Immunology

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Dr Aaser Abdelazim Lecturer of Medical
Biochemistry
Biochemical basis of
Immunology
Aaser Abdelazim
Assistant professor of Medical Biochemistry
Zagazig University
aaserabdelazim@yahoo.com

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Biochemistry
1. What do Immunology means?
2. History of immunology
3. Human immune system
4. Development of immune system
5. Components of immune system
6. Types of immunity
Station 1

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Biochemistry
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Immunology
Definition: Immunology is a science that examines the structure and
function of the immune system.
Medicine
Immunology
plague of Athens in 430 BC
Trails of Louis Moreau to examine scorpion
venome and found that certain dogs and
mice were immune to this venom.
Viruses were confirmed as human pathogens
in 1901, with the discovery of the yellow fever
virus by Walter Reed.
Robert Koch's 1891 proofs, for which he
was awarded a Nobel Prize in 1905, that
microorganisms were confirmed as the cause
of infectious disease
Paul Ehrlich, who proposed the side-chain
theory to explain the specificity of the
antigen-antibody reaction

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Biochemistry
4
Human immune system

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Dr Aaser Abdelazim Lecturer of Medical Biochemistry
5
Development of immune system in bone and thymus
Hollow shafts of long bones
Immune cells
Stem cells
Lymphocytes
Phagocytes
B lymphocytes
T lymphocytes
Maturation
Maturation
Thymus
1. Become immunocompotent
cells in a process called T
cell education
2. Learn how recognizes self
and non self non self was
eliminated
Lymph nodes
Abdomen
Groin
Neck
armpits

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Biochemistry
6
Spleen
White pulp
Red pulp
Blood cells
contains lymphoid tissue
Microorganisms carried by blood
Macrophages
1. Man can live without spleen
2. But it is very important for children and
immunosupressed patients
Role of spleen in immunity

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Biochemistry
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Paracortex
Incoming lymph vessel
Cortex
Vein Out coming lymph vessel
Artery
Follicle
Medulla
Germinal center
Structure of lymph node

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Biochemistry
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Lymph
Ingoing Lymph vessel
Contains lymphocytes,
macrophages, and foreign
antigens, drains out of tissues
and seeps across the thin
walls of tiny lymphatic vessels
Lymph nodes
Lymphocytes
Blood vessel
Outgoing lymph vessel
Thoracic duct
Blood stream
In lymph nodes
Tissues

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Biochemistry
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Immune system
Primary lymphoid organs Secondary lymphoid organs
Thymus Bursa (in birds) Gut associated
lymphoid tissues
(bursa equivalent)
Lymph node Spleen lymphoid
tissues lining
all tracts inside
the body
Cells of Immune system

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Biochemistry
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1. Gut (Payer’s patches):
Lymph drains from intestinal villi in to them
and travels to thoracic duct.
2. Pharynx:
Lymphoid tissues i.e. tonsils responded to
antigens from nose and thorax, contains
both B- cells and T-cells.
3. Skin:
Langerhans cells in skin introduce antigens
to local lymph nodes.
Uncapsulated lymphoid organs:

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Biochemistry
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Components of the immune system
Innate immune system Adaptive immune system
Response is non-specific Pathogen and antigen specific
response
Exposure leads to immediate maximal
response
Lag time between exposure and
maximal response
Cell-mediated and humoral
components
Cell-mediated and humoral
components
No immunological memory Exposure leads to immunological
memory
Found in nearly all forms of life Found only in jawed vertebrates

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Biochemistry
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Types of immunity
Cellular immunity Humoral immunity
T cells are responsible B cells are responsible
T cells activation Antibodies production
Immune response

Immunoglobulins (antibodies)
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Biochemistry
Station 2

•Glycoprotein molecules that are produced by plasma
cells in response to an immunogen and which
function as antibodies. Immunoglobulins are the
critical ingredients of humoral acquired immune
response.
• The immunoglobulins are present in the serum and
tissue fluids of all mammals.
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Biochemistry

1. Proteins; gamma
globulins
2. Produced from B-
lymphocytes or plasma
cells
3. All are similar in basic
structure
4. They are 5 types M, A,
G, E and D
5. Can be produced to
directed to 1 million of
Ags Immune serum
Ag adsorbed serum
α
1
α
2
β γ
+ -
albumin
globulins
Mobility
Amount
of
protein
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Biochemistry

Membrane-bound receptor Soluble antibody
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Biochemistry

1. Activate both the classical and alternative
complement cascades,
2. cross epithelial cell layers to provide a barrier
to pathogens at mucosal surfaces,
3. Travel transplacentally to confer maternal
humoral immunity to the fetus and neonate,
4. Induce phagocytosis by macrophages and
granulocytes via the process of opsonization,
Soluble
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Biochemistry

5. Foster antibody-dependent cellular
cytotoxicity by lymphocytes and NK cells,
6. Encourage anti-parasite immune responses by
eosinophils,
7. Promote degranulation by mast cells and
basophils,
8. Bind and inactivate foreign antigenic entities
directly.
Soluble
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Biochemistry

–Bound-
1. The induction of activation and differentiation,
2. Energy,
3. Apoptosis of B lymphocytes,
4. To act as a high-affinity receptor for the
recognition,
5. Internalization, degradation, and
eventual presentation of specific antigens to T
cells.
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Biochemistry

1. All formed from 4 polypeptide chains
• 2 light chains (L) of low molecular weight 25 KDa
• 2 heavy chains (H) of high molecular weight 50 KDa
•The two chains linked by disulfide bonds
2. Each chain have 2 regions
• C- terminus, Constant region (Fc) fragment
Constant amino acids in all types of Igs
• N- terminus, Variable region (Fv)
Variable amino acids in each type
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Biochemistry

