Immunology
Concept, Functions and Types
of Immunity
Concept, Functions and Types of Immunity
Introduction
Concept and functions of Immunity
Types of Immunity
Part I Concept and functions
of Immunity
I Concept of Immunity
1)Tranditional concept----Immunity refers to
protection against infectious diseases.
2)Modern concept---- Immunity is a function of
which an individual recognizes and excludes
antigenic foreign substances. It is normally
beneficial,but sometimes,it is injurious.
II Concept of Immunology
1) Tranditional concept----anti-infection immunity
to
different
types
of
pathogenic
microorganisms.
2)
Modern
concept----Immunology
is
an
independent
subject
about
composition,functions of immune system;
mechanism of immune response and the disease
associated with immunity.
III Functions of Immunity
Immune defense
Immune homeostasis
Immune surveillance
Functions and Manifestation of Immunity
Functions
Normal Manifestation
Abnormal Manifestation
Immune
Hypersensitivity
Defense
Immunodeficiency
Immune
Homeostasis
Immune
Surveillance
infection
Eliminate injured and senile cells
Tolerate to self components
Anti-infection
immune dismodulation
Autoimmune disease
destroy transformed cells
(anti-tumor )
Prevent from persistent infection
Tumor or
Persistent virus
Part II Types of Immunity
I. Innate Immunity
(or native immunity/ non-specific immunity
/congenital immunity)
II. Adaptive Immunity
(or acquired immunity/specific immunity)
I. Innate immunity
( natural immunity/ non-specific immunity )
Innate immunity:
Protection against infection that relies on
mechanisms that exist before infection,are
capable of a rapid response to microbes,and
react in essentially the same way to repeated
infections.
 Exists at birth
 Be the first line of defense against infection
Innate immunity
1. Characteristics
 Exists naturally
 Non–specific
 No immune memory (innate immunity can’t
be enhanced by the second stimulation of
the same antigen)
Immune memory: Exposure of the immune
system to a foreign antigen enhances its
ability to respond again to that antigen.
 Hereditable
 No racial difference
2. Composition
(1) Barriers
 Physical barrier : skin and mucosa
 Chemical barrier: antimicrobial substances in
secretion of skin and mucosa
 Biotic barrier: normal flora existing on the surface
of skin and mucosa
 Anatomic barrier
. blood- brain barrier
. blood- placental barrier
. blood- tymus barrier
(2) Humoral factors
 Complement
 Lysozyme
 Interferons(IFN)
 C-reactive protein
(3)Cells participating in innate immunity
 Phagocyte: endocytosis and phagocytosis
mononuclear phagocytes
----Monocytes,Macrophages (M Φ)----PRR
Neutrophils
 Nature killer cells (NK)—KAR/KIR,IgG
receptor
 Dentritic cells(DC)
 γδ T cells
 B1 cells
 Other cells participating in innate immunity
Fc
Macrophages
NK cells
Neutrophils
Macrophages
Macrophages excluding the
pathogen
Over view




What are the main types of white
blood cells?
Name the two main types of immunity?
What are the main distinctions between
these two categories?
What cells are involved in which aspects
of the immune system?
Lymphocytes



Many types; important in
both humoral and cellmediated immunity
B-cells produce
antibodies (APC cell)
T- cells



Cytotoxic T cells
Helper T cells
Memory cells
Lymphocytes

Natural Killer cells



Large granular lymphocytes (not B or T)
Kills tumor cells
Kills cells infected with certain viruses
(intracellular pathogens)
Monocytes/Macrophage

Phagocytosis and killing of
microorganisms




Activation of T cells and
initiation of immune
response
Monocyte is a young
macrophage in blood
There are tissue-specific
macrophages
APC cells
Dendritic Cells



Phagocytosis and killing
of microorganisms
Function as antigen
presenting cells (APC)
In the blood and
tissues – mature and
migrate to the lymph
nodes
Neutrophil

Granulocyte






Cytoplasmic granules
Polymorphonuclear
Phagocytosis
Short life span (hours)
Very important at “clearing” bacterial
infections
Innate Immunity
Eosinophils





Kills Ab-coated parasites
through degranulation
Involved in allergic
inflammation
A granulocyte
Double Lobed nucleus
Orange granules contain toxic
compounds
Basophils


Might be “blood Mast
cells’
A cell-killing cells


Blue granules contain toxic
and inflammatory
compounds
Important in allergic
reactions
Antigen-presenting cells (APC)




Highly specialized
Process antigen and display peptide
fragments on cell surface
Involved in T-cell activation
Macrophages, dendritic cells and B-cells
Over view




What are the main types of white blood
cells?
Name the two main types of
immunity?
What are the main distinctions
between these two categories?
What cells are involved in which aspects
of the immune system?
Immune system divisions


Innate immunity
 First line of defense
Adaptive (acquired) immunity
 Takes time to develop
 Humoral immunity
(antibody–mediated
specific immunity)
 Cell-mediated immunity
(The aspect of the
adaptive immune response
where antigen-specific T
cell have a main role)


Active immunity
Passive or maternal
immunity


Injection of Immunoglobulin
Absorption of maternal
antibodies
Innate vs. adaptive immunity


Innate immunity
 First line of defense (present in all individuals at all
times)
 Immediate (0 – 4 hours)
 Non-specific
 Does not generate lasting protective immunity
Adaptive immune response (late: > 96 hours)
 Is initiated if innate immune response is not adequate
(> 4 days)
 Antigen-specific immunity
 Generates lasting protective immunity (e.g. Antibodies,
memory T-cells)
Over view




What are the main types of white blood
cells?
Name the two main types of immunity?
What are the main distinctions between
these two categories?
What white blood cells are
involved in which aspects of the
immune system?
Immune system cells

Innate immunity
 Granulocytes
(i.e. neutrophils)
 Macrophages
 Dendritic cells
 Natural killer (NK)
cells

Adaptive
immunity
 Lymphocyte
B cells
 T cells




Cytotoxic T cells (CTLs)
Helper T cells (Th)
Memory cells
Innate immune system

The first line of defense:




Penetration of the epithelial surface of the body by
microorganism (e.g. bacteria)
Engulfment of microorganism by macrophages,
neutrophils, and dendritic cells
Release of cytokines and chemokines
Inflammation
Killing by granulocytes



Macrophages and neutrophils recognize pathogen by means of
cell-surface receptors
 Example: mannose receptor, CD14 receptor, scavenger
receptors, glucan receptor etc.
Binding of MØ/neutrophils with pathogen leads to phagocytosis
 Bound pathogen is surrounded by phagocyte membrane
 Internalized (phagosome)
 Killing of pathogen (Phagolysosome*)
 Oxidative burst (synthesis of hydrogen peroxide (H2O2)or
free oxygen radicals)
 Acidification
 Antimicrobial peptides (e.g. defensins)
* Phagolysosome = lysosome +phagosome
Phagocytosis
Lipid
mediators
Mannose
receptor
Lysosome
Phagosome
Scavenger
receptor
LPS receptor
(CD14)
The macrophage
expresses receptors for
many bacterial
constituents
Cytokines
Bacteria binding to
macrophage receptors
initiate the release of
cytokines and small lipid
mediators of inflammation
Phagolysosome
Macrophages engulf and
digest bacteria to which
they bind
Phagocytosis

(Immunology animation: Janeway)



http://www.blink.biz/immunoanimations/#
Immune response (IV)
9.1 - Phagocytosis
Humoral immune response

Cell-surface immunoglobulin
receptors (BCR) detect
extracellular pathogens


Once activated, secrete
immunoglobulins as soluble
antibodies
Antibodies


Variable region (2 identical
antigen-binding sites)
Constant region (determines
how antibody disposes of the
pathogen once it is bound)
V region; At binding
Fc region
Cell killing – NK cells




NK cells do not require prior
immunization or activation
They attach to ‘target’ cells
(ADCC)
Cytotoxic granules are
released onto surface of cell
Effector proteins penetrate
cell membrane and induce
programmed cell death
Inflammation
Inflammatory cells
migrate into tissue,
releasing inflammatory
mediators that cause
pain
Chemokines
Cytokines
Bacteria
trigger
macrophages
to release
cytokines and
chemokines
Proteins
Fluids
Vasodilation and
increased vascular
premeability cause
redness, heat, and
swelling
Cytokines


Low molecular weight, soluble proteins that are
produced in response to an antigen and function as
chemical messengers for regulating the innate and
adaptive immune system
Innate immune system

Macrophages and Dendritic cells




Tumor necrosis factor-alpha (TNF-)
Interleukin-1 (IL-1)
Interleukin-12 (IL-12)
Adaptive immune system

