Chapter 1 – an overview of the immune system: important concepts & principles of innate and
adaptive immunity
The immune system is responsible for: biological defense, providing protection against he diversity of
pathogens that cause human & animals infectious diseases.
- It is capable of recognizing, reacting with varying degrees of efficacy (viruses, bacteria, fungi, protozoa
and helminth parasites) and eliminating foreign organisms to attempt to colonize epithelial surfaces,
and/or invade and replicate the host tissue.
- Responsible for: inflammation response, tissue repair, response to external threat and internal
abnormal cells that arise during neoplastic transformation against cell/tissues that have been
transplanted.
The immune system is comprised of 2 related components:
1. Innate immune responses
- Earliest form of immune defense
- Intrinsically interlinked with the acute and chronic inflammatory responses
- Rapid response team
Principles of innate immunity
Epithelial barriers provide both physical and biochemical defense systems, and protect the interface between
host and environment, to prevent invasion of pathogens and infection. Innate immunity is particularly active at
anatomical sites that are likely the first contact point for pathogens, such as: skin, GI-tract, respiratory tract,
urogenital tract, mammary glands and ocular mucosa. The systems strategy for detecting the presence of an
infection as quickly as possible: utilizing pattern- recognition receptors (PRRs, not very specific) for detection
intrinsically foreign molecules called MAMPs (microbe-associated molecular patterns) that include
peptidoglycan walls, particularly prominent in Gram- positive and lipopolysaccharide (LPS; found in the outer
membrane of Gram-negative bacteria) which are not synthesized by eukaryotic cells, so they serve as markers
to indicate presence. PRRs can also be utilized for detection of substances released by damaged/dying host
cells present at the infection site, called DAMPs (damage- associated molecular patterns), they include
cytoplasmic contents that are released into the extracellular fluid as cell membranes break down and other
molecules that are synthesized as a result of the cells encountering an adverse tissue environment. Triggering
of PRRs leads to stimulation of the processes of phagocytosis and inflammation.
- Soluble PRRs are present in the plasma and tissue, or they are cell-associated, allowing cells
(particularly WBC) to sense the presence of MAMPs in the extracellular, intracellular and endosomal
compartments, which signal to the cell to deploy their biological defense systems.
- Soluble mediators that include complement proteins, which are organized into an amplification
system culmination in formation of the membrane- attack complex, that damage microbial cell walls
and production of by- products that are inflammatory.
- White blood cells are rapidly recruited to the infection side contributing to inflammatory response.
- Since viruses have simple structures that lack obvious MAMPs, the innate system finds it difficult to
detect and counteract viral infection. And some even can avoid PRR detection.
- Toll receptors (type of PRRs) bind to MAMP, PAMP and DAMP to trigger in innate response.
Kinds of cells used:
- Epithelial and stromal cells can initiate defense response through secretion of AMPs (antimicrobial
peptides) and alert the immune system by releasing cytokines(immunological hormones) and
chemokines (chemo- attractants).
- Neutrophils and tissue macrophages are adapted to recognize bacteria and engage in phagocytosis
(digestion and killing infected microorganisms).
- Eosinophils and tissue mast cells are adapted to recognize helminth parasites and react by
degranulation, releasing inflammatory, toxic and digestive enzymes onto pathogen surfaces.
, 2. Adaptive immune responses
- More complex immune system due to evolution in order to survive
- To protect against an increasing number and complexity of microorganisms that have adapted to a
more parasitic lifestyle gaining a biological advantage
- The increasing complexity of host immunity was made possible by: gene duplication (giving rise to
related immunological molecules, as pattern- recognition receptors, immunoglobulins and cytokines)
Principles of adaptive immunity
is the typically dominant form of immunity in higher species, since the innate immunity has become less
effective over evolution. The adaptive system is much more specific and more potent in its effect, but it there is
a lag period (delay) between the onset of infection and the production of an effector response, which is why the
innate system is not redundant; to keep the host alive long enough fir the adaptive immune response to have
affect.
