilus influenzae type
b (Hib) and hepatitis B (Hep B) at 6 weeks, 10 weeks and 14 weeks
o Finally, immunization for measles is done at 9 months
Table 53.1: Routine Childhood Immunization Schedule in Tanzania
|Vaccine |Dose |Route of |Sites |Age |
| | |administratio| | |
| | |n | | |
|Polio (OPV) |2 drops |Oral |In the |At birth |
| | | |mouth |At 6th week after |
| | | | |birth |
| | | | |At 10th week |
| | | | |At 14th week |
|(Rotarix) | | |mouth |At 10th week |
|(DPT-Hib Hep B| | |thigh |At 10th week |
| | | | |At 14th week |
|(PCV 13) | | |thigh |At 10th week |
| | | | |At 14th week |
|a | | | |At 18th month |
o For women of child bearing age or in pregnancy the schedule is to
receive first dose at time of encounter (TT1), at 4 weeks after
first dose (TT2), at 6 months after second dose (TT3), then 1 year
after third dose (TT4) and finally 1 year after fourth dose (TT5)
o Protection time (in years) if doses are given in recommended
interval
STEP 5: Key Points (5 minutes)
protective immune response against an infectious agent
against subsequent infection or disease
basis
STEP 5: Evaluation (5 minutes)
References
Hugo and Russell (2011), Pharmaceutical Microbiology 8th Edition, Willey-
Blackwel publications
Karen C. Carroll et al (2013); Jawetz, Melnick and Adelberg’s Medical
Microbiology 26th Ed. McGraw Hill Co. Inc.
Greenwood et al (2012); Medical Microbiology, 18th edition Churchill
Livingstone
Immunizationhttp://www.who.int/topics/immunization/en/
Session 48: Immunization in Tanzania
Total Session Time: 60 minutes
Pre-requisites
Students Learning Tasks
By the end of this session students are expected to be able to:
Resources Needed:
SESSION OVERVIEW
|Step |Time |Activity/ |Content |
| | |Method | |
|1 |5 minutes |Presentation |Introduction, Learning Tasks |
|2 | 10 minutes|Presentation |The Concept of Immunization |
|3 |10 minutes |Buzzing/ |Objectives of Immunization |
| | |Presentation | |
|4 |25 minutes |Presentation |Schedule of Immunization in |
| | | |Tanzania |
|5 |5 minutes |Presentation |Key Points |
|6 |5 minutes |Presentation |Evaluation |
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing
STEP 2: The Concept of Immunization (10 minutes)
resistant to an infectious disease, typically by the administration of
a vaccine
against subsequent infection or disease
in the vaccine
threatening infectious diseases and is estimated to avert between 2
and 3 million deaths each year
strategies that make it accessible to even the most hard-to-reach and
vulnerable populations
through outreach activities; and vaccination does not require any
major lifestyle change
Expanded Programme on Immunization
STEP 3: Objectives of Immunization (10 minutes)
o Prevention of serious diseases and their complications
o Protection of individuals and communities
o Containment of outbreaks
o Elimination of certain diseases, e.g. neonatal tetanus
o Eradication of diseases, e.g. smallpox, polio
STEP 4: Schedule of Immunization in Tanzania (25 minutes)
basis
African countries starts with the Bacille Calmette-Guérin (BCG) for
Tuberculosis and oral polio vaccine (OPV) for poliomyelitis at birth,
followed by diphtheria-tetanus-pertussis (DPT) for diphtheria,
neonatal tetanus and whooping cough, OPV, Haemophilus influenzae type
b (Hib) and hepatitis B (Hep B) at 6 weeks, 10 weeks and 14 weeks
o Finally, immunization for measles is done at 9 months
Table 53.1: Routine Childhood Immunization Schedule in Tanzania
|Vaccine |Dose |Route of |Sites |Age |
| | |administratio| | |
| | |n | | |
|Polio (OPV) |2 drops |Oral |In the |At birth |
| | | |mouth |At 6th week after |
| | | | |birth |
| | | | |At 10th week |
| | | | |At 14th week |
|(Rotarix) | | |mouth |At 10th week |
|(DPT-Hib Hep B| | |thigh |At 10th week |
| | | | |At 14th week |
|(PCV 13) | | |thigh |At 10th week |
| | | | |At 14th week |
|a | | | |At 18th month |
o For women of child bearing age or in pregnancy the schedule is to
receive first dose at time of encounter (TT1), at 4 weeks after
first dose (TT2), at 6 months after second dose (TT3), then 1 year
after third dose (TT4) and finally 1 year after fourth dose (TT5)
o Protection time (in years) if doses are given in recommended
interval
STEP 5: Key Points (5 minutes)
protective immune response against an infectious agent
against subsequent infection or disease
basis
STEP 5: Evaluation (5 minutes)
References
Hugo and Russell (2011), Pharmaceutical Microbiology 8th Edition, Willey-
Blackwel publications
Karen C. Carroll et al (2013); Jawetz, Melnick and Adelberg’s Medical
Microbiology 26th Ed. McGraw Hill Co. Inc.
Greenwood et al (2012); Medical Microbiology, 18th edition Churchill
Livingstone
Immunizationhttp://www.who.int/topics/immunization/en/
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