3. Immunoglubulins units:
• IgG: one unit (Monomer)
• Ig A: two units (Dimmer)
• IgM: five units (Pentamer)
4. Antigen binding site:
Formed by few amino acids in variable regions of H
and L chains so each Ig has 2 binding sites for Ag
what is called by Divalency.
5. Carbohydrates residues, (2-12%) mannose,
galactose, fructose, NANA, glucosamine
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Biochemistry

S
S
S
S
S
S
Variable region
N- terminus
C - terminus
Light chain
Heavy chain
Constant region
CHO
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Biochemistry

• hypervariable
region
• also called
Complementarity
Determining
Regions(CDRs),
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Biochemistry

1. Classes of light and heavy chains
2. Types of immunoglobulins
3. Allo-antibody and Auto-antibody
4. Genes of light and heavy chains
5. Diversity of antibodies
6. Over/Under production of antibodies
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Biochemistry
Station 3

1. L chains:
•Kappa(κ) 70% of Igs
•Lambda(λ) 30% of Igs
Either type of L chain can be associated with each H
chains
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Biochemistry

2. H chains:
The H chain is specific to the class e.g.
1. IgG: γ chains
2. IgA: α- chains
3. IgM: µ- chains
4. IgD: δ- chains
5. IgE: ε- chains
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Biochemistry

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Biochemistry
Table 1:

1. Immunoglobulin G (IgG):
1. 80% of serum Igs
2. Only cross placenta
3. Low molecular weight
4. One unit only
5. Subclasses IgG1,2,3,4
6. Contain 2-4% carbohydrates
7. is secreted during the
secondary immune
response, its presence means
old infection
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Biochemistry

2. Immunoglobulin A (IgA)
1. Present in serum as monomer
but in body secretions as
dimmer.
2. J chian joind to Fc region links
the two monomers.
3. Can not cross the placenta.
4. Contains 5-10%
crabohydrates.
5. Produced in intestinal wall then
diffused to blood or binds to
secretory component
(glycoprotein) or secretory
piece to from secretory IgA.
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Biochemistry

Intestinal lumen
Blood stream
IgA
IgA
J chain
Secretory piece
Secretory IgA
Secretory component protects IgA
from digestion by the action of
intestinal proteolytic enzymes.
Function of IgA:
Protects body surface against invading
M.Os
Since it is the major Ig in intestinal,
respiratory, urogenital tract as well as
milk, colostrum, tears.
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Biochemistry

3. Immunoglobulin M (IgM):
1. Present in serum
2. Has the highest MW
3. Formed from 5 units
4. Not cross placenta
5. The units bind to each others by
disulfide bonds in circular fashion to
form a star then J chain join two units
to complete the circle
6. Contains 10% carbohydrates.
7. Has short half life.
8. Its function, produced in response to
primary immune response its presnce
means recent infection.
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Biochemistry

4. Immuno globulin E (IgE)
1. Present in serum by low concentration.
2. Has shortest half life(2-3 days).
3. Largely responsible for the immunity of
parasites.
4. Can not cross placenta
+
IgE
Mast cell Fc region
Histamine release
ALLARGY
Antigen
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Biochemistry

5. Immuno globulin D (IgD)
1. Present in serum by low concentration.
2. Found on the surface of B-
lymphocytes
3. It act as a specific antigen receptor
4. Has activity against insulin, thyroid
tissues, penicillin and diptheria toxins.
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Biochemistry

• Antigens that initiate the immune cascades results in the
formation of either allo-abs or auto-abs.
• Allo-antibodies: are produced after exposure to genetically
different or non-self, antigens of the same species.
• Auto-antibodies: are produced in response to self antigens.
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Biochemistry

Heavy chain
Light chain
Variable region gene VL
Joining region gene J
Constant region gene CL
Variable region gene VH
Diversity region gene D
Joining region gene J
Constant region gene CH
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Biochemistry

•There are 1 million antibodies that are derived from the 5 types
•They are all have the same constant regions
•But differ in the variable regions
No 2 variable region are
identical among all million
antibodies
Antigen
1. Diffuse hypergammaglobulinemia : all
classes are increase
2. Discrete hypergammaglobulinemia :
(paraprotienemia) single or fraction only
increases
a. Malignant : multiple myeloma
b. Benign:
Hypogammaglobulinemia: acquired or congenital reinfection and
immunodeficiency.
IgG, M, A can
combine the
same antigen
because they
have the same
variable region
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Biochemistry

IgG IgA IgM IgE IgD
% 80 20
Crossing
placenta
Only cross - - - -
Units 1 1 or 2 5 1 1
Heavy chain ɣ α
µ
ε δ
Light chain λor κ λor κ λor κ λor κ λor κ
CHO 2-4 5-10 10 10-12 2
J chain - + + - -
Secretory
component
-
+ - - -
Half life Long Short Short Short Short
Function
Secondry
immune
response
Body surfaces Primary
Parasitic
immunity
B- lymphocytes
antigen
receptors
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Biochemistry

1. Antigens / haptens
2. Chemical nature of antigens
3. Antigenic determinant sites
4. Properties of antigens
5. Occurrence of antigens
6. Types of antigens
7. Immunopotency
8. Antigen – antibody interaction
9. Antigen – antibody reaction
10.Dynamics of immune response
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Biochemistry
Station 4

Antigen: stimulate immune response
Hapten: by itself no, but should join a
larger molecules to do so.
Immunogenicity: ability of certain
substances to induce detectable
immune response
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Biochemistry

Chemical nature of antigens
1. Proteins, polysaccharides or synthetic polymers
2. Lipids are not until it join to proteins or polysaccharides
3. Nucleic acids have not antigenic properties
Lymphocyte
Antigen
Antigenic determinant
Antigenic receptor
So typical antigen:
1. Particulate: cell, bacteria, large
proteins, polysaccharides,
glycoprotein, egg white, snake
venom
2. Soluble: tissue constituents of
animal or plant
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Biochemistry

