Microbiology- a clinical approach by Anthony
Strelkauskas et al. 2010
Chapter 16: The adaptive immune response



The adaptive immune response is a very powerful
system that protects us from a multitude of
infectious organisms.
It has the gift of memory, which provides rapidly a
more powerful reaction if the same pathogen is
seen again. This is the basis for vaccinations.
Without the adaptive immune response we would
not survive.


The adaptive immune response is
the second line of defense.
The innate response is a
prerequisite for the adaptive
immune response.
◦ Alerts and activates the adaptive immune
response via cytokines and chemokines.
◦ Presents antigens

Dendritic cells are the most
important innate cells for the
proper development of an
adaptive immune response. This is
because:
◦ They take up and process antigens.
◦ They migrate to lymph nodes and present
antigens to T cells.
◦ They have enormous surface areas and can
interact with many different T cells.

The adaptive immune response involves
lymphocytes which develop from the
hematopoietic stem cell in the bone marrow
◦ B-lymphocytes (B cells)
◦ T-lymphocytes (T cells)

It is a response to specific antigens via highly
specific antigen receptors
◦ Antibody molecule on B cells
◦ T cell receptor on T cells


It can adapt to any infection.
It has memory.
◦ This confers life-long immunity.

The adaptive immune response has two types of
response:
◦ Humoral – production of antibodies by B cells
◦ Cellular – strengthening immune cells and killing and
regulation of infected cells by T cells

Antigen is any molecule that can induce a
specific adaptive immune response.
◦ Originally defined as antibody generating agent


There are two types of antigens:
◦ Self
◦ Non-self
During early cell development or maturation
lymphocytes are schooled to become tolerant
for self antigens.
◦ B cells mature in the bone marrow
◦ T cells mature in the thymus

The adaptive response is associated with the
lymphatic system.
◦ It patrols (almost ) the entire body.
◦ It involves lymphocytes and lymphoid structures such
as lymph nodes.
The strategic placement of these
lymphoid structures makes it
possible for the adaptive immune
system to deal with potential
pathogens from almost any place
that is involved in infection.

Strategic lymphoid structures are found in
places where pathogens typically enter.
◦ GALT – gut associated lymphoid tissue
 Examples include the tonsils, adenoids, appendix, and
Peyer’s patches.
◦ BALT – bronchial associated lymphoid tissue
 Associated with the respiratory portal of entry
 Most available portal of entry
◦ MALT – mucosal associated lymphoid tissue
 Associated with mucous membranes
 An important portal of entry




Peyer’s patches are the most important part of
GALT.
They contain M cells (M for microfold).
M cells are antigen collecting cells.
Under M cells are germinal centers
◦ Filled with B cells
◦ Surrounded by T cells
 There
are two types of T cell:
◦ Helper T cells (TH)
◦ Cytotoxic (CTL)

Helper T cells differentiate into subtypes
including:
◦ TH1 cells
◦ TH2 cells


TH1 cells activate macrophages to synthesize
more antimicrobial factors
TH2 cells instruct B cells to make large
amounts antibodies which in turn block
pathogens from entering the body and improve
phagocytosis

Cytotoxic T cells kill host cells that have been
taken over by specific microbes
◦ Virus infected
◦ Cells infected with intracellular bacteria
◦ Protozoan infected cells

Cytotoxic T cells kill similar to NK cells, they
command the target cell to commit suicide.
However, they only target specific cells which they
recognize with their antigen receptor.

When B cells and T cells mature, they acquire
specific antigen receptors.
◦ The B cell receptor is an immunoglobulin (antibody)
molecule.
 It has two antigen binding sites.
◦ The T cell receptor is related to immunoglobulins , but
 It has only one antigen binding site.
B cell
T cell


Once lymphocytes passed schooling and are found
not to react with self they are released into the
bloodstream and they continuously circulate the
lymphatic system.
If an antigen is encountered and fits to the antigen
receptor on the lymphocyte, the lymphocyte is
activated.
 It begins to divide and proliferate.
 It forms a clone of cells specific for one antigen.

Lymphocytes that never encounter antigen
eventually die.

Once signaled, lymphocytes stop migrating and
become activated.
They become larger and multiply.