T-lymphocytes


Interleukin-2 (IL-2)
Interleukin-4 (IL-4)
II.Adaptive immunity
( acquired immunity/specific immunity)
Adaptive immunity:
The form of immunity that is mediated by
T or B lymphocytes and stimulated by
exposure to infectious agents.
 Take effects after innate immune response
 Be the second line of defense against
infection
1.Characteristics
 Specificity
 Acquired (set up after birth )
 Immune memory
(Adaptive immunity can be enhanced by the
second stimulation of the same antigen)
 Transferable
 Self-limitation
2.Composition
T cell : Cell-mediated immunity (CMI)
B cell : Humoral immunity(HI) or
antibody-mediated immunity
3.The process of immune
response
in adaptive immunity
Recognition of antigens
Activation,proliferation and
differenciation of T or B lymphocytes
Effector phase of immune response
----Elimination of antigens
Comparison of Adaptive and Innate
Immunity
Innate immunity
Adaptive immunity
Characteristics Exists naturally
Acquired by antigen stimulation after birth
Responds rapidly in the early
develops slowly
stage of infection
No antigen specificity
Has antigen specificity
No immune memory
Has immune memory
Participates in natural defence
Participates in specific immune response
Cells
Neutrophil,Phagocytes,NK cell et al.
T cell, B cell, APC
Molecules Complement.lysozyme,cytokines et al
Antibody,cytokines
What is immunology?
• Immune (Latin- “immunus”)
– To be free, exempt
– People survived ravages of epidemic diseases
when faced with the same disease again
• The study of physiological mechanisms that
humans and other animals use to defend
their bodies from invading organisms
– Bacteria
– Fungi
- Viruses
- Parasites
- Toxins
Immunology Terms
• Antigen
– Any molecule that binds to immunoglobulin or T cell receptor
• Pathogen
– Microorganism that can cause disease
• Antibody (Ab)
– Secreted immunoglobulin
• Immunoglobulin (Ig)
– Antigen binding molecules of B cells
• Vaccination
– Deliberate induction of protective immunity to a pathogen
• Immunization
– The ability to resist infection
Types of Immunity
• Innate Immunity
– Host defense mechanisms that act from the
start of an infection but do not adapt to a
particular pathogen
– Recognize “patterns’ of a.a., saccharides,
etc..
• Adaptive Immunity
– Response of an antigen specific B and T
lymphocytes to an antigen
– Immunological memory
Types of Immunity
• Humoral immunity
– Immunity that is mediated by antibodies
– Can be transferred by to a non-immune
recipient by serum
• Cell Mediated Immunity
– Immune response in which antigen specific T
cells dominate
Immunology cell histology
• Polymorphonuclear
– Lobed nucleus
• Mononuclear
– Non-lobed nucleus
• Granulocyte
– Many granules seen in cytoplasm
• Neutral
– Does not stain to acidic or basic compounds
• Acidic (red-pink)
– Stains to acidic compounds (Eosin)
• Basic (blue-purple)
– Stains to basic compounds
Cells of the Immune system
• Many cells of
the immune
system derived
from the bone
marrow
• Hematopoetic
stem cell
differentiation
Components of blood
Serum vs. Plasma
• Serum: cell-free liquid, minus the
clotting factors
• Plasma: cell-free liquid with clotting
factors in solution (must use an
anticoagulant)
Components of blood
Lymphocytes
• Many types; important
in both humoral and
cell-mediated immunity
• B-cells produce
antibodies
• T- cells
– Cytotoxic T cells
– Helper T cells
• Memory cells
Lymphocytes
• Plasma Cell (in tissue)
– Fully differentiaited B
cells, secretes Ab
• Natural Killer cells
– Kills cells infected with
certain viruses
– Both innate and adaptive
– Antigen presentation
Monocytes/Macrophage
• Phagocytosis and killing of
microorganisms
– Activation of T cells and
initation of immune
response
• Monocyte is a young
macrophage in blood
• There are tissue-specific
macrophages
• Antigen Presentation
Dendritic Cells
• Activation of T cells and
initiate adaptive immunity
• Found mainly in
lymphoid tissue
• Function as antigen
presenting cells (APC)
• Most potent stimulator of
T-cell response
Mast Cells
• Expulsion of parasites through
release of granules
• Histamine, leukotrienes,
chemokines, cytokines
• Also involved in allergic responses
Neutrophil
• Granulocyte
– Cytoplasmic granules
•
•
•
•
Polymorphonuclear
Phagocytosis
Short life span (hours)
Very important at “clearing” bacterial
infections
• Innate Immunity
Eosinophils
• Kills Ab-coated parasites
through degranulation
• Involved in allergic inflammation
• A granulocyte
• Double Lobed nucleus
• Orange granules contain toxic
compounds
Basophils
• Might be “blood Mast cells’
• A cell-killing cells
– Blue granules contain toxic
and inflammatory
compounds
• Important in allergic
reactions
Other Blood Cells
• Megakaryocyte
– Platelet formation
– Wound repair
• Erythrocyte
– Oxygen transport
2º
2º
1º
2º
2º
2º
2º
2º
1º
Major Tissues
• Primary Lymph
tissues
– Cells originate
or mature
• Secondary
Lymph Tissues
Immunity
• Immunity
– The ability of the body to fight infection and/or foreign invaders by
producing antibodies or killing infected cells.
• Immune System
– The system in the body responsible for maintaining homeostasis
by recognizing harmful from nonharmful organisms and produces
an appropriate response.
Foreign Invaders
• Called Pathogens
– Viruses, bacteria or
other living thing that
causes
disease/immune
response.
• Antigens
– Toxins that pathogens
produce that cause
harm to an organism.
Parts of the Immune System
1.
2.
3.
4.
Blood - White Blood Cells in particular.
Lymph nodes
Thymus Gland – Produces T Lymphocytes
Bone Marrow – Produces B Lymphocytes
How does the body fight infection/foreign invaders?
The Body’s THREE lines of Defense
First Line of Defense – The Skin
•
Provides Physical and Chemical barriers
•
•
Physical – hard to penetrate, made of indigestible keratin
Chemical – tears, sweat
Second Line of Defense – Nonspecific Immune Response
These are defenses the body uses no matter what the invader
may be. These defenses include:
–
–
–
–
Phagocytosis – done by Macrophages
Natural Cell Killers
Inflammation - caused by release of Histamine from leukocytes
Fever – caused by histamines. The fever (high temp) kills invaders by
denaturing their proteins.
Macrophage: A phagocytic cell found in the liver, spleen, brain and lungs. Travels
to all areas of the body to find and eat pathogens.
Third Line of Defense – Specific Immune Response
This is a specific response to a specific
pathogen/antigen.
• The response involves the creation of Antibodies.
Antibodies
• Y-shaped protein
molecule.
• Made up of variable and
constant regions.
• Made up of Heavy and
Light chains.
• Produced by BLymphocytes
• Function: Recognize
antigens, bind to and
deactivate them.
– Note: Variable region
recognizes the anitgens.
How an antibody operates/works?
Deactivation of a bacterium by an antibody.
The Pathway of Specific Immune Response
Step 1
Pathogens eaten by Macrophage
Step 2
Displays portion of Pathogen
on surface
Step 3
Pathogens
Helper-T cell recognizes
Pathogen
Activates B- Cell
Activates Cytotoxic
T- Cell
Memory T-Cell
Memory B-Cell
Antibodies
Kills Infected Cells
Cellular Immunity .vs. Antibody Immunity
Cellular Immunity
• Carried out by T-Cells
• Infected cells are killed by
Cytotoxic T –Cells.
Antibody or Humoral Immunity
• Carried out by B-cells
• Antibodies are produced
and dumped into blood