The adaptive system is intrinsically linked to the functionality of the lymphocytes, which express cell surface
receptors to detect the presence of an antigen, since pathogens synthesize and express proteins that are
different in sequence and shape/structure compared to host cells. These protein antigens can be recognized
as foreign by lymphocyte antigen receptors (each small element of an antigen that can be recognized is an
epitope).
2 types of lymphocytes used:
1. B lymphocytes
- Express antigen receptors designed to; detect epitopes of intact antigen on the surface of pathogens in
the extracellular space
2. T lymphocytes
- Recognize digested fragments of antigen that has undergo intracellular processing and are pre3sented
on the surface of other cells, in association with a specialist carrier molecule MHC (major
histocompatibility complex).
Lymphocytes must design uniquely shaped antigen receptor during development in primary lymphoid tissues.
All lymphocytes are initially derived from lymphoid progenitors in the bone marrow, in here B cells complete
their development, while T cells must leave bone marrow and complete their development in the thymus where
they either come beCD4+ or CD8+ T cells.
- During development, antigen receptor diversity is engineered by a process of gene rearrangement.
- First challenge: Receptors constructed from a constant region (common to all receptors) and a
variable region (which differs between lymphocytes). → through a random process of variable gene
segment selection; antigen receptors are generated and diverse repertoire or antigen receptors is
created. This random generation of antigen-specific receptors inevitably results in receptors that
recognize self-antigens.
- Immunological tolerance: Deletion, inactivation, or suppression of such self-reactive lymphocytes
normally avoids reactivity to the host’s own cells and tissues.
- Second challenge: each lymphocyte recognizes specific antigenic epitope, but has no way of knowing
the port of entry of a pathogen expressing that particular antigen.
- Third challenge: within the pool of lymphocytes in the body, only a relatively small number will react
against a specific pathogen and, on their own, they would be insufficient to deal with the infection.
To solve these issues, a secondary lymphoid tissue is strategically located around the body, both sites of
accumulation of antigen and preferential sites for migration of naïve lymphocytes.
The second tissue include lymph nodes that filter lymph fluid during its return to the circulation, capturing
foreign material and acting as deposition.
In addition, antigen presenting cells; dendritic cells, that acquire antigen in the skin, mucosal epithelial
surfaces or within tissues, and subsequently migrate to the nearest lymphoid tissue to present their antigen,
thereby alerting T lymphocytes as to their presence.
,Specialized blood vessels within the lymph node parenchyma allow lymphocytes to leave the blood and
inspect the antigen present. The same thing is done by the spleen, which also filter antigen blood, in particular
blood-borne pathogens, while mucosal-associated lymphoid tissues, such as Peyer’s patches in the intestine,
allow the immune system to ‘sample’ the antigen coming in through mucosal epithelial surfaces.
Through the secondary lymphoid tissue an effective immune surveillance for the presence of infection is
allowed.
Step by step:
1. Individual lymphocyte encounters its target antigen in the secondary lymphoid organ
2. Lymphocyte ceases its migratory nature and proliferates into copies of daughter cells with the same
antigen specificity → clonal selection and expansion
3. B cells activated within the secondary lymphoid tissues differentiate to become plasma cells
4. Plasma cells migrate locally within lymph nodes to the medullary cords or may travel a greater distance
to the bone marrow, where they reconfigure their antigen receptor to be secreted in the form of antibody
5. Antibodies act as molecules that target the pathogens
6. The infection has been overcome and the host has recovered, the final components of adaptive
immunity are the development of memory and regulatory responses
7. The lymphocyte clones that develop in the lymphoid tissues towards the end of the recovery period,
instead of becoming effector cells (front-line soldiers), become quiescent and are known as memory
lymphocyte
After a period of proliferation, the CD4+ T cells differentiate to one of several effector subtypes: CD4+ helper T
cells release cytokines to enhance the activity of other cell types, including B cells and macrophages. The
activated, CD8+ killer T cells must be mobilized from the regional lymphoid tissue and sent to the site of
infection, where they undertake a search and destroy mission against virus-infected cells. This involves cells
moving into lymphatic vessels and blood where they interact with the endothelial lining of blood vessels. Once
these cells reach the site of infection, they are able to mount a full-scale ‘effector’ response, which is
considerably stronger than that permitted by innate immunity.