They differentiate into effector cells


◦ They multiply fourfold every 24 hours for 3-5 days.
◦ B cells become Plasma cells that are antibody factories.
◦ T cells become armed effector cells that put out a huge
amount of cytokines (TH) or kill the target cells (CTL)
Some will differentiate into memory cells that are
able to quickly become effector cells upon restimulation



The consequences of lymphocyte activation are
dramatic.
As a safeguard, antigen that binds to the antigen
receptor is not enough to trigger a full adaptive
response.
Other danger signals must be present, called costimulatory signals:
◦ Pro-inflammatory cytokines
◦ Other cell surface molecules expressed only under stress
◦ TLR binding.


Once the infection is cleared lymphocytes are no
longer stimulated and will die by apoptosis
Lymphocytes never activated also die by “neglect”, or
also entering the apoptotic pathway.



B cells recognize native antigens.
T cells cannot detect native antigen. They can
see antigen only after it has been processed
(degraded, taken apart) into short amino acid
stretches and placed onto a specialized
molecule, the major histocompatibility
complex (MHC).
There are two types of MHC:
◦ Class I is found on all cells.
◦ Class II is found only on specialized antigen
presenting cells
 Monocytes/macrophages, dendritic cell, B cells


Antigens are delivered by the MHC
in different ways:
Class I molecules associate with
cytoplasmic or endogenous
antigens.
◦ They present to cytotoxic T cells.
◦ These antigens are derived from
microbes replicating in the host cell.

MHC I
Class II molecules associate with
antigens from phagocytic cell
vesicles or exogenous.
◦ They present to helper T cells.
◦ These antigens are degradation
products from the phagolysosome.
MHC II
CTL
TH

T cell receptors must recognize both the antigen and
the MHC.
◦ This is referred to as the antigen-MHC complex.

Additional molecules are required to make sure that the
right T cell acts on the right target cell
◦ T helper cells should only act on immune cells that need help
to deal with the invading microbe
◦ Cytotoxic T cells should only kill infected cells that have been
taken over by the microbe.

To guarantee this there are additional molecules
involved in the formation of the antigen-MHC complex.
◦ CD 4 on T helper cells binds to MHC class II
◦ CD8 on cytotoxic T cells binds to MHC class I
TH
CTL
Induce apoptosis
INFg
Cytotoxic
granules
Cytokines
Ag presenting cell
Any nucleated cell
Note: antigen and antigen receptor are omitted.
CD
MHC
(on T cell)
(on target cell)
T Helper cells
CD4
MHC II
Cytokine production
Augmentation of immune
response
Cytotoxic T cells
CD8
MHC I
Release of cytotoxic
granules
Apoptosis of target cell
Cell Type
Effect


T cells can respond to superantigens.
◦ These are distinct classes of antigens produced by many
pathogens.
Superantigens do not need to be bound to the MHC
to be recognized.
◦ They can bind to the outside of MHC molecules.



They cause massive overproduction of cytokines.
They cause systemic toxicity and suppression of
the adaptive response.
Example: toxic shock syndrome toxin




First described in menstruating women using certain types of
tampons
High fever, rash, skin peeling in palms, shock, multiple organ
failure
Staphylococcus TSST production triggered in high absorbency
tampons
TSST resorption through vaginal mucosa
A.
B.
C.
D.
E.
bind to antigen
presented on MHC
I.
express CD8.
Release INFg to
stimulate
macrophages.
All of the above is
correct.
None of the above
is correct.
A.
B.
C.
D.
E.
that they both induce
apoptosis in the target
cell.
that they release
cytotoxic granules.
they recognize only
specific infected cells.
that they can kill more
than one cell.
All of the above are
correct.



The humoral response is carried out by B
lymphocytes.
It involves the production of the antibody.
In most cases, activation of B cells requires
help from T cells.
◦ Some B cells proliferate and differentiate into plasma
cells.
◦ Plasma cells produce massive amounts of antibody.
◦ Some B cells become memory cells.


Antibodies are found in the blood and in
extracellular spaces.
They contribute to the adaptive response in three
ways:
◦ Neutralization
 Neutralizes toxins and viruses
 Prevents bacterial attachment
◦ Opsonization
 Facilitates uptake of pathogens by phagocytic cells
◦ Complement
 Activates the classical pathway


Antibodies are also called immunoglobulins (Ig).
All Ig molecules have a Y shape.
◦ They are composed of 4 polypeptide chains.
 Two light chains
 Two heavy chains
◦ The 4 amino terminal ends make up the antigen-binding
site.
◦ Remainders of the heavy chains make up the constant
region that interacts with host cells
 E.g. phagocytes




Is based on contacts between the antigen and
binding site.
Depends on the size and shape of the antigen.
◦ Binding is along the side of large antigens.
Antibody binding involves hydrophobic and
electrostatic forces but is never covalent.
Antibodies are generally made against epitopes.
◦ Epitopes are small surface regions of antigens.