stream.
• Antibodies bind to
antigens and deactivate
them.
Immune Response Explained
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Antigen infects cells.
Macrophage ingests antigen and displays portion on its surface.
Helper T- Cell recognizes antigen on the surface of the
macrophage and becomes active.
Active Helper T-Cell activates Cytotoxic T-Cells and B-Cells.
Cytotoxic T-Cells divide into Active Cytotoxic T-cells and Memory
T – Cells.
Active Cytotoxic T-Cells kill infected cells.
At the same time, B-Cells divide into Plasma Cells and Memory
B- Cells.
Plasma cells produce antibodies that deactivate pathogen.
Memory T and Memory B cells remain in the body to speed up the
response if the same antigen reappears.
Supressor T-Cells stop the immune response when all antigens
have been destroyed.
Immune Response Summary
Displays copy of antigen
on surface of cell
Antigen
Macrophage
Antibody Immunity
Helper T - Cell
Cellular Immunity
Active Cytotoxic T-Cell
Kills Infected Cells
Memory T- Cell
Active B - Cell
Plasma Cell
Antibodies
Deactivates Antigens
Memory B-Cell
Primary .vs. Secondary Immune Response
• Primary Immune Response
– This is a response to an invader the First time the
invader infects the body.
• No measurable immune response for first few days.
• Next 10 – 15 days antibody production grows steadily
• Secondary Immune Response
– A more rapid response to an invader the 2nd time it
invades the body.
• Antibody production increases dramatically and in a much
shorter time period..
Primary .vs. Secondary Immune Response
Passive .vs. Active Immunity
1.
Active Immunity
This is immunity where the body is “actively” producing antibodies
to fight infection.
Ex: You have a throat infection and you are actively creating
antibodies to fight it.
Vaccination:
An injection of a weakened strain of an
infectious microbe (pathogen) that causes the body to undergo
active immunity (produce antibodies).
2.
Passive Immunity
This is immunity where antibodies are given to a
person from the blood of another person or animal.
This immunity only lasts for a short period of time.
ex: Breastfeeding mothers pass antibodies to their
children through the milk.
Autoimmune Disease
• Autoimmune diseases are diseases where the immune
system begins to attack itself.
– Ex:
• Rheumatoid Arthritis – crippling disease of the
joints.
• Lupus – disease of blood and organs.
• Multiple Sclerosis – disease of nervous system
• Cause(s):
unknown
• Cures/Treatments: No known cures. Usually treated
with drugs.
Allergies
Allergy
- An exaggerated response by the immune system to an allergen.
Allergen: a normally harmless substance that causes an allergic
reaction.
ex: dust, pollen, mould, food, insect stings
Types of Allergic reactions
There are two types of allergic reactions.
a. Immediate – occurs within seconds and normally lasts for about
30 mins.
b. Delayed – takes longer to react and can last for a much longer
time.
What happens during an allergic reaction?
•
During an allergic reaction antibodies cause histamines to be
released from certain cells.
Histamines cause:
a. Swelling of tissues
b. Release of fluids (runny noses and eyes)
c. muscle spasms (some cases)
Anaphylaxis or anaphylactic shock:
This is the sudden and severe allergic reaction to a substance that
can cause death.
Treatments for Allergies
1. Avoidance of material – especially food.
2. Epinephrine – “epi – pen”
3. Antihistamines -- benadryl
Antibodies – structure, classes and function
Objectives
By the end of the session you should be able to:
• illustrate and describe the basic structure of antibodies in terms
of heavy and light chains
• explain the structure in relation to function of the molecules
• define the terms ‘isotype’, ‘allotype’ and ‘idiotype’
• describe the structure of each of the five main classes of
antibody
• describe the location and function of each class of antibody
• define the terms ‘affinity’ and avidity’ of antibodies
Basic structure of antibodies
Primary antibody structure
IgG
The fragment antigen binding (Fab fragment) is a
region on an antibody which binds to antigens. It is
composed of one constant and one variable domain of
each of the heavy and the light chain. These domains
shape the paratope—the antigen binding site—at the
amino terminal end of the monomer. The two variable
domains bind the epitope on their specific antigens.
An epitope, also know as antigenic determinant, is the
part of a macromolecule that is recognized by the
immune system, specifically by antibodies, B cells, or
T cells. The part of an antibody that recognizes the
epitope is called a paratope. Although epitopes are
usually thought to be derived from nonself proteins,
sequences derived from the host that can be
recognized are also classified as epitopes.
Antibody structure
Binding of lysozyme to V domains of heavy and light
chains
Heavy Chain
Lysozyme
(antigen)
Light chain
Antibody heterogeneity
Isotypes
Two light chain isotypes – k and l :
Five heavy chain isotypes - m,g,d, and e
Allotypes
Genetic markers- (rather like blood groups and usually the result of
minor amino acid differences) on immunoglobulins that segregated
within the species and inherited in Mendelian fashion eg. Km (on k
light chains) and Gm (on IgG heavy chains)
Idiotypes
Each antibody varies in its amino acid sequences in the variable
regions of both heavy and light chains to create different specificities
Different classes of antibody have:
1. Different distribution within the body
2. Different primary functions (but with some overlaps)
ie. There is ‘division of labour’ within the antibody system
Ig class
Heavy chain
Light chain
IgM
m (mu)
k (kappa) or l (lambda)
IgG
g (gamma)
k (kappa) or l (lambda)
IgA
 (alpha)
k (kappa) or l (lambda)
IgE
e (epsilon)
k (kappa) or l (lambda)
IgD
d (delta)
k (kappa) or l (lambda)
IgM
Large molecule, pentameric
structure: mainly confined to the
circulation: prominent in early
responses to most antigens:
provides first line of defence
against bacteraemia
Antibodies - electron micrographs
IgM (pentameric)
IgA (dimeric)
IgG
Predominant antibody in internal
body fluids, including extravascular
sites where it combats microbes
and toxins; only class of antibody
to cross the placenta to provide the
newborn with protection
IgA
Provides the primary defence against local infections owing to its
abundance in saliva, tears, bronchial secretions, nasal mucosa,
prostatic fluid, vaginal secretions and mucous secretions in the
small intestine
IgE
Provides protection at mucosal surfaces where
it enhances acute inflammation through mast
cells and recruits anti-microbial agents; is
raised in parasitic infections; is responsible for
the symptoms of allergies
IgD
Mostly present on the surface of B
lymphocytes with monovalent IgM where
it acts as an antigen receptor controlling
lymphocyte activation and suppression
Summary of different classes and subclasses of antibodies
Antigenic determinants (epitopes) recognised
by antibodies
Physical forces holding antibodies and antigen together
Affinity and avidity of antibodies
Affinity
The tightness with which the antigen binding site attaches to an
antigen determinant (epitope)
Avidity
The tightness of binding when several antigen binding sites
attach to several antigenic determinants
Immunoglobulin
Immunoglobulin