Antigenic determinant:
Location
Structure
Number
Determine the intensity of immune response
Antigen
Antigenic determinant
1. Size:200-700 ºA
2. 10-15 amino acids
residue
3. Every 5000 Da on
the chain have
one antigenic
determinant site
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Biochemistry

1. High MW > 10,000 Da
But there is no limit above or under to determine the antigenicity
2. Foreign to body (foreignness)
Serum obtained from a rabbit and re injected again to it not induce immune response
3. Posses certain degree of complexity
More complex more antigenic
Copolymers contains more type of amino acids more antigenic
Why plastic (arginine polymer) not induce immune response? not processed by macrophage?
Rapid destroyed proteins not induce immune reponse
4. Molecular surface
Should have large molecular surface
Some low MW particles become antigenic if it join charcoal or aluminum hydroxide
This gives it some degree of rigidity
Hydrocarbons not antigens why? Not rigid
Aromatic amino acids more antigenic why? Rigidity
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Biochemistry

Variability and species variations
e.g., injection of polysaccharides induce immune response in human and rats
not in guinea pigs.
As quantity of Ag increase , immune response increase
Higher
Immune paralysis Lower
Silent/
Subclinical
infection
I/V
I/P
I/M
S/C
Gradual increase in IR Routes
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Biochemistry

e.g., oils, aniline, lanoline, Al hydroxide
• Mechanism of its action not fully known
• Increase the immune response when mixed
with antigens
• Act as depots for antigens from it slowly
released
• Stimulate local immune response
(aggregate macrophages)
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Biochemistry

The capacity of a region of the antigenic determinant to induce
formation of specific antibodies
e.g., oval albumin (42,000Da have 5-6 DS)
thyroglobin (70,000 Da have 40 Ds )
Factors affecting immunopotency
1. Accessibility (easy to reach ): more in aqueous media
2. Charge: hydrophilic groups intensify the binding
Protein 1
-COO -Asp
Protein 2 lys-NH3+
More closer contact
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Biochemistry

Cell
Virulent antigen (Vi)
On surface
Somatic antigen (O)
inside
1. Organ specificity
Lens of eyes
Testicles
Brain
Liver
Heart
To specify the structure and function of that organ
2. Species specificity
Serum albumin of human is differ from cattle serum albumin
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Biochemistry

•Related
•Not identical
•Occurs in unrelated species
•Human granular fever agglutinate sheep RBCs
•Present in one locus in body
•Induce immune response if it re-injected in
anther tissue.
•Its immune response magnified by adjuvant.
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Biochemistry

A) Lock and Key Concept
Antigen
Antibody
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Biochemistry

B) Non-covalent Bonds:
Hydrogen bond
Hydrophobic bond
Van der waals forces
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Biochemistry

Affinity
•It is the strength of the reaction between antigenic
determinant site and antibody.
•Usually every antibody has a high affinity to its antigen.
Avidity
Over all strength of antigen antibody binding
Affinity refers to the strength of binding
between a single antigenic determinant
and an individual antibody combining
site whereas avidity refers to the overall
strength of binding between multivalent
antigens and antibodies.
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Biochemistry

Specificity
Ability of antibody binding site to bind with
only one antigen or more one antibody with one
antigen
Usually antibody can identify:
1. The primary structure of an antigen
2. Isomeric forms of an antigen
3. Secondary and tertiary structure of an antigen
Cross reactivity
Ability of one antibody to react with more than one antigen OR
more antibodies with more antigens
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Biochemistry

1 2
3 4
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Biochemistry

Facts ! On Ab –Ag reaction
First : antibody produced
Second : complex between Ab and Ag is
formed
Third: antigen become neutralized or
weaken
Fourth: complement fixed
Fifth: the reaction strats 48 hrs later of
infection
Sixth: immunity normally produced or
allergy or autoimmunity.
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Biochemistry

1 Months
2 4
3 7
5 weeks
6
Primary immune response
Secondary immune response
Antibody
level
in
blood
Primary immunization
Secondary immunization
•First time
•Ab appear with in 5-10 days
•Titer raised for 2-3 weeks
•Ab still detected for a month
•Memory formed
•IgM appear earlier than IgG
•Begains after primary Ab go out.
•More rapid Ab response
•Ab raised for shorter time
•Ab Still for many years
•Persisitant memory is formed
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Biochemistry

Duration period (the period of Abs appearance in blood)
differ according to the methods used in detection.
Body differ in its response to every type of antigens e.g.,
respond to particulate antigen with in 3-5 days
The curve of 1ray and 2ndry immune response varied with the
species
Not all antigens produced the known secondary response
e.g., pneumococcal polysaccharides its secondary
response appeared after 2 years of the infection
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Biochemistry

Complement system
- History
- Definitions
- Chemical nature
- Function
- Complement activation
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Biochemistry
Station 5

Hans Ernst August Buchner
History overview
1. Buchner discover a blood factor kills the
bacteria
2. In 1896, Bordet, discover properties of
two factors one
- Heat stable against specific M.Os
- Heat labile one against non specific
microbial immune response (now we
call it complement !) Jules Bordet
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Biochemistry

Paul Ehrlich
3. Ehrlich used term Complement in his theory
for immune system
-Immune system is formed of cells
-These cells produce receptor to receive antigens
-These receptors called amboceptors.
-Now we call these receptors as antibodies
-These antibody not act by them selves rather
need the help of a factor binds it, Ehrlich call it
complement providing that it complete the action
of antibodies.
4. Jackie Stanley team proved the role of complement in both
the innate as well as the cell-mediated immune response.
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Biochemistry

It what helps antibodies and
phagocytes to eliminate pathogen from
an organism.
It is a part of innate system (not
changed over all the life) but can be brought
into the action by the adaptive
immune system
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Biochemistry