- Not all CD4+ T lymphocytes become helper T cells and towards the end of the response to infection,
some differentiate into regulatory T cells, that suppress the response when it is no longer required to
avoid collateral damage.
- Immunological memory is a key feature of adaptive immunity, whereby the adaptive immune system
learns from experience and remembers what pathogens look like, in case they seek to re-infect the
host in the future.
Chapter 2- cells and tissues of the immune system
Cells in the immune system are produced in the bone marrow, then circulate in the blood to reach the tissues.
Although, some cells need further differentiation after they leave the bone marrow. White blood cells include:
1. Neutrophils
2. Eosinophils
3. Basophils
4. Monocytes – which can differentiate into macrophages and dendritic cells after bone marrow
5. Lymphocytes – proliferate and differentiate in lymphoid tissues in response to antigenic stimulus
Also, tissue mast cells are important immune cells, which are capable of triggering and inflammatory response
(particularly in the presence of helminth parasites).
, Primary lymphoid tissues
The sites where lymphocyte development occurs. In here cells undergo initial maturation to a naïve phenotype
that are capable of engaging in immune surveillance.
- The development of B and T lymphocytes, independent of exposure to specific antigens
- Within the bone marrow is a population of pluripotent stem cells, which give rise to precursors
responsible for production of the various haematopoietic lineages: erythroid, platelet, myeloid and
lymphoid cells
Lymphoid precursor commit to innate lymphocyte lineages B cell or T cell lineages in the bone marrow
(including NK cells).
1. Immature B cells leave the bone marrow into peripheral lymphoid tissues under influence of cytokines
such as BAFF and the intestinal microbiome
2. The location and extent of B cell development in the peripheral lymphoid tissues varies by species
3. the final maturation phase of B cells occurs in secondary lymphoid tissues including the spleen and
lymph nodes
The thymus, an organ found in the cranial mediastinum of the thoracic cavity, is the primary lymphoid organ for
T cell development. The thymus is of maximal size during the first few months after birth and involutes during
puberty to become difficult to identify in adult animals, since it is replaced by adipose tissue. It is an
encapsulated organ consisting of lobules; outer cortex and inner medulla.
- Has a network formed by cortical and medullary epithelial cells that is closely packed with immature T
lymphocytes, with fewer interspersed macrophages and dendritic cells.
- Hassall’s corpuscles, made up of clusters of concentrically arranged epithelial cells in the medulla,
are thought to produce growth factors that influence T cell development.
1. Precursor cells are exported from the bone marrow to the thymus to undergo development into mature
T cells
2. The precursor T cells enter the subcapsular region of the thymus from the blood and initiate their
development into functional naïve T cells, while they migrate through the outer cortex into the medulla
3. they enter the general circulation as functional naïve T cells
4. naïve T cells continue to be produced from the thymus, even into relatively old age. In congenitally
athymic animals there is a total lack of cell-mediated immunity (CMI), for which T cells are necessary
adaptive immunity
The immune system is responsible for: biological defense, providing protection against he diversity of
pathogens that cause human & animals infectious diseases.
- It is capable of recognizing, reacting with varying degrees of efficacy (viruses, bacteria, fungi, protozoa
and helminth parasites) and eliminating foreign organisms to attempt to colonize epithelial surfaces,
and/or invade and replicate the host tissue.
- Responsible for: inflammation response, tissue repair, response to external threat and internal
abnormal cells that arise during neoplastic transformation against cell/tissues that have been
transplanted.