Element of adaptive immune mechanism
Better known as antibody
It recognize the foreign objects
How they work (examples)


Animation1
Animation2
Structure of immunoglobulin

Two identical
heavy (H) chains
and two identical
light (L) chains
combine to form
this Y-shaped
antibody molecule
Disulfide bonds



Bonds between two amino acids result of the SH
(sulfhydral) group of one amino acid covalently
bonding to the SH group of another amino acid
Stronger than hydrogen bonds
Eg. Hair proteins are held together by disulfide bonds
Heavy chains

The heavy chains
each have four
domains


Variable domains
(VH)
Constant domains
(CH1,2,3)
Light chain

The light chains
are constructed of
two domains


Variable (VL)
Constant (CL)
Structure of immunoglobulin



The fragment antigen
binding (Fab fragment)
The fragment crystallizable
region (Fc region)
Antibodies bind to antigens
by reversible, noncovalent
interactions, including
hydrogen bonds and
charge interactions
How variety is maintained



The variable heavy chain is coded
combining 3 genes (VH, DH, JH)
The variable light chain is coded
combining 2 genes (VL, JL)
Most likely humans produce between
107 and 109 different shaped Fabs
Antibody Fab region



Antibody (Fab)
molecular surface, with
the PorA antigen
superimposed.
The dark colored groove
on the surface of the
antibody matches
precisely the shape of
the PorA antigen
Any changes in the
sequence of PorA in this
region can disrupt
antibody binding
http://www.bact.wisc.edu/themicrobialworld/neisseria.html
Antigen binding some pictures
Antigen binding some pictures
Structure of immunoglobulin

Functional
consequences:


(VH) and (VL) are
positioned to
stereochemically
react with antigen
The stem is good
for mediate
effector functions
Hinge


Two disulfide bonds in the
hinge region unite the two
heavy chains
The hinge allows the two
antigen-binding Fab regions
of each antibody molecule
to move
Conclusion


Changes in the antigen binding site
conformation are vital for antigen
recognition
Herewith the variety of antibody
conformation is vital for our health
Reference








http://www.callutheran.edu/Academic_Programs/Departments/BioDev/omm/jmol/ig_div/start.html
http://en.wikipedia.org/
http://www.path.cam.ac.uk/~mrc7/mikeimages.html
http://www.tulane.edu/~biochem/med/igg.htm
http://www.biology.arizona.edu/IMMUNOLOGY/tutorials/antibody/structure.html
http://student.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/abystructure/abystructure.html
http://www.mun.ca/biochem/courses/3107/Topics/Antibodies.html
Abul K. Abbas, Andrew H. Lichtman. Basic Immunology Functions and Disorders of the Immune System.
Second Edition 2004
Humoral Immunity



Results in production of proteins called
“immunoglobulins” or “antibodies”.
Body exposed to “foreign” material
termed “antigen” which may be
harmful to body: virus, bacteria, etc.
Antigen has bypassed other protective
mechanisms, ie, first and second line
of defense.
Dynamics of Antibody Production

Primary immune response




Latent period
Gradual rise in antibody production taking
days to weeks
Plateau reached
Antibody level declines
Dynamics of Antibody Production

Antibody production





Initial antibody produced in IgM
Lasts 10-12 days
Followed by production of IgG
Lasts 4-5 days
Without continued antigenic challenge
antibody levels drop off, although IgG
may continue to be produced.
Secondary Response




Second exposure to SAME antigen.
Memory cells are a beautiful thing.
Recognition of antigen is immediate.
Results in immediate production of
protective antibody, mainly IgG but
may see some IgM
Humoral Immune Response
Dynamics of Antibody Production
Cellular Events




Antigen is “processed” by T
lymphocytes and macrophages.
Possess special receptors on surface.
Termed “antigen presenter cell” APC.
Antigen presented to B cell
Basic Antibody Structure

Two identical heavy chains





Gamma
Delta
Alpha
Mu
Epsilon
Basic Antibody Structure

Two identical light chains


Kappa OR
Lambda
Basic Antibody Structure
Basic Structure of Immunoglobulins
IgG





Most abundant
Single structural unit
Gamma heavy chains
Found intravascularly AND
extravascularly
Coats organisms to enhance
phagocytosis (opsonization)
IgG



Crosses placenta – provides baby with
immunity for first few weeks of infant’s
life.
Capable of binding complement which
will result in cell lysis
FOUR subclasses – IgG1, IgG2, IgG3
and IgG4
IgG
IgA





Alpha heavy chains
Found in secretions
Produced by lymphoid tissue
Important role in respiratory, urinary
and bowel infections.
15-10% of Ig pool
Secretory IgA


Exists as TWO basic structural units, a
DIMER
Produced by cells lining the mucous
membranes.
Secretory IgA
IgA



Does NOT cross the placenta.
Does NOT bind complement.
Present in LARGE quantities in breast
milk which transfers across gut of
infant.
IgM







Mu heavy chains
Largest of all Ig – PENTAMER
10% of Ig pool
Due to large size restricted to intravascular
space.
FIXES COMPLEMENT.
Does NOT cross placenta.
Of greatest importance in primary immune
response.
IgM
IgE








Epsilon heavy chains
Trace plasma protein
Single structural unit
Fc region binds strongly to mast cells.
Mediates release of histamines and
heparin>allergic reactions
Increased in allergies and parasitic
infections.
Does NOT fix complement
Does NOT cross the placenta
IgE
IgD







Delta heavy chains.
Single structural unit.
Accounts for less than 1% of Ig pool.
Primarily a cell bound Ig found on the surface of B
lymphocytes.
Despite studies extending for more than 4 decades,
a specific role for serum IgD has not been defined
while for IgD bound to the membrane of many B
lymphocytes, several functions have been
proposed.
Does NOT cross the placenta.
Does NOT fix complement.
Cellular Immune Response



Important in defending against: fungi,
parasites, bacteria.
Responsible for hypersensitivity,
transplant rejection, tumor
surveillance.
Thymus derived (T) lymphocytes
Cell Mediated Reaction



