The Immune Response and
immune system
The Immune Response
Immunity: “Free from burden”. Ability of
an organism to recognize and defend itself
against specific pathogens or antigens.
Immune Response: Third line of defense.
Involves production of antibodies and
generation of specialized lymphocytes
against specific antigens.
Antigen: Molecules from a pathogen or
foreign organism that provoke a specific
immune response.
The Immune System is the Third Line
of Defense Against Infection
Barrier Defenses
 Barrier defenses include the skin and mucous
membranes of the respiratory, urinary, and
reproductive tracts
 Mucus traps and allows for the removal of microbes
 Many body fluids including saliva, mucus, and tears
are hostile to many microbes
 The low pH of skin and the digestive system
prevents growth of many bacteria
The First Line of Defense
~Skin~
- The dead, outer
layer of skin, known
as the epidermis,
forms a shield
against invaders and
secretes chemicals
that kill potential
invaders
- You shed between
40 – 50 thousand
skin cells every day!
The structure of the skin reflects the
complexity of its functions as a protective
barrier, in maintaining the body temperature,
in gathering sensory information from the
environment and in having an active role in
the immune system. The epidermis contains
the stratum basale, the stratum spinosum,
the stratum granulosum and the outermost
layer, the stratum corneum, which is
responsible for the vital barrier function of
the skin. Specialized cells in the epidermis
include melanocytes, which produce
pigment (melanin), and Langerhans cells.
Rare T cells, mainly CD8+ cytotoxic T cells,
can be found in the stratum basale and
stratum spinosum. The dermis is composed
of collagen, elastic tissue and reticular
fibres. It contains many specialized cells,
such as dendritic cell (DC) subsets,
including dermal DCs and plasmacytoid
DCs (pDCs), and T cell subsets, including
CD4+ T helper 1 (TH1), TH2 and TH17
cells, γδ T cells and natural killer T (NKT)
cells. In addition, macrophages, mast cells
and fibroblasts are present. Blood and
lymphatic vessels and nerves (not shown)
are also present throughout the dermis.
Ultraviolet (UV) light, trauma, irritants or infection
(essentially any type of barrier disruption) triggers a
coordinated immune response to maintain skin
homeostasis. Skin-resident immune cells are key
sentinels for restoring homeostasis but can also be
effector cells during tissue pathology. Epidermal
Langerhans cells are key immunological sentinels.
Keratinocytes sense and react to noxious stimuli by
producing pro-inflammatory cytokines (such as
interleukin-1β (IL-1β), IL-6, IL-18 and tumour necrosis
factor (TNF)), which in turn activate dermal dendritic
cells (DCs) in the presence or absence of antigen
encounter. Innate immune cells, such as plasmacytoid
DCs (pDCs), activated by stress signals derived from
keratinocytes, can also contribute to dermal DC
activation by releasing interferon-α (IFNα). Fibroblasts
can produce TNF and IL-6 and natural killer T (NKT)
cells can produce TNF and IFNγ, thereby contributing to
the local inflammatory response. Dermal DCs activate
and promote the clonal expansion of skin-resident
memory CD4+ or CD8+ T cells. T cell-derived proinflammatory
cytokines and chemokines in turn can
further stimulate epithelial and mesenchymal cells,
including keratinocytes and fibroblasts, thus amplifying
the inflammatory reaction. Moreover, skin-resident T
cells can migrate into the epidermis, engaging in an
immune–epithelial cell crosstalk.
Nonconventional T cells, such as γδ T cells and
natural killer T (NKT) cells, are involved in
skin immunosurveillance. Both γδ T cells and
NKT cells are cytolytic and release granzyme B
and perforin and cause apoptosis of
transformed or infected cells. They activate
dermal dendritic cells (DCs) by producing
tumour necrosis factor (TNF) and interferonγ
(IFNγ). Moreover, γδ T cells produce growth
factors that are essential for wound healing,
such as connective tissue growth factor
(CTGF), fibroblast growth factor 9 (FGF9; also
known as GAF) and keratinocyte growth factor
(KGF). Finally, both γδ T cells and NKT cells
produce cytokines that are usually associated
with T helper 1 (TH1), TH2 and TH17 cells.