There are 5 isotypes:
◦
◦
◦
◦
◦
IgG
IgM
IgA
IgD
IgE
They differ in the type
of the constant region.
A B cell always makes
IgM isotype first and
then switches to other
isotypes with the help of
cytokines that have been
released by T helper
cells. The antigen binding
site remains the same.

The constant region of any immunoglobulin has
three main functions:
◦ Recognition by specialized receptors on phagocytic
cells (IgG)
◦ Forming antigen-antibody complexes that initiate
classical complement pathway (IgM, IgG)
◦ Delivering antibody to tissues and secretions (IgG,
IgA)

IgM is the first antibody to be produced.
◦ IgM can be in a pentamer structure.
 This has ten binding sites and great binding strength.
◦ It is usually found in blood.
◦ It is an excellent activator of the complement
system.
◦ It is the primary response to bloodborne pathogens.
◦ It is also found in pleural spaces.
 This protects against environmental pathogens.




IgG is smaller than IgM and can easily diffuse
out of the blood.
The principle isotype of IgG is found in the
blood and extracellular fluid.
It is very effective for opsonization and
complement activation.
It can cross the placenta and protect the
unborn embryo and fetus.
◦ IgG in a sick newborn does not prove infection!
◦ Maternal IgG lasts for about 6 - 9 months.




IgA is the principle antibody in secretions.
It is found in the respiratory and digestive
tracts.
It is present in colostrum and milk and protects
the newborn.
It is very effective in blocking pathogen
attachment to the host and toxin inactivation.

IgE is found in low levels in the blood and
extracellular fluids.
◦ It binds tightly to mast cells just below the skin and
mucosa.
◦ It is also found along the blood vessels in connective
tissue.
◦ After antigen binding, powerful chemical mediators
are released by the mast cell.
 They cause coughing, sneezing and vomiting.



IgD is found in very small amounts in the blood.
It is found on the surface of B cells.
It plays a role in B cell maturation.
A.
B.
C.
D.
E.
IgM & complement
activation
IgG & opsonin
IgA &
neutralization
IgD & placenta
transfer
All are correctly
matched.
A.
B.
C.
D.
E.
Moderate titer ++ for
IgG.
IgM ++ , IgG +++
High ++++ titer for IgG
High IgA +++
High IgD +++

Antibodies can also activate the following cells
to release their granules filled with bioactive
molecules:
◦ NK cells: IgG
◦ Basophils
IgE (important for parasitic infections)
◦ Mast cells


A substantial amount of IgE is bound to mast cells.
When bound to antigen, antibody crosslinking
causes the immediate release of histamine.
◦ This occurs in seconds.
◦ It causes an increase in blood flow – vascular dilation.
◦ It promotes the movement of blood proteins and fluids in
tissue.
◦ There is a following influx of neutrophils, macrophages, and
lymphocytes.

Photo courtesy of Ann Dvorak


B cells have an antigen receptor that is a
surface immunoglobulin molecule.
The bound antigen is endocytosed and
degraded.
◦ It is then combined with MHC class II and sent to
the surface.


The complex is recognized by helper T cells.
The B cell is activated and differentiates into a
plasma cell.
◦ It produces antibody against the antigen.

Naive B cells express both IgM and IgD on
their surface.
◦ After activation, IgD disappears.
◦ IgM is the first isotype of antibody produced.
◦ This is the primary response.

Isotype switching occurs in the secondary response.
◦ IgM gives way to IgG and later on other isotypes depending on the
cytokine
◦ INFg: IgG
◦ IL4: IgE





The secondary response occurs when the antigen is seen
again.
It is faster and more powerful than the primary response.
Helper T cells regulate the production and isotype of
antibody.
These activated B cells become plasma cells.
Some become memory cells.

Produce large amounts of antibodies of one
isotype (no more switch)
http://millette.med.sc.edu/Lab%206%20pages/Connective%20tissue%20cell
s.htm

The cellular immune response is generated by T
cells.
◦ Cytotoxic T cells
◦ Helper T cells


T cells that have not seen antigen are
considered to be naive.
After encountering antigen, both types become
armed effector T cells.