Helper T cells – turn on immune
response
Suppressor T cells – turn off immune
response
Cytotoxic T cells directly attack antigen
Cell Mediated Immunity
The Immune System:
Innate and Adaptive
Body Defenses
Antibodies
 Also called immunoglobulins
 Constitute the gamma globulin portion of blood
proteins
 Are soluble proteins secreted by activated B cells
and plasma cells in response to an antigen
 Are capable of binding specifically with that
antigen
 There are five classes of antibodies: IgD, IgM, IgG,
IgA, and IgE
Classes of Antibodies
 IgD – monomer attached to the surface of B cells, important
in B cell activation
 IgM – pentamer released by plasma cells during the primary
immune response
 IgG – monomer that is the most abundant and diverse
antibody in primary and secondary response; crosses the
placenta and confers passive immunity
 IgA – dimer that helps prevent attachment of pathogens to
epithelial cell surfaces
 IgE – monomer that binds to mast cells and basophils,
causing histamine release when activated
Basic Antibody Structure
 Consists of four looping polypeptide chains linked
together with disulfide bonds
 Two identical heavy (H) chains and two identical
light (L) chains
 The four chains bound together form an antibody
monomer
 Each chain has a variable (V) region at one end and
a constant (C) region at the other
 Variable regions of the heavy and light chains
combine to form the antigen-binding site
Basic Antibody Structure
Figure 21.12a, b
Antibody Structure
 Antibodies responding to different antigens have different V
regions but the C region is the same for all antibodies in a
given class
 C regions form the stem of the Y-shaped antibody and:
 Determine the class of the antibody
 Serve common functions in all antibodies
 Dictate the cells and chemicals that the antibody can bind to
 Determine how the antibody class will function in
elimination of antigens
Mechanisms of Antibody Diversity
 Plasma cells make over a billion different types of antibodies
 Each cell, however, only contains 100,000 genes that code
for these polypeptides
 To code for this many antibodies, somatic recombination
takes place
 Gene segments are shuffled and combined in different ways
by each B cell as it becomes immunocompetent
 Information of the newly assembled genes is expressed as B
cell receptors and as antibodies
Antibody Diversity
 Random mixing of gene segments makes unique
antibody genes that:
 Code for H and L chains
 Account for part of the variability in antibodies
 V gene segments, called hypervariable regions,
mutate and increase antibody variation
 Plasma cells can switch H chains, making two or
more classes with the same V region
Antibody Targets
 Antibodies themselves do not destroy antigen; they
inactivate and tag it for destruction
 All antibodies form an antigen-antibody (immune)
complex
 Defensive mechanisms used by antibodies are
neutralization, agglutination, precipitation, and
complement fixation
Complement Fixation and Activation
 Complement fixation is the main mechanism used against
cellular antigens
 Antibodies bound to cells change shape and expose
complement binding sites
 This triggers complement fixation and cell lysis
 Complement activation:
 Enhances the inflammatory response
 Uses a positive feedback cycle to promote phagocytosis
 Enlists more and more defensive elements
Other Mechanisms of Antibody Action
 Neutralization – antibodies bind to and block
specific sites on viruses or exotoxins, thus
preventing these antigens from binding to receptors
on tissue cells
Other Mechanisms of Antibody Action
 Agglutination – antibodies bind the same
determinant on more than one antigen
 Makes antigen-antibody complexes that are crosslinked into large lattices
 Cell-bound antigens are cross-linked, causing
clumping (agglutination)
 Precipitation – soluble molecules are cross-linked
into large insoluble complexes
Mechanisms of Antibody Action
Figure 21.13
Monoclonal Antibodies
 Commercially prepared antibodies are used:
 To provide passive immunity
 In research, clinical testing, and treatment of certain
cancers
 Monoclonal antibodies are pure antibody
preparations
 Specific for a single antigenic determinant
 Produced from descendents of a single cell
Monoclonal Antibodies
 Hybridomas – cell hybrids made from a fusion of a
tumor cell and a B cell
 Have desirable properties of both parent cells –
indefinite proliferation as well as the ability to
produce a single type of antibody
Cell-Mediated Immune Response
 Since antibodies are useless against intracellular antigens,
cell-mediated immunity is needed
 Two major populations of T cells mediate cellular immunity
 CD4 cells (T4 cells) are primarily helper T cells (TH)
 CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy
cells harboring foreign antigens
 Other types of T cells are:
 Suppressor T cells (TS)
 Memory T cells
Major Types of T Cells
Figure 21.14
Importance of Humoral Response
 Soluble antibodies
 The simplest ammunition of the immune response
 Interact in extracellular environments such as body
secretions, tissue fluid, blood, and lymph
The Humoral Immune Response (HIR) is the aspect
of immunity that is mediated by secreted antibodies
(as opposed to cell-mediated immunity which involves
T lymphocytes) produced in the cells of the B
lymphocyte lineage (B cell). Secreted antibodies bind
to antigens on the surfaces of invading microbes
(such as viruses or bacteria), which flags them for
destruction.[1] Humoral immunity is called as such,
because it involves substances found in the humours,
or body fluids.
Importance of Cellular Response
 T cells recognize and respond only to processed
fragments of antigen displayed on the surface of
body cells
 T cells are best suited for cell-to-cell interactions,
and target:
 Cells infected with viruses, bacteria, or intracellular
parasites
 Abnormal or cancerous cells
 Cells of infused or transplanted foreign tissue
Antigen Recognition and MHC Restriction
 Immunocompetent T cells are activated when the V
regions of their surface receptors bind to a
recognized antigen
 T cells must simultaneously recognize:
 Nonself (the antigen)
 Self (a MHC protein of a body cell)
The major histocompatibility complex (MHC) is a large
genomic region or gene family found in most vertebrates. It is
the most gene-dense region of the mammalian genome and
plays an important role in the immune system, autoimmunity,
and reproductive success. The proteins encoded by the MHC
are expressed on the surface of cells in all jawed vertebrates,
and display both self antigens (peptide fragments from the
cell itself) and nonself antigens (e.g. fragments of invading
microorganisms) to a type of white blood cell called a T cell
that has the capacity to kill or co-ordinate the killing of
pathogens, infected or malfunctioning cells.
MHC Proteins
 Both types of MHC proteins are important to T cell