Immune function of GIT
 Large surface
 The significance of intact gastrointestinal
mucosa
 Mucosal barrier - mucus, lysozymes,
phagocytes, pH of environment, humoral
factors
 The immune system of the digestive tract:
 Peyer plaques - lymphoid follicles, antibody
production
 Immune cells - intraepithelial lymphocytes, the
lymphocytes in the lamina propria immunoglobulin
production
 Drainage system of portal blood and lymph
The First Line of Defense
~Saliva~
What’s the first thing you do when you
cut your finger?
- Saliva contains many
chemicals that break down
bacteria
- Thousands of different types
of bacteria can survive these
chemicals, however
- Swallowed bacteria are
broken down by HCl in
the stomach
- The stomach must produce
a coating of special mucus
or this acid would eat
through the stomach!
The First Line of Defense
~Stomach Acid~
• Goblet cells – mucins
• M cells - ability to take up antigen from the lumen via endocytosis, phagocytosis,
or transcytosis to antigen presenting cells, such as dendritic cells, and
lymphocytes
• Paneth cells - synthesize and secrete substantial quantities of antimicrobial
peptides and proteins
Lungs and immunity
= opsonins to coat bacteria and viruses, thereby
promoting phagocytosis by macrophages resident in
the alveoli
Think of the human body as a
hollow plastic tube…
The food is digested within the hole in
the tube, but it never actually enters
into the solid plastic material.
Tube inner surface
~Digestive System~
Plastic
interior
~Body~
Tube outer
surface ~Skin~
Innate or Genetic Immunity: Immunity an
organism is born with.
Genetically determined.
May be due to lack of receptors or other
molecules required for infection.
 Innate human immunity to canine distemper.
 Immunity of mice to poliovirus.
Acquired Immunity:Immunity that an
organism develops during lifetime.
Not genetically determined.
May be acquired naturally or artificially.
 Development of immunity to measles in response to
infection or vaccination.
Innate versus acquired immunity
Innate immunity
 neutrophils, macrophages, NK cells
 Toll and toll-like receptors = affinity to bacterial lipopolysaccharides,
lipoproteins, peptidoglycans, DNA = molecular patterns expressed by
pathogens
Innate immunity is the first line of defense against infection. The innate immune system is composed of germ-line encoded
receptors that collectively serve as a sensor to monitor extracellular and intracellular compartments for signs of infection or
tissue injury. Since the discovery linking Toll in the fly to anti-fungal defense, seminal discoveries have identified families of
mammalian Toll-like receptors (TLRs), Nod-like receptors, Rig-I like receptors, C-type lectins, Aim2-like receptors and other
DNA sensors and highlighted their ability to recognize microbial products. Activation of innate immune sensing receptors
leads to the transcription of hundreds of genes involved in antimicrobial defense, phagocytosis, cell migration, metabolic
reprogramming, tissue repair and regulation of adaptive immunity. These responses curb pathogen growth and spread and also
mobilize the T-cells and B-cells of the adaptive immune system. The ability of the innate immune system to mobilize, instruct
and regulate adaptive immunity is well established.
Innate versus acquired immunity
Acquired
immunity
 Ability of lymphocytes to
produce antibodies (B cells)
or cell-surface receptors (T
cells) = specific!
 Antigens (proteins,
polypeptides, nucleic acids,
lipids)
 Humoral immunity –
circulating antibodies
(plasma cells, activation of
complement system,
bacterial infection)
 Cellular immunity – T-
lymphocytes
Components of Human Immune System
Reticuloendothelial system – tissue macrophage system
Types of Acquired Immunity
I. Naturally Acquired Immunity: Obtained in
the course of daily life.
A. Naturally Acquired Active Immunity:
 Antigens or pathogens enter body naturally.
Body generates an immune response to antigens.
Immunity may be lifelong (chickenpox or mumps)
or temporary (influenza or intestinal infections).
B. Naturally Acquired Passive Immunity:
Antibodies pass from mother to fetus via placenta
or breast feeding (colostrum).
No immune response to antigens.
Immunity is usually short-lived (weeks to months).
Protection until child’s immune system develops.
Types of Acquired Immunity (Continued)
II. Artificially Acquired Immunity: Obtained by
receiving a vaccine or immune serum.
1. Artificially Acquired Active Immunity:
 Antigens are introduced in vaccines (immunization).