The immune system is comprised of 2 related components:
1. Innate immune responses
- Earliest form of immune defense
- Intrinsically interlinked with the acute and chronic inflammatory responses
- Rapid response team
Principles of innate immunity
Epithelial barriers provide both physical and biochemical defense systems, and protect the interface between
host and environment, to prevent invasion of pathogens and infection. Innate immunity is particularly active at
anatomical sites that are likely the first contact point for pathogens, such as: skin, GI-tract, respiratory tract,
urogenital tract, mammary glands and ocular mucosa. The systems strategy for detecting the presence of an
infection as quickly as possible: utilizing pattern- recognition receptors (PRRs, not very specific) for detection
intrinsically foreign molecules called MAMPs (microbe-associated molecular patterns) that include
peptidoglycan walls, particularly prominent in Gram- positive and lipopolysaccharide (LPS; found in the outer
membrane of Gram-negative bacteria) which are not synthesized by eukaryotic cells, so they serve as markers
to indicate presence. PRRs can also be utilized for detection of substances released by damaged/dying host
cells present at the infection site, called DAMPs (damage- associated molecular patterns), they include
cytoplasmic contents that are released into the extracellular fluid as cell membranes break down and other
molecules that are synthesized as a result of the cells encountering an adverse tissue environment. Triggering
of PRRs leads to stimulation of the processes of phagocytosis and inflammation.
- Soluble PRRs are present in the plasma and tissue, or they are cell-associated, allowing cells
(particularly WBC) to sense the presence of MAMPs in the extracellular, intracellular and endosomal
compartments, which signal to the cell to deploy their biological defense systems.
- Soluble mediators that include complement proteins, which are organized into an amplification
system culmination in formation of the membrane- attack complex, that damage microbial cell walls
and production of by- products that are inflammatory.
- White blood cells are rapidly recruited to the infection side contributing to inflammatory response.
- Since viruses have simple structures that lack obvious MAMPs, the innate system finds it difficult to
detect and counteract viral infection. And some even can avoid PRR detection.
- Toll receptors (type of PRRs) bind to MAMP, PAMP and DAMP to trigger in innate response.
Kinds of cells used:
- Epithelial and stromal cells can initiate defense response through secretion of AMPs (antimicrobial
peptides) and alert the immune system by releasing cytokines(immunological hormones) and
chemokines (chemo- attractants).
- Neutrophils and tissue macrophages are adapted to recognize bacteria and engage in phagocytosis
(digestion and killing infected microorganisms).
- Eosinophils and tissue mast cells are adapted to recognize helminth parasites and react by
degranulation, releasing inflammatory, toxic and digestive enzymes onto pathogen surfaces.
, 2. Adaptive immune responses
- More complex immune system due to evolution in order to survive
- To protect against an increasing number and complexity of microorganisms that have adapted to a
more parasitic lifestyle gaining a biological advantage
- The increasing complexity of host immunity was made possible by: gene duplication (giving rise to
related immunological molecules, as pattern- recognition receptors, immunoglobulins and cytokines)
Principles of adaptive immunity
is the typically dominant form of immunity in higher species, since the innate immunity has become less
effective over evolution. The adaptive system is much more specific and more potent in its effect, but it there is
a lag period (delay) between the onset of infection and the production of an effector response, which is why the
innate system is not redundant; to keep the host alive long enough fir the adaptive immune response to have
affect.
The adaptive system is intrinsically linked to the functionality of the lymphocytes, which express cell surface
receptors to detect the presence of an antigen, since pathogens synthesize and express proteins that are
different in sequence and shape/structure compared to host cells. These protein antigens can be recognized
as foreign by lymphocyte antigen receptors (each small element of an antigen that can be recognized is an
epitope).
2 types of lymphocytes used:
1. B lymphocytes
- Express antigen receptors designed to; detect epitopes of intact antigen on the surface of pathogens in
the extracellular space
2. T lymphocytes
- Recognize digested fragments of antigen that has undergo intracellular processing and are pre3sented
on the surface of other cells, in association with a specialist carrier molecule MHC (major
histocompatibility complex).