activation
 Class I MHC proteins
 Always recognized by CD8 T cells
 Display peptides from endogenous antigens
Class I MHC Proteins
 Endogenous antigens are:
 Degraded by proteases and enter the endoplasmic
reticulum
 Transported via TAP (transporter associated with
antigen processing)
 Loaded onto class I MHC molecules
 Displayed on the cell surface in association with a
class I MHC molecule
Class I MHC Proteins
Figure 21.15a
Class II MHC Proteins
 Class II MHC proteins are found only on mature B
cells, some T cells, and antigen-presenting cells
 A phagosome containing pathogens (with exogenous
antigens) merges with a lysosome
 Invariant protein prevents class II MHC proteins
from binding to peptides in the endoplasmic
reticulum
Class II MHC Proteins
 Class II MHC proteins migrate into the phagosomes
where the antigen is degraded and the invariant
chain is removed for peptide loading
 Loaded Class II MHC molecules then migrate to the
cell membrane and display antigenic peptide for
recognition by CD4 cells
Class II MHC Proteins
Figure 21.15b
Antigen Recognition
 Provides the key for the immune system to
recognize the presence of intracellular
microorganisms
 MHC proteins are ignored by T cells if they are
complexed with self protein fragments
Antigen Recognition
 If MHC proteins are complexed with endogenous or
exogenous antigenic peptides, they:
 Indicate the presence of intracellular infectious
microorganisms
 Act as antigen holders
 Form the self part of the self-antiself complexes
recognized by T cells
T Cell Activation: Step One – Antigen Binding
 T cell antigen receptors (TCRs):
 Bind to an antigen-MHC protein complex
 Have variable and constant regions consisting of
two chains (alpha and beta)
T Cell Activation: Step One – Antigen Binding
 MHC restriction – TH and TC bind to different
classes of MHC proteins
 TH cells bind to antigen linked to class II MHC
proteins
 Mobile APCs (Langerhans’ cells) quickly alert the
body to the presence of antigen by migrating to the
lymph nodes and presenting antigen
T Cell Activation: Step One – Antigen Binding
 TC cells are activated by antigen fragments
complexed with class I MHC proteins
 APCs produce co-stimulatory molecules that are
required for TC activation
 TCR that acts to recognize the self-antiself complex
is linked to multiple intracellular signaling pathways
 Other T cell surface proteins are involved in antigen
binding (e.g., CD4 and CD8 help maintain coupling
during antigen recognition)
T Cell Activation: Step One – Antigen Binding
Figure 21.16
T Cell Activation: Step Two – Co-stimulation
 Before a T cell can undergo clonal expansion, it
must recognize one or more co-stimulatory signals
 This recognition may require binding to other
surface receptors on an APC
 Macrophages produce surface B7 proteins when
nonspecific defenses are mobilized
 B7 binding with the CD28 receptor on the surface of
T cells is a crucial co-stimulatory signal
 Other co-stimulatory signals include cytokines and
interleukin 1 and 2
T Cell Activation: Step Two – Co-stimulation
 Depending on receptor type, co-stimulators can
cause T cells to complete their activation or abort
activation
 Without co-stimulation, T cells:
 Become tolerant to that antigen
 Are unable to divide
 Do not secrete cytokines
T Cell Activation: Step Two – Co-stimulation
 T cells that are activated:
 Enlarge, proliferate, and form clones
 Differentiate and perform functions according to
their T cell class
T Cell Activation: Step Two – Co-stimulation
 Primary T cell response peaks within a week after
signal exposure
 T cells then undergo apoptosis between days 7 and
30
 Effector activity wanes as the amount of antigen
declines
 The disposal of activated effector cells is a
protective mechanism for the body
 Memory T cells remain and mediate secondary
responses to the same antigen
Cytokines
 Mediators involved in cellular immunity, including
hormonelike glycoproteins released by activated T
cells and macrophages
 Some are co-stimulators of T cells and T cell
proliferation
 Interleukin 1 (IL-1) released by macrophages costimulates bound T cells to:
 Release interleukin 2 (IL-2)
 Synthesize more IL-2 receptors
Cytokines
 IL-2 is a key growth factor, which sets up a positive
feedback cycle that encourages activated T cells to
divide
 It is used therapeutically to enhance the body’s
defenses against cancer
 Other cytokines amplify and regulate immune and
nonspecific responses
Cytokines
 Examples include:
 Perforin and lymphotoxin – cell toxins
 Gamma interferon – enhances the killing power of
macrophages
 Inflammatory factors
Helper T Cells (TH)
 Regulatory cells that play a central role in the
immune response
 Once primed by APC presentation of antigen, they:
 Chemically or directly stimulate proliferation of
other T cells
 Stimulate B cells that have already become bound
to antigen
 Without TH, there is no immune response
Helper T Cells (TH)
Figure 21.17a
Helper T Cell
 TH cells interact directly with B cells that have antigen
fragments on their surfaces bound to MHC II receptors
 TH cells stimulate B cells to divide more rapidly and begin
antibody formation
 B cells may be activated without TH cells by binding to T
cell–independent antigens
 Most antigens, however, require TH co-stimulation to
activate B cells
 Cytokines released by TH amplify nonspecific defenses
Helper T Cells
Figure 21.17b
Cytotoxic T Cell (Tc)
 TC cells, or killer T cells, are the only T cells that can
directly attack and kill other cells
 They circulate throughout the body in search of body cells
that display the antigen to which they have been sensitized
 Their targets include:
 Virus-infected cells
 Cells with intracellular bacteria or parasites
 Cancer cells
 Foreign cells from blood transfusions or transplants
Cytotoxic T Cells
 Bind to self-antiself complexes on all body cells
 Infected or abnormal cells can be destroyed as long
as appropriate antigen and co-stimulatory stimuli
(e.g., IL-2) are present
 Natural killer cells activate their killing machinery
when they bind to MICA receptor
 MICA receptor – MHC-related cell surface protein
in cancer cells, virus-infected cells, and cells of
transplanted organs
Mechanisms of Tc Action
 In some cases, TC cells:
 Bind to the target cell and release perforin into its
membrane
 In the presence of Ca2+ perforin causes cell lysis
by creating transmembrane pores
 Other TC cells induce cell death by:
 Secreting lymphotoxin, which fragments the target
cell’s DNA
 Secreting gamma interferon, which stimulates
phagocytosis by macrophages
Mechanisms of Tc Action
Figure 21.18a, b
Other T Cells
 Suppressor T cells (TS) – regulatory cells that
release cytokines, which suppress the activity of
both T cells and B cells
 Gamma delta T cells (Tgd) – 10% of all T cells
found in the intestines that are triggered by binding
to MICA receptors