 Body generates an immune response to antigens.
 Immunity can be lifelong (oral polio vaccine) or temporary
(tetanus toxoid).
2. Artificially Acquired Passive Immunity:
 Preformed antibodies (antiserum) are introduced into body
by injection.
 Snake antivenom injection from horses or rabbits.
 Immunity is short lived (half life three weeks).
 Host immune system does not respond to antigens.
Serum: Fluid that remains after blood has clotted
and cells have been removed.
Antiserum: Serum containing antibodies to a
specific antigen(s). Obtained from injecting an
animal (horse, rabbit, goat) with antigen (snake
venom, botulism or diphtheria toxin).
Serology: The study of reactions between
antibodies and antigens.
Gamma Globulins: Fraction of serum that
contains most of the antibodies.
Serum Sickness: Disease caused by multiple
injections of antiserum. Immune response to
foreign proteins. May cause fever, kidney
problems, and joint pain. Rare today.
Duality of Immune System
I. Humoral (Antibody-Mediated) Immunity
 Involves production of antibodies against foreign
antigens.
 Antibodies are produced by a subset of lymphocytes
called B cells.
 B cells that are stimulated will actively secrete
antibodies and are called plasma cells.
 Antibodies are found in extracellular fluids (blood
plasma, lymph, mucus, etc.) and the surface of B cells.
 Defense against bacteria, bacterial toxins, and viruses
that circulate freely in body fluids, before they enter
cells.
 Also cause certain reactions against transplanted
tissue.
Antibodies are Proteins that Recognize Specific Antigens
Duality of Immune System II. Cell
Mediated Immunity
 Involves specialized set of lymphocytes called T cells
that recognize foreign antigens on the surface of cells,
organisms, or tissues:
 Helper T cells
 Cytotoxic T cells
 T cells regulate proliferation and activity of other cells
of the immune system: B cells, macrophages,
neutrophils, etc.
 Defense against:
 Bacteria and viruses that are inside host cells and are
inaccessible to antibodies.
 Fungi, protozoa, and helminths
 Cancer cells
 Transplanted tissue
Cell Mediated Immunity is Carried Out by T Lymphocytes
Antigens
 Most are proteins or large polysaccharides from
a foreign organism.
 Microbes: Capsules, cell walls, toxins, viral capsids,
flagella, etc.
 Nonmicrobes: Pollen, egg white , red blood cell
surface molecules, serum proteins, and surface
molecules from transplanted tissue.
 Lipids and nucleic acids are only antigenic when
combined with proteins or polysaccharides.
 Molecular weight of 10,000 or higher.
 Hapten: Small foreign molecule that is not antigenic. Must be
coupled to a carrier molecule to be antigenic. Once antibodies
are formed they will recognize hapten.
Antigens
Epitope:
Small part of an antigen that interacts
with an antibody.
Any given antigen may have several
epitopes.
Each epitope is recognized by a different
antibody.
Epitopes: Antigen Regions that Interact
with Antibodies
Antibodies
 Proteins that recognize and bind to a particular
antigen with very high specificity.
 Made in response to exposure to the antigen.
 One virus or microbe may have several antigenic
determinant sites, to which different antibodies
may bind.
 Each antibody has at least two identical sites
that bind antigen: Antigen binding sites.
 Valence of an antibody: Number of antigen
binding sites. Most are bivalent.
 Belong to a group of serum proteins called
immunoglobulins (IGs).
Antibody Structure
 Monomer: A flexible Y-shaped molecule with
four protein chains:
 2 identical light chains
 2 identical heavy chains
 Variable Regions: Two sections at the end of Y’s
arms. Contain the antigen binding sites (Fab).
Identical on the same antibody, but vary from
one antibody to another.
 Constant Regions: Stem of monomer and lower
parts of Y arms.
 Fc region: Stem of monomer only. Important
because they can bind to complement or cells.
Antibody Structure
Immunoglobulin Classes
I. IgG
 Structure: Monomer
 Percentage serum antibodies: 80%
 Location: Blood, lymph, intestine
 Half-life in serum: 23 days
 Complement Fixation: Yes
 Placental Transfer: Yes
 Known Functions: Enhances phagocytosis,
neutralizes toxins and viruses, protects fetus and
newborn.
