MICR 201 Microbiology for Health Related Sciences

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.

Why is this chapter important?

Map for chapter 16

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.

Introduction: initiation of the adaptive immune response

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.

Introduction: overview

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

Introduction: types of adaptive immune response

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

Introduction: antigens

Thymus gland

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.

Introduction: lymphatic system

Introduction: lymphatic system

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

Introduction: lymphoid structures

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

Peyer’s patches

M cells and Peyer’s patches

There are two types of T cell:◦Helper T cells (TH)◦Cytotoxic (CTL)

Development, differentiation, and maturation of lymphocytes

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

Development, differentiation, and maturation of lymphocytes

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.

Development, differentiation, and maturation of lymphocytes

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.

Development, differentiation, and maturation of lymphocytes

The antigen receptor of lymphocytes

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.

Clonal selection of lymphocytes

Clonal selection of lymphocytes

Once signaled, lymphocytes stop migrating and become activated.

They become larger and multiply.◦ They multiply fourfold every 24 hours for 3-5 days.

They differentiate into effector cells◦ 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 re-stimulation

Proliferation and differentiation of lymphocytes into effector cells

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 co-stimulatory 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.

Co-stimulatory signals are required for lymphocyte activation

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

Antigen presentation to T 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. 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.

Antigen presentation: delivery

MHC I CTL

MHC II 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

Antigen presentation: T cells

MHC I/II and CD 8/4 interaction

TH CTL

Any nucleated cellAg presenting cell

Cytokines Cytotoxic granules

Note: antigen and antigen receptor are omitted.

INFgInduce apoptosis

Cell Type CD(on T cell)

MHC(on target cell)

Effect

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

Effector T cells

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

T cells respond to superantigens

Toxic shock syndrome 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

T helper cells____________.A. bind to antigen

presented on MHC I.

B. express CD8.C. Release INFg to

stimulate macrophages.

D. All of the above is correct.

E. None of the above is correct.

NK cell and CTL are alike in all of the following except_______.

A. that they both induce apoptosis in the target cell.

B. that they release cytotoxic granules.

C. they recognize only specific infected cells.

D. that they can kill more than one cell.

E. 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.

The humoral B cell response

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

The humoral response: antibodies

The humoral response:Antibody production

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

The antibody molecule

The antibody molecule

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.

The antibody molecule: antigen binding

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.

Antibody (immunoglobulin) isotypes

Antibody isotypes

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)

Antibody isotypes

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.

IgM

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.

IgG

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.

IgA

Transcytosis of IgA

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.

IgE

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.

IgD

Which of the following antibody isotype & function is mismatched?A. IgM &

complement activation

B. IgG & opsoninC. IgA &

neutralizationD. IgD & placenta

transferE. All are correctly

matched.

A newborn baby has a rash and organ anomalies. You determine antibody titers against rubella. Which of the following results from the baby’s serum suggests that the baby had an intrauterine infection with rubella?

A. Moderate titer ++ for IgG.

B. IgM ++ , IgG +++C. High ++++ titer for

IgGD. High IgA +++E. High IgD +++

Antibodies can also activate the following cells to release their granules filled with bioactive molecules:◦ NK cells: IgG◦ Basophils◦ Mast cells

Antibody mediated cell activation

IgE (important for parasitic infections)

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.

Activation of mast cells by IgE

Photo courtesy of Ann Dvorak

Activation of mast cells by IgE

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.

B cell activation by T cells

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.

B cell 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.

B cell activation by T cells: secondary response

B cell primary and secondary response

Produce large amounts of antibodies of one isotype (no more switch)

Plasma cells

http://millette.med.sc.edu/Lab%206%20pages/Connective%20tissue%20cells.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.

The cellular T cell response

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.

Cytotoxic T cell: antigen encounter

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.

Helper T cells: antigen encounter

Summary of T cell effector function

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.

Immunological memory

Summary of the hallmarks of the lymphocytes

+Specific antigen recognition

Clonal proliferationm

Memory

mm

mm

mm

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.

Immunity to infection

Immunity to infection

Cellular cooperation in the immune response

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.

Vaccination

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.

Types of vaccinations

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.

Risks of vaccinations

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.

Chapter 16 key concepts

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.

Chapter 16 key concepts

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.

Chapter 16 key conceptsMICR 201 Chap 15 2013.pptx

MICR 201 Class Evaluation STUDY 4 units x 2-3 hours = 8-12 hours/week LEARN

◦ Terms, Glossary◦ Concepts

EVALUATION◦ Lecture◦ Chapter questions◦ Quiz, MT, Final

MICR 201 Evaluation: Revised Completed:

◦ Quiz #1 = 50 pts.◦ Midterm = 100pts.

Quiz #2 = 50 pts.:◦ Wed. May 15◦ Chapter 14,15,16,17

Quiz #3 = 50 pts.:◦ Wed. May 29◦ Chapter 18,19,20,21

Final Exam = 200 pts. :◦ Wed. June 12◦ 65%: Chapter 14-26◦ 35%: Chapter 1-13

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