Small
Proteins
Produced
by liver
Induce massive
immune response
Form
MAC
Secreted in
pro-protein form
Triggers production
of cytokines
25 proteins and
protein fragment
5% of total blood
Globulins
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Biochemistry

1. OPSONIZATION - enhancing phagocytosis of
antigens
2. CHEMOTAXIS - attracting Macrophages and
Neutrophils
3. LYSIS - rupturing membranes of foreign cells
4. CLUMPING of antigen-bearing agents
5. ALTERING the molecular structure of viruses
Macrophage
Neutophil
Lysis
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Biochemistry

Hepatocytes
Monocytes
UGT epithelium
Macrophages
GIT epithelium
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Biochemistry

C3
Convertase
Classical pathway Alternative mannose-binding lectin
C3b
C3a
Pathogen
Opsonization
Chemotaxis
More phagocytosis
Overview
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Biochemistry

C3a C5a
Degranulation of mast cells
1. Increase Blood vessel
permeability
2. Smooth muscle contraction
C5b Initiates MAC
C5b C6 C7 C8 C9
Trans membrane channel lead to osmotic cell lysis
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Biochemistry

1
Activates C1 complex C1q
C1r
C1r
C1s
C1s
C1q
Pathogen
C1q
IgM IgG
or
C1q
Antigen
Antigen
C1r
C1r
Serine proteases
+ +
C1s
C1s
C2
C4 +
C4a C4b C2a C2b
C1 complex
C1-
inhibitor
-
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Biochemistry

C4b + C3
C3b
C3a
C2a
C3 convertase
C4b C2a
C3b
C4b C2a
C5 convertase
DAF
-
1
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Biochemistry

2 1. C3 hydrolysis
2. Not depend
pathogen-binding
antibodies
C3b
Pathogen
If no pathogen in blood C3b
C3a +
If pathogen in blood
C3
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Biochemistry

C3b
Pathogen
How this binding is occur ?!
Factor B
Factor D
Bb
Ba +
C3b Bb
Alternative C3 convertase
C3b Bb
Pathogen
Chainsaw
2
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Biochemistry

C3b Bb
Pathogen
C3b C3a
C3b Bb
+
C3
In
blood C3 convertase
C3b
C3b Bb
C5 convertase
C5
+
C5a +
2
C5b
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Biochemistry

C6 C7 C8 C9
C5b
C5a
C5b
Membrane attack complex MAC
punches a hole and initiates cells lysis
C3a
Degranulation of mast cell
+
2
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Biochemistry

3
1. As classical
2. Opsonin, mannose –
binding lectin, ficolin
are in stead of C1q.
Activation
Pathogen
Mannose
MBL
Mannose
residue
MASP-1 MASP-2
+
Mannose asociated serine proteases
Split C4 and C2
Ficolin
or
Ficolins
1. Are homologus to MBL
2. Used to compensate for
the lack of pathogen-
specific recognition
molecules.
Like classical pathway
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Biochemistry

C1q
C4b
C3b
•This complex enable the antibody to
detect its antigen as a guiding stick
•Complement can bind non self
pathogens but after detecting their
pathogen-associated molecular
patterns (PAMPs).
•Complement can detect antigens
more specifically than antibody.
•The binding of complement to
antibody is directed towards the
antigen not to the antibody.
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Biochemistry

Complement should stop after finishing its
action !
It stops by Complement control proteins
Complement control proteins
concentration is higher than complement
protein themselves.
CD59: inhibits c9 during MAC formation
C1-inhibitor inhibits c1
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Biochemistry

1. Complement fixation test
2. Immunity in action
3. Vaccination
4. Antiserum
5. Genetic control of immunity
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Biochemistry
Station 6

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Detects the existence of specific
antibody or antigen in a patient serum
Diagnose microbial infections which
can not be detected by culture
methods
Principle
In the presence of antigen – antibody
reaction a cell membrane is destructed
indicate specific antigen/ antibody

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Serum Complement resist heat
Antibodies destructed
Add standard amount of complement
From guinea pigs
Heated ∆
Add antigens
Add sheep RBCs bounded to antibody
Procedures
1 2
3
4
5

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Presence of specific antibody Absence of specific antibody
Complement reacts with ag-ab complex
No lysis of RBCs
There is No ag-ab complex
Complement reacts with RBCs
Induce RBCs lysis
Positive Negative
Interpretation of results

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Innate immunity, or nonspecific, immunity
Man born with it
Tissue epithelium/ barriers
Cytokines Antimicrobial substances
Inflammatory condition
Phagocytosis

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Adaptive immunity
Naturally acquired immunity
Artificially acquired immunity
No deliberate infection
deliberate infection
Vaccination
Passive
Active
Transfer
antibody
or T cells
Short life
Transfer
antigens
Long life

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Passive immunity
Transfer of antibodies
Maternal antibodies Artificial antibodies
Advantages
1. Develops faster immune response in high risk infections or when
the body unable to develop an immune response.
2. Reduce the symptoms of ongoing or immunosuppressive diseases.
Disadvantages
Body does not develop memory, therefore the patient is at risk of
being infected by the same pathogen later.

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Naturally acquired passive immunity
Maternal antibodies
1. Through placenta
2. FcRn receptor
3. third month of gestation.
IgG
IgA Until he synthesizes own abs
Milk

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Artificially acquired passive immunity
Antibody transfer in the form of:
1) Human or animal blood plasma
2) Pooled human immunoglobulin for intravenous or intramuscular use
3) Monoclonal antibodies (MAb).
-Immunodeficiency diseases, such as hypogammaglobulinemia
-Acute infection, and to treat poisoning.
Risk for hypersensitivity reactions
serum sickness, especially from gamma globulin of non-human origin.