Immunoglobulin Classes
II. IgM
 Structure: Pentamer
 Percentage serum antibodies: 5-10%
 Location: Blood, lymph, B cell surface (monomer)
 Half-life in serum: 5 days
 Complement Fixation: Yes
 Placental Transfer: No
 Known Functions: First antibodies produced
during an infection. Effective against microbes and
agglutinating antigens.
Immunoglobulin Classes
III. IgA
 Structure: Dimer
 Percentage serum antibodies: 10-15%
 Location: Secretions (tears, saliva, intestine, milk),
blood and lymph.
 Half-life in serum: 6 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: Localized protection of mucosal
surfaces. Provides immunity to infant digestive
tract.
Immunoglobulin Classes
IV. IgD
 Structure: Monomer
 Percentage serum antibodies: 0.2%
 Location: B-cell surface, blood, and lymph
 Half-life in serum: 3 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: In serum function is unknown.
On B cell surface, initiate immune response.
Immunoglobulin Classes
V. IgE
 Structure: Monomer
 Percentage serum antibodies: 0.002%
 Location: Bound to mast cells and basophils
throughout body. Blood.
 Half-life in serum: 2 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: Allergic reactions. Possibly
lysis of worms.
How Do B Cells Produce Antibodies?
B cells develop from stem cells in the bone
marrow of adults (liver of fetuses).
After maturation B cells migrate to lymphoid
organs (lymph node or spleen).
Clonal Selection: When a B cell encounters an
antigen it recognizes, it is stimulated and divides
into many clones called plasma cells, which
actively secrete antibodies.
Each B cell produces antibodies that will
recognize only one antigenic determinant.
Clonal Selection of B Cells is Caused
by Antigenic Stimulation
Humoral Immunity
Apoptosis
Programmed cell death (“Falling away”).
Human body makes 100 million lymphocytes
every day. If an equivalent number doesn’t die,
will develop leukemia.
B cells that do not encounter stimulating antigen
will self-destruct and send signals to phagocytes
to dispose of their remains.
Many virus infected cells will undergo apoptosis,
to help prevent spread of the infection.
Humoral Immunity
Clonal Selection
Clonal Selection: B cells (and T cells) that
encounter stimulating antigen will proliferate into
a large group of cells.
Why don’t we produce antibodies against our
own antigens? We have developed tolerance to
them.
Clonal Deletion: B and T cells that react against
self antigens appear to be destroyed during fetal
development. Process is poorly understood.
Consequences of Antigen-Antibody Binding
Antigen-Antibody Complex: Formed when an
antibody binds to an antigen it recognizes.
Affinity: A measure of binding strength.
1. Agglutination: Antibodies cause antigens
(microbes) to clump together.
 IgM (decavalent) is more effective that IgG (bivalent).
 Hemagglutination: Agglutination of red blood cells.
Used to determine ABO blood types and to detect
influenza and measles viruses.
2. Opsonization: Antigen (microbe) is covered with
antibodies that enhances its ingestion and lysis by
phagocytic cells.
Consequences of Antibody Binding
Humoral Immunity
3. Neutralization: IgG inactivates viruses by
binding to their surface and neutralize toxins by
blocking their active sites.
4. Antibody-dependent cell-mediated cytotoxicity:
Used to destroy large organisms (e.g.: worms).
Target organism is coated with antibodies and
bombarded with chemicals from nonspecific
immune cells.
5. Complement Activation: Both IgG and IgM
trigger the complement system which results in
cell lysis and inflammation.
All three of these pathways converge on generating C3 and C5 convertase enzyme
complexes, which cleave C3 into the anaphylatoxin C3a and the opsonin C3b, and
C5 into the anaphylatoxin C5a and into C5b, respectively. Deposition of C5b onto
a target site initiates formation of the membrane attack complex (MAC) and blasts
apart the target.
Consequences of Antibody Binding
Immunological Memory
Antibody Titer: The amount of antibody in the
serum.
Pattern of Antibody Levels During Infection
Primary Response:
After initial exposure to antigen, no antibodies are
found in serum for several days.
A gradual increase in titer, first of IgM and then
of IgG is observed.
Most B cells become plasma cells, but some B cells
become long living memory cells.