Some antigens are degraded in the cytoplasm of
infected cells.
◦ They are carried to the cell surface by class I MHC
molecules.
◦ They are then presented to cytotoxic (CD8+) T cells.

Cytotoxic T cells proliferate and look for any
cells also expressing that antigen.
◦ They will kill those cells.


Phagocytes take up antigens via phagocytosis. B cells
take up antigen via endocytosis of antigen bound to
their surface antibody .
Both cells degrade this exogenous antigen, load bits and
pieces onto MHC II, and present it to (CD4 + ) TH cells
◦ Antigen presenting cells (APC)

Helper T cells then differentiate into TH1 or TH2 cells.
◦ TH1 cells help phagocytes to improve phagocytosis and killing.
◦ TH2 cells trigger antibody production good for extracellular
organism and parasites.




Immunological memory is one of the most
important properties of the adaptive immune
response.
It can be seen in both T cells and B cells and is
produced after infection or vaccination.
Memory is due to a persistent population of
memory cells.
Most are at rest but a small percentage is
dividing at all times.
Specific antigen recognition
+
Memory
Clonal proliferation
m m
m
m
m
m
m





Innate and adaptive immune responses work
together as fully integrated systems to defeat
infection.
The end result is the control and elimination of
infection and protection from re-infection.
The innate response works primarily in the early
stages of the infection.
The adaptive immune response takes place a few
days after first exposure to an antigen.
Once pathogens have established an infection, it is
only the adaptive response that can get rid of
them.


Vaccination is essentially an artificially derived
infection.
Weakened or dead pathogens are administered
to a healthy individual with the intent of
conferring immunity.
◦ Boosters are typically required.


In many case, antigen is derived from the toxin
produced by the pathogen.
Most vaccinations are administered in
childhood.

Active versus passive
◦ Antigen is administered in active vaccinations;
antibodies are given in passive vaccinations

Live versus dead versus subcomponent vaccines
◦ An attenuated (weakened) strain is given in a live
vaccine, a dead but whole cell/agent is given in a dead
vaccine, and purified isolated antigenic compounds are
given in a subcomponent vaccine.



There can be risks with vaccinations.
Some vaccines can contain adjuvants, which are
chemicals designed to boost immune response.
In some people, adjuvants and some
preservatives in vaccines can cause adverse
reactions.
Vaccines composed of weakened pathogens may
cause a small percentage of vaccinated
individuals to become infected.






The adaptive immune response is specific and involves
both cellular and humoral responses.
T cells and B cells are involved in the adaptive immune
response.
Both T cells and B cells have receptors for antigen..
There are lymphoid structures strategically placed in
major portals of entry..
The adaptive immune response is connected to the
innate immune response.
T cells mature in the thymus, and B cells mature in
the bone marrow.





Clonal selection and deletion are processes that allow
some lymphocytes to mature while others are deleted
from the body.
T cells are initially naive and become armed effector
cells after encountering their specific antigen.
Antigen presentation involves combining antigen with
class II MHC molecules.
CD4 helper T cells recognize class II MHC molecules,
whereas CD8 cytotoxic T cells recognize class I MHC
molecules.
B cells are responsible for antibody production. B
cells differentiate into plasma cells that produce
antibody.
MICR 201 Chap 15 2013.pptx





There are five types of antibody molecule: IgG, IgM,
IgA, IgD, and IgE.
T cells direct the production of antibody.
CD8 cytotoxic T cells kill specifically identified
targets and remember them through the development
of memory cells.
CD4 helper T cells can be divided into two groups,
Th1 and Th2, each with a different helper function.
The adaptive immune response can be divided into a
primary phase and a secondary phase.



STUDY
4 units x 2-3 hours = 8-12 hours/week
LEARN
◦ Terms, Glossary
◦ Concepts

EVALUATION
◦ Lecture
◦ Chapter questions
◦ Quiz, MT, Final

Completed:

Quiz #2 = 50 pts.:

Quiz #3 = 50 pts.:

Final Exam = 200 pts. :


◦ Quiz #1 = 50 pts.
◦ Midterm = 100pts.
◦ Wed. May 15
◦ Chapter 14,15,16,17
◦ Wed. May 29
◦ Chapter 18,19,20,21
◦ Wed. June 12
◦ 65%: Chapter 14-26
◦ 35%: Chapter 1-13
Lecture, Chapter Questions
Use reading to understand lecture and Chapter questions