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Passive transfer of cell-mediated immunity
1. Transfer activated T cell from one individual to another
2. Rare used why ?
Because it Requires histocompatible (matched) donors, which are often
difficult to find.
1) Carries severe risks of graft versus host disease.
2) Used to treat cancer and immunodeficiency.
3) Differs from a bone marrow transplant, in which (undifferentiated)
hematopoietic stem cells are transferred.

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Active Immunity
It means that the body can prepare it
self for future infection
This need formation of memory
Cell-mediated and humoral immunity

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Naturally acquired active immunity
live pathogen Body Forms primary immune response
Memory is formed
Affected by
1. Immunodeficiency
2. Immunosuppression.

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Artificially acquired active immunity
(Vaccination)
Vaccine
Stimulate
primary
immunity
without
symptoms
Inactivated
Killed by heat or chemicals
flu, cholera, plague, and hepatitis A.
Live, attenuated vaccines
Cultivated at unsitable condition to be unable to induce disease
yellow fever, measles, rubella, and mumps.
Toxoids
Inactive Toxins of a M.O
tetanus and diphtheria.
Subunit-vaccines
Small fragmant of caustive agents
Hepatitis B virus

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blood serum containing polyclonal antibodies.
Uses
1. Prophylactic
2. passive antibody transfusion
3. antitoxin or antivenom, to treat envenomation.
Types of antiserum
Antitoxic : which neutralize the toxins
Antibacterial : sensitizing the organisms
Adult serum : in certain viral diseases e.g., gamma globulins.

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How antiserum works ?
1. Antibodies binds to antigen.
2. Immune system then recognizes foreign agents
bound to antibodies and triggers a more robust
immune response.
3. existence of antibodies to the agent therefore
depends on an initial "lucky survivor" whose immune
system by chance discovered a counteragent to the
pathogen, or a "host species" which carries the virus
but does not suffer from its effects.

1. Genetic control of immunity
2. Major Histocompatibility Complex (MHC)
3.
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Biochemistry
Station 7

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Biochemistry
91
Genes for immunity
1. Control of immune
performance
2. Production and maturation
of immune cells
MHC ?!

20-03-2018
Biochemistry
92
3.6-Mb (3 600 000 base pairs)
Codes 140 genes
Major histocompatibility molecules

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Biochemistry
93
1. MHC molecules display
fragments of processed proteins
on the cell surface.
2. Allows for pathogen surveillance
by immune cells, usually a T cell
or natural killer (NK) cell.
3. Develops immune response to
pathogens.
MHC
Pathogen proteins
Role of MHC

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Biochemistry
94
MHC genes must produce a wide variety of molecules
How it achieves this?!
(1) The MHC locus is polygenic. More one copy, determined by a
number of genes
(2) MHC genes are highly polymorphic and numerous
alleles have been described. having multiple alleles of a gene within
a population, usually expressing different phenotypes, no two persons have the
same MHC genes except twins.
(3) MHC genes are codominantly expressed and
several MHC genes are expressed concomitantly.
Continuous and dominant

20-03-2018
Biochemistry
95
Class I Class II
Macrophage Dendertic cell
APCs
Lymphocyte
Process the pathogen in to peptide fragments
MHC II introduce these fragments to Th
Stimulate immune reaction
Cytotoxic T cell
Class III ?

20-03-2018
Biochemistry
96
Pathogen
Virus
Baceria
Cancerous tissue
Nucleated cell
Pathogen peptide
Cytotoxic T cell
Self peptide
MHC-I
MHC-I
MHC-I
Protein turnover
No pathogen
No Infection
Infection

20-03-2018
Biochemistry
97
One of APCs
Pathogen peptides
MHC - II
Immune response
Pathogen peptides in phagosomes
Pathogen
MHC-II
Phagocytosis
Act as signposts

20-03-2018
Biochemistry
98
MCH and HLA are they the same ?!
MHC
Antigen-presenting proteins
Human leukocyte antigen (HLA) genes
Gene
Gene
Products

20-03-2018 99
Biochemistry
HLA genes
1. HLA-A
2. HLA-B
3. HLA-C
4. HLA-DPA1
5. HLA-DPB1
6. HLA-DQA1
7. HLA-DQB1
8. HLA-DRA
9. HLA-DRB1
MCH-II
MHC-I
Maternal class I
Paternal class I
Each individual
have 2 haplotypes
one from mother
and the other from
father

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Biochemistry
100
MHC proteins manage the dialogue between T cells and other immune cells
T cells
TCR
MHC anchored in membrane
Display self and
nonself peptides
Only T cells reacts with non self ones
and ignore self one
At maturity

20-03-2018
Biochemistry
101
T cells
T cell need presentation by help of MHC
B cells
Antibody
MHC
BCR
TCR
Checks and balances
No help
Avoid amok of immune system
‫والتوازنات‬ ‫الضوابط‬
Antigen peptide
Antigen

20-03-2018 102
Biochemistry
MHC class I
Transmembrane region
Structure
1. α unit
2. ᵦ2 microglobin
All nucleated cells and platelets
Cleft for peptide presentation
Functions
1. Presents peptides for
cytotoxic T cells
2. Binds the inhibitory
receptors on NK cells

20-03-2018
Biochemistry
103
Categorizations of class I MHC molecules:
Classical MHC molecules Nonclassical molecules
Present cytosolic or
cross-presented peptides
to CD8+ T lymphocytes
HLA-A, HLA-B and HLA-C
Man
H-2K, H-2D, H-2L
Mice
Differ from the classical MHC in
1. Limited polymorphism.
2. Variable expression patterns.
3. Types of antigen presented.
HLA-E, -F, -G
Coded by
Interact with both CD8+ T cells,
NKT cells, and NK cells.