Gradual decline of antibodies follows.
Immunological Memory (Continued)
Secondary Response:
Subsequent exposure to the same antigen displays
a faster and more intense antibody response.
Increased antibody response is due to the
existence of memory cells, which rapidly produce
plasma cells upon antigen stimulation.
Antibody Response After Exposure to Antigen
T Cells and Cell Mediated Immunity
Antigens that stimulate this response are mainly
intracellular.
Requires constant presence of antigen to remain
effective.
Unlike humoral immunity, cell mediated immunity
is not transferred to the fetus.
Cytokines: Chemical messengers of immune cells.
Over 100 have been identified.
Stimulate and/or regulate immune responses.
 Interleukins: Communication between WBCs.
 Interferons: Protect against viral infections.
 Chemokines: Attract WBCs to infected areas.
T Cells and Cell Mediated Immunity
Cellular Components of Immunity:
T cells are key cellular component of immunity.
T cells have an antigen receptor that recognizes
and reacts to a specific antigen (T cell receptor).
T cell receptor only recognize antigens combined
with major histocompatability (MHC) proteins on
the surface of cells.
 MHC Class I: Found on all cells.
 MHC Class II: Found on phagocytes.
Clonal selection increases number of T cells.
T Cells Only Recognize Antigen Associated
with MHC Molecules on Cell Surfaces
T Cells and Cell
Mediated Immunity
Types of T cells
1. T Helper (TH) Cells:
Central role in immune
response.
 Most are CD4+
 Recognize antigen on the surface of
antigen presenting cells (e.g.:
macrophage).
 Activate macrophages
 Induce formation of cytotoxic T cells
 Stimulate B cells to produce
antibodies.
Central Role of Helper T Cells
Types of T cells (Continued)
2. Cytotoxic T (Tc) Cells: Destroy target cells.
 Most are CD4 negative (CD4 -).
 Recognize antigens on the surface of all cells:
• Kill host cells that are infected with viruses or bacteria.
• Recognize and kill cancer cells.
• Recognize and destroy transplanted tissue.
 Release protein called perforin which forms a pore in
target cell, causing lysis of infected cells.
 Undergo apoptosis when stimulating antigen is gone.
Cytotoxic T Cells Lyse Infected Cells
Types of T cells (Continued)
3. Delayed Hypersensitivity T (TD) Cells: Mostly T
helper and a few cytotoxic T cells that are
involved in some allergic reactions (poison ivy)
and rejection of transplanted tissue.
4. T Suppressor (Ts) Cells: May shut down
immune response.
Nonspecific Cellular Components
1. Activated Macrophages: Stimulated phagocytes.
 Stimulated by ingestion of antigen
 Larger and more effective phagocytes.
 Enhanced ability to eliminate intracellular bacteria,
virus-infected and cancerous cells.
2. Natural Killer (NK) Cells:
 Lymphocytes that destroy virus infected and tumor
cells.
 Not specific. Don’t require antigen stimulation.
 Not phagocytic, but must contact cell in order to lyse it.
Relationship Between Cell-Mediated
and Humoral Immunity
1. Antibody Production
T-Dependent Antigens:
 Antibody production requires assistance from T helper cells.
 A macrophage cells ingest antigen and presents it to TH cell.
 TH cell stimulates B cells specific for antigen to become plasma
cells.
 Antigens are mainly proteins on viruses, bacteria, foreign red
blood cells, and hapten-carrier molecules.
T-Independent Antigens:
 Antibody production does not require assistance from T cells.
 Antigens are mainly polysaccharides or lipopolysaccharides with
repeating subunits (bacterial capsules).
 Weaker immune response than for T-dependent antigens.
Humoral Response to T Dependent Antigens
Humoral Response to T Dependent Antigens
Relationship Between Cell-Mediated
and Humoral Immunity
2. Antibody Dependent Cell Mediated
Cytotoxicity (ADCC)
 Target cell is covered with antibodies, leaving Fc
portion sticking outwards.
 Natural killer and other nonspecific cells that have
receptors for Fc region are stimulated to kill targeted
cells.
 Target organism is lysed by substances secreted by
attacking cells.
 Used to destroy large organisms that cannot be
phagocytosed.
Destruction of Large Parasites by ADCC