Summary of the Primary Immune Response
Figure 21.19
Organ Transplants
 The four major types of grafts are:
 Autografts – graft transplanted from one site on the
body to another in the same person
 Isografts – grafts between identical twins
 Allografts – transplants between individuals that
are not identical twins, but belong to same species
 Xenografts – grafts taken from another animal
species
Prevention of Rejection
 Prevention of tissue rejection is accomplished by
using immunosuppressive drugs
 However, these drugs depress patient’s immune
system so it cannot fight off foreign agents
Immunodeficiencies
 Congenital and acquired conditions in which the function or
production of immune cells, phagocytes, or complement is
abnormal
 SCID – severe combined immunodeficiency (SCID)
syndromes; genetic defects that produce:
 A marked deficit in B and T cells
 Abnormalities in interleukin receptors
 Defective adenosine deaminase (ADA) enzyme
 Metabolites lethal to T cells accumulate
 SCID is fatal if untreated; treatment is with bone marrow
transplants
Acquired Immunodeficiencies
 Hodgkin’s disease – cancer of the lymph nodes leads
to immunodeficiency by depressing lymph node
cells
 Acquired immune deficiency syndrome (AIDS) –
cripples the immune system by interfering with the
activity of helper T (CD4) cells
 Characterized by severe weight loss, night sweats,
and swollen lymph nodes
 Opportunistic infections occur, including
pneumocystis pneumonia and Kaposi’s
sarcoma
AIDS
 Caused by human immunodeficiency virus (HIV)
transmitted via body fluids – blood, semen, and vaginal
secretions
 HIV enters the body via:
 Blood transfusions
 Contaminated needles
 Intimate sexual contact, including oral sex
 HIV:
 Destroys TH cells
 Depresses cell-mediated immunity
AIDS
 HIV multiplies in lymph nodes throughout the
asymptomatic period
 Symptoms appear in a few months to 10 years
 Attachment
 HIV’s coat protein (gp120) attaches to the CD4
receptor
 A nearby protein (gp41) fuses the virus to the target
cell
AIDS
 HIV enters the cell and uses reverse transcriptase to
produce DNA from viral RNA
 This DNA (provirus) directs the host cell to make
viral RNA (and proteins), enabling the virus to
reproduce and infect other cells
AIDS
 HIV reverse transcriptase is not accurate and
produces frequent transcription errors
 This high mutation rate causes resistance to drugs
 Treatments include:
 Reverse transcriptase inhibitors (AZT)
 Protease inhibitors (saquinavir and ritonavir)
 New drugs currently being developed that block
HIV’s entry to helper T cells
Autoimmune Diseases
 Loss of the immune system’s ability to distinguish
self from nonself
 The body produces autoantibodies and sensitized TC
cells that destroy its own tissues
 Examples include multiple sclerosis, myasthenia
gravis, Graves’ disease, Type I (juvenile) diabetes
mellitus, systemic lupus erythematosus (SLE),
glomerulonephritis, and rheumatoid arthritis
Mechanisms of Autoimmune Diseases
 Ineffective lymphocyte programming – self-reactive
T and B cells that should have been eliminated in
the thymus and bone marrow escape into the
circulation
 New self-antigens appear, generated by:
 Gene mutations that cause new proteins to appear
 Changes in self-antigens by hapten attachment or as
a result of infectious damage
Mechanisms of Autoimmune Diseases
 If the determinants on foreign antigens resemble
self-antigens:
 Antibodies made against foreign antigens crossreact with self-antigens
Hypersensitivity
 Immune responses that cause tissue damage
 Different types of hypersensitivity reactions are distinguished by:
 Their time course
 Whether antibodies or T cells are the principle immune elements
involved
 Antibody-mediated allergies are immediate and subacute
hypersensitivities
 The most important cell-mediated allergic condition is delayed
hypersensitivity
Immediate Hypersensitivity
 Acute (type I) hypersensitivities begin in seconds
after contact with allergen
 Anaphylaxis – initial allergen contact is
asymptomatic but sensitizes the person
 Subsequent exposures to allergen cause:
 Release of histamine and inflammatory
chemicals
 Systemic or local responses
Immediate Hypersensitivity
 The mechanism involves IL-4 secreted by T cells
 IL-4 stimulates B cells to produce IgE
 IgE binds to mast cells and basophils causing them
to degranulate, resulting in a flood of histamine
release and inducing the inflammatory response
Acute Allergic Response
Figure 21.20
Anaphylaxis
 Reactions include runny nose, itching reddened skin,
and watery eyes
 If allergen is inhaled, asthmatic symptoms appear –
constriction of bronchioles and restricted airflow
 If allergen is ingested, cramping, vomiting, or
diarrhea occur
 Antihistamines counteract these effects
Anaphylactic Shock
 Response to allergen that directly enters the blood (e.g.,
insect bite, injection)
 Basophils and mast cells are enlisted throughout the body
 Systemic histamine releases may result in:
 Constriction of bronchioles
 Sudden vasodilation and fluid loss from the bloodstream
 Hypotensive shock and death
 Treatment – epinephrine is the drug of choice
Subacute Hypersensitivities
 Caused by IgM and IgG, and transferred via blood
plasma or serum
 Onset is slow (1–3 hours) after antigen exposure
 Duration is long lasting (10–15 hours)
 Cytotoxic (type II) reactions
 Antibodies bind to antigens on specific body cells,
stimulating phagocytosis and complement-mediated
lysis of the cellular antigens
 Example: mismatched blood transfusion reaction
Subacute Hypersensitivities
 Immune complex (type III) hypersensitivity
 Antigens are widely distributed through the body or
blood
 Insoluble antigen-antibody complexes form
 Complexes cannot be cleared from a particular area
of the body
 Intense inflammation, local cell lysis, and death
may result
 Example: systemic lupus erythematosus (SLE)
Delayed Hypersensitivities (Type IV)
 Onset is slow (1–3 days)
 Mediated by mechanisms involving delayed
hypersensitivity T cells and cytotoxic T cells
 Cytokines from activated TC are the mediators of the
inflammatory response
 Antihistamines are ineffective and corticosteroid
drugs are used to provide relief
Delayed Hypersensitivities (Type IV)
 Example: allergic contact dermatitis (e.g., poison
ivy)
 Involved in protective reactions against viruses,
bacteria, fungi, protozoa, cancer, and rejection of
foreign grafts or transplants
Developmental Aspects
 Immune system stem cells develop in the liver and
spleen by the ninth week
 Later, bone marrow becomes the primary source of
stem cells
 Lymphocyte development continues in the bone
marrow and thymus system begins to wane
Developmental Aspects
 TH2 lymphocytes predominate in the newborn, and
the TH1 system is educated as the person encounters
antigens
 The immune system is impaired by stress and
depression
 With age, the immune system begins to wane