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Biochemistry
MHC class II
Cleft
Transmembrane region
APCs
Structure
Function
Presents pepetide
to helper T cells

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Biochemistry
105
Classic molecules Nonclassic molecules
MHC-II molecules in humans
Presenting peptides to T4 helper
lymphocytes
HLA-DP, HLA-DQ, HLA-DR
Not exposed in the cellular membrane
Present in Internal membrares in lysosomes
Load the antigenic peptides on
the classic MHC-II molecules
HLA-DM and HLA-DO.

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Biochemistry
106
1) Components of the complement system (such as
C2, C4 and B factor)
2) Molecules related with inflammation (cytokines
such as TNF-α, LTA, LTB)
3) Heat Shock Proteins (HSP)
Located between class I and class II on short arm of chromosome 6

20-03-2018
Biochemistry
107
Facts on Functions of MHC-I and II molecules
1. Present antigenic peptides to T lymphocytes
2. MHC molecules can display only peptides; only protein in
origin
4. In the same time it can display many peptides
3. Each MHC molecule can display only one peptide each time
5. MHC-I presents peptides from cytosol while MHC-II
presents peptides from intracellular vesicles
6. Only stable if they loaded a peptide even though they will
degraded

20-03-2018
Biochemistry
108
Cell cytosol
MHC-I
Peptides
coming from
self, virus,
phagocytic
molecules
MHC-II
Nucleus
Cell vesicles
Peptides from
microbe ingested in
vesicles, only in
cells of phagocytic
capacity
MHC site action

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Biochemistry
MHC class I processing
Transporter
Associated with
Antigen Processing
(TAP) or Tapasin
It acts mainly on peptides of
Cytoplasm origin

20-03-2018
Biochemistry
110
Nucleus
MHC loaded peptide
Not loaded Degraded
Remain in cell membrane
for days
Self
Non self
Much more
abundant
T cells detects
0.1-1% of
peptides
displayed by
MHC
Not stimulate
immune
response
Except in
autoimmunity
It is very important for supervising T cell functions
Stimulate
immune
response

20-03-2018
Biochemistry
111
HLA-A
HLA-B
350 alleles
620 alleles
90 alleles
400 alleles
HLA-DQ
HLA-DR
Inherited and expressed
in different
combinations
Each individual will express MHC different
To the another

20-03-2018
Biochemistry
112
Donor
MHC on transplants
Immune response
Antigen
Receptor

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Biochemistry
113
Peptides MHC
Self Foreign Self Foreign
Self – self
Foreign – foreign complex
T cells Don’t know !!
Weakly know !!
Found in transplanted cells
‫؟‬ ‫المشكلة‬ ‫فين‬
!!!
During
maturation in
thymus

20-03-2018
Biochemistry
114
Receptor
T cells
Donor
MHC
Similar
Foreign peptide – Self MHC
on transplanted organ/cells
Severe immune response
Rejecting the organ
Mistake – Cross reaction
Allorecognition

1. Cell mediated immunity
2. T cells
3. T cell markers
20-03-2018 115
Biochemistry
Station 8

20-03-2018
Biochemistry
116
Macrophage
Dendertic cell Lymphocyte
Cytokines With out cytokines

20-03-2018
Biochemistry
117
How cell-mediated immunity protects the body?!
CD8+ cytotoxic
Apoptosis 1. Virus-infected cells
2. Cells with intracellular bacteria
3. Cancer cells
Macrophage
Intracellular pathogens
Destroy
Cytokines Affects other cells functions
Other cells
1. Fungi
2. Transplant rejection

20-03-2018
Biochemistry
118
Cells of immunity
Helper T cell
Regulatory/ suppressor T cell
Cytotoxic T cell
Delayed hypersensitivity T cells

20-03-2018
Biochemistry
119
Helper T cell
1. They are essential in determining B cell antibody class switching. is a
biological mechanism that changes a B cell's production of antibody from one class to another, for
example, from an isotype IgM to an isotype IgG. During this process, the constant region portion of the
antibody heavy chain is changed, but the variable region of the heavy chain stays the same (the terms
"constant" and "variable" refer to changes or lack thereof between antibodies that target different
epitopes)
2. Have a role in Activation and growth of cytotoxic T cells
3. Have a role in maximizing bactericidal activity of phagocytes such
as macrophages.
4. Mature Th cells are believed to always express the surface protein
CD4 and are referred to as CD4+ T cells.

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Biochemistry
120

20-03-2018
Biochemistry
121
Regulatory/ suppressor T cell
Suppress the immune system
1. Autoimmune diseases
2. Cancer immunotherapy
3. Facilitate transplant tolerance
Regulatory T cell (Treg)
CD8+ T cells CD4+CD25+ regulatory T cells Suppressive T cells
shutting down immune responses

20-03-2018
Biochemistry
122
Functions of regulatory T cells
Prevent pathological self-reactivity

20-03-2018
Biochemistry
123
During infection Down regulated
Other cells
T reg
Pathogens express them
to face immunity
Up regulated T reg
1. Retroviral infections (HIV)
2. Mycobacterial infections (TB)
3. Parasitic infestations (Leishmania and malaria).
Treg Up/Down regulation

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Biochemistry
124
Cytotoxic T cell

20-03-2018
Biochemistry
125
Tc
Perforin
Granzymes
Granulysin
Target cell
Cleavage at aspartate residue
Granzymes
Serine proteases
Granzymes
Cystine proteases
Caspase
Apoptosis
Infection 1st mechanism

20-03-2018
Biochemistry
126

20-03-2018 Dr Aaser Abdelazim Lecturer of Medical
Biochemistry
127
Tc
Target cell
FasL Fas
Death induced silencing complex(DISC)
ligand
Fas- Associated Death Domain (FADD)
Procaspase 8 Procaspase 10
Caspase 7
Caspase 6
Caspase 3
lamin A
lamin B2
lamin B1
PARP
DNAPK
Death substrates
Programmed cell death
2nd mechanism

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Biochemistry
128
Cytotoxic T cell activation
TCR on T cells and
peptide-bound MHC class
I molecule on APCs.
1. Includes CD28 molecule
on the T cell and either
CD80 or CD86 (also
called B7-1 and B7-2) on
APCs.
2. CD80 and CD86 are
known as costimulators
for T cell activation

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Biochemistry
129
Delayed hypersensitivity T cells
1. These are cells of non antigenic specific factors
2. They respond to the antigens that previously sensitized the T – cells
3. Produce specific non antigenic products called lymphokines.

20-03-2018
Biochemistry
130
T cell receptor TCR complex
TCR

20-03-2018
Biochemistry
131
CD2
CD2
Target
1. T cells
2. NK cells
Functions of CD2:
1. It interacts with other
adhesion molecules, such
as lymphocyte function-
associated antigen-3 (LFA-
3/CD58) in humans, or
CD48 in rodents, which are
expressed on the surfaces
of other cells.
2. CD2 also acts as a co-
stimulatory molecule on T
and NK cells.

20-03-2018 132
Biochemistry
CD3
Included in TCR complex

20-03-2018 Dr Aaser Abdelazim Lecturer of Medical
Biochemistry
133
CD4
CD4
Targets
1. T helper cells
2. Regulatory T cells
3. Macrophages
4. Dendertic cells
5. Monocytes
CD4 receptor

20-03-2018
Biochemistry
134
Functions of CD4
Helps TCR with antigen
presenting cells
Amplify TCR signal
Tyrosine kinase
T cell activation
Reacts directly with MHC-II
Using its extracellular domain

20-03-2018
Biochemistry
135
CD8
CD8 co receptor
CD8
Its extracellular domain reacts with α3 of MHC-I
This affinity keeps the T cell receptor
of the cytotoxic T cell and the target
cell bound closely together during
antigen-specific activation.

1. Cytokines
2. Interferon
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Biochemistry
Station 9

20-03-2018
Biochemistry
137
CYTOKINES
Substances of immunomodulating action
Immune cells
Glial nerve cells
Interleukins Interferon
Cyto = cell kinos = Movement
Proteins
Peptides Glycoprotein
Cell to cell communication

20-03-2018
Biochemistry
138
Points Cytokines Hormones
Concentration of
circulation
Picomolar
(10-12 )
Nanomolar concentration
(10-9 )
Fold increase 1000 folds e.g., during
infection
One fold or less
Cells of
secretions
All nucleated cells especially
epithelial cells and
macrophages
Special cells in glands like B
cells of pancreas secretes
insulin etc
Action Systemic immunomodulating
action
Local in action
Specificity Not specific in their action
Immunomodulating and role
during embryogenesis
Specific in their action
Type of action Autocrine in chemotaxis or
paracrine as pyrogens
Almost hormones are
paracrine in their action
Cytokines / hormones

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Biochemistry
139
Cytokines
Interleukins Chemokines Lymphokines
Leukocytes
T helper cells
Variable in action
Special type of interleukins
Chemotaxis
Lymphocytes
Cell signaling
Aid B cells to produce antibodies
Activation / attraction of other immune cells
IL- 2…..6 , GMCSF

20-03-2018
Biochemistry
140
Classification of cytokines
Structural classification Functional classification
Four-α-helix
bundle family
IL-1 family IL-17 family
IL-2 IL-10
INF
Erythropoietin (EPO)
Thrombopoietin (TPO)
IL-18 IL-1
Enhance
cellular
immune
responses,
type 1
Enhance
cellular
immune
responses
type 2
IFN-γ, TGF-β IL-4, IL-10, IL-13

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Biochemistry
141
Effect of cytokines
Cell
Cytokine
Receptor
Target cell
l
Different cell cascades
Key genes
Up/down regulation

20-03-2018
Biochemistry
142
cytokine Producer cell Target cell Functions
Interleukin- 1 Macrophage,
monocyte and T helper
cells
T cell and B cells Activating lymphocytes
inflammatory mediator
Interleukin-2 T cells and NK cells T cells and NK cells
and Macrophage
Activates T4, T8 and B
cells
Interleukin-3 T cells Hemopiotic cells of
bone marrow
Activates bone marrow
to produce different
cells
Interleukin-4 T cells T cells, B cells and
mast cells
Activation and
proliferation of T and B
cells
Interleukin-5 T cells T cells, B cells and
eosinophils
Interleukin-6 T cells and fibroblast T cells, B cells
Interleukin-7 Stroma cells,
monocytes and
macrophages
Immature lymphoid
cells

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Biochemistry
143
Interleukin-8 Macrophages Eosinophils,
macrophages and
neutophils
Chemotactic effect
Interleukin-9 T cells T cells Hemopiosis
Interleukin-10 Th cells T helper cells Stem cell
differentiation and
growth factor of
most cells
Interleukin-11 B cells and stroma
cells
B cells Absorption
Interleukin-12 Monocytes and B
cells and
Mcrophages
Th cells and NK cells Interferon population
and cytotoxic
activity.
cytokine Producer cell Target cell Functions

20-03-2018
Biochemistry
144
INTERFERONS
lymphocyte
What is interferon?!
IFN
Virus
Bacteria
Tumor
Other cell
Protection
10 INFs in
mammals 7 of
them in human
Activates immune cells
(NK, macrophages)
Increase recognition
of infection
Increase resistance
of the non infected cells

20-03-2018
Biochemistry
145
Human interferon

20-03-2018
Biochemistry
146
Types of interferon
Interferon type I Interferon type III
Interferon type II
bind to a specific
cell
surface receptor
(IFN-α receptor)
IFN-β IFN-ω
IFN-α
IFN-γ
bind to a specific
cell
surface receptor
(IL-10R2
receptor)
bind to a specific
cell
surface receptor
(IFN-ɣ receptor)

20-03-2018
Biochemistry
147
Functions of interferons
Antiviral effect
Virus
Infected cell
Cell lysis
Release of viruses
To infect other cells
PKR
eIF-2 P
Reduce protein
biosynthesis
inactive
RNAse L
+
+
Destroys RNA
within the cells
P
Reduce
protein
synthesis of
both viral and
host genes.

20-03-2018
Biochemistry
148
INFs
Interferon-
stimulated
genes (ISGs)
+
+
p53
Promoting
apoptosis
Other INFs functions
MHC
Viral peptides
presentation
and
destruction
Viral
destruction
+

20-03-2018
Biochemistry
149
Interferon therapy
Treatment of Cancer
leukemia lymphomas
Type I (IFNs)
1. Antiproliferative
2. Apoptotic effects
3. Anti-angiogenic
effects
4. Activating dendritic
cells, cytolytic T cells
and NK cells.
Viral hepatitis
Hepatitis B Hepatitis C
IFN-α
1. Used in combinations with
other drugs (interferon-
α/ribavirin).
2. Immediately after infection
by C virus prevents
chronicity.
3. Chronic hepatitis control by
INFs can reduce HCC
Respiratory diseases
Cold and Flu
1. With non under
stood mechanism
2. In small doses
3. May act as
adjuvant to
influenza virus
4. Used now to
formulate flu
adjuvant vaccine

20-03-2018
Biochemistry
150
Adverse effects of interferon therapy
1. Increased body temperature.
2. Feeling ill, fatigue, headache.
muscle pain, convulsion.
3. Dizziness. hair thinning,
4. Depression and Erythema
and pain at the spot of
injection.
Systemic effect Immunosuppression
Flu like symptoms
1. Neutropenia
2. Infections manifestations by
unusual ways.

20-03-2018 151
Biochemistry
1.Cancer immunology
2.Organ transplantation
Station 10

20-03-2018
Biochemistry
152
CANCER IMMUNOLOGY
Immunosurveillance Immunoediting
Protects host cells
from continuously
arising, nascent
transformed cells.
Lymphocytes
Protection of body
cells from tumor
growth and
development
Elimination Equilibrium Escape
‫المناعي‬ ‫الترصد‬ ‫التحرير‬

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Biochemistry
153
Elimination phase
Phase 1
Immune Cells recognize the tumor
Local tissue damage
1. killer cells
2. Natural killer
3. Macrophages
4. Dendritic cells
INF-ɣ
Tumor cells (growth)
Inflammatory signals
Starts the antitumor immune response
(Tumor death)

20-03-2018
Biochemistry
154
Phase 2
INF-ɣ
Tumor death (to a limited amount)
Production of chemokines
+
+
Formation of new blood vessels
-
Tumor cell debris
Recruitment of
more immune cells
+
Dendertic cell

20-03-2018
Biochemistry
155
Phase 3
Macrophage
Transactivation
IFN-ɣ IL-12
Promotes more killer cells
Production of
reactive oxygen and nitrogen
Dendertic cell
Differentiation of Th1
Development of CD8+ T cells
1 2 3
Destruction of tumor
NK cells

20-03-2018
Biochemistry
156
NK cells (yellow) try to kill tumor cell (red)

20-03-2018
Biochemistry
157
Phase 4
Destruction of antigen bearing tumors by cytolytic T cells

20-03-2018
Biochemistry
158
Equilibrium and escape phase
For tumor cells that survive the elimination phase
Immune cells
Increase the pressure
IFN-ɣ
Tumor cells continue to
grow and expanded with
un controlled manner
Winning of
immune
response
1 2

20-03-2018
Biochemistry
159
Immunoediting

20-03-2018
Biochemistry
160
ORGAN TRANSPLANTATION
Donor Recipient
Organ
Tissue
Stem cells

20-03-2018
Biochemistry
161
Types of organ transplantation
Autograft
Skin grafting
Vein extraction
for coronary
artery paypass
surgery(CABG)
1

20-03-2018
Biochemistry
162
Allograft
Two genetically non-identical persons
Stimulate an immune response
Organ rejection
2

20-03-2018
Biochemistry
163
Isograft
Two genetically identical persons
Not Stimulate an immune response
No Organ rejection
3

20-03-2018
Biochemistry
164
Xenograft
Porcine heart valve
Islet transplant (pancreas)
4

20-03-2018
Biochemistry
165
Split transplant
Heart transplant
Deceased person
Child
Adult
Split liver transplant
5

20-03-2018
Biochemistry
166
Domino transplant
Heart & lung Heart
Recipient 2
Recipient 1
Cystic fibrosis
Lung failure
6

20-03-2018
Biochemistry
167
Special from of liver transplant
Familial
amyloidotic
polyneuropathy
Liver produces protein damage other organs
Recipient 2
Recipient 1

20-03-2018
Biochemistry
168
TRANSPLANT REJECTION
Hyperacute rejection
Complement-mediated
response
Rapid –
immediate
Non identical
persons
Pre- existing
antibodies from
blood transfusion
Cross
matching
Acute rejection
One week- months –
years
Xenograft
Need
immunosuppressive
drugs
caused by
mismatched HLA
T cell mediated
immunity
Chronic rejection
long-term loss of
function in
transplanted organs
On long run
Chronic inflammatory
response to the transplanted
organ

20-03-2018
Biochemistry
169
Organ/tissue Mechanism
Blood Antibodies (isohaemagglutinins)
Kidney Antibodies, CMI
Heart Antibodies, CMI
Skin CMI
Bonemarrow CMI
Cornea
Usually accepted unless
vascularised, CMI
Rejection mechanisms

Immunology

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