Lymphocytes must design uniquely shaped antigen receptor during development in primary lymphoid tissues.
All lymphocytes are initially derived from lymphoid progenitors in the bone marrow, in here B cells complete
their development, while T cells must leave bone marrow and complete their development in the thymus where
they either come beCD4+ or CD8+ T cells.
- During development, antigen receptor diversity is engineered by a process of gene rearrangement.
- First challenge: Receptors constructed from a constant region (common to all receptors) and a
variable region (which differs between lymphocytes). → through a random process of variable gene
segment selection; antigen receptors are generated and diverse repertoire or antigen receptors is
created. This random generation of antigen-specific receptors inevitably results in receptors that
recognize self-antigens.
- Immunological tolerance: Deletion, inactivation, or suppression of such self-reactive lymphocytes
normally avoids reactivity to the host’s own cells and tissues.
- Second challenge: each lymphocyte recognizes specific antigenic epitope, but has no way of knowing
the port of entry of a pathogen expressing that particular antigen.
- Third challenge: within the pool of lymphocytes in the body, only a relatively small number will react
against a specific pathogen and, on their own, they would be insufficient to deal with the infection.
To solve these issues, a secondary lymphoid tissue is strategically located around the body, both sites of
accumulation of antigen and preferential sites for migration of naïve lymphocytes.
The second tissue include lymph nodes that filter lymph fluid during its return to the circulation, capturing
foreign material and acting as deposition.
In addition, antigen presenting cells; dendritic cells, that acquire antigen in the skin, mucosal epithelial
surfaces or within tissues, and subsequently migrate to the nearest lymphoid tissue to present their antigen,
thereby alerting T lymphocytes as to their presence.
,Specialized blood vessels within the lymph node parenchyma allow lymphocytes to leave the blood and
inspect the antigen present. The same thing is done by the spleen, which also filter antigen blood, in particular
blood-borne pathogens, while mucosal-associated lymphoid tissues, such as Peyer’s patches in the intestine,
allow the immune system to ‘sample’ the antigen coming in through mucosal epithelial surfaces.
Through the secondary lymphoid tissue an effective immune surveillance for the presence of infection is
allowed.
Step by step:
1. Individual lymphocyte encounters its target antigen in the secondary lymphoid organ
2. Lymphocyte ceases its migratory nature and proliferates into copies of daughter cells with the same
antigen specificity → clonal selection and expansion
3. B cells activated within the secondary lymphoid tissues differentiate to become plasma cells
4. Plasma cells migrate locally within lymph nodes to the medullary cords or may travel a greater distance
to the bone marrow, where they reconfigure their antigen receptor to be secreted in the form of antibody
5. Antibodies act as molecules that target the pathogens
6. The infection has been overcome and the host has recovered, the final components of adaptive
immunity are the development of memory and regulatory responses
7. The lymphocyte clones that develop in the lymphoid tissues towards the end of the recovery period,
instead of becoming effector cells (front-line soldiers), become quiescent and are known as memory
lymphocyte
After a period of proliferation, the CD4+ T cells differentiate to one of several effector subtypes: CD4+ helper T
cells release cytokines to enhance the activity of other cell types, including B cells and macrophages. The
activated, CD8+ killer T cells must be mobilized from the regional lymphoid tissue and sent to the site of
infection, where they undertake a search and destroy mission against virus-infected cells. This involves cells
moving into lymphatic vessels and blood where they interact with the endothelial lining of blood vessels. Once
these cells reach the site of infection, they are able to mount a full-scale ‘effector’ response, which is
considerably stronger than that permitted by innate immunity.
- Not all CD4+ T lymphocytes become helper T cells and towards the end of the response to infection,
some differentiate into regulatory T cells, that suppress the response when it is no longer required to
avoid collateral damage.
- Immunological memory is a key feature of adaptive immunity, whereby the adaptive immune system
learns from experience and remembers what pathogens look like, in case they seek to re-infect the
host in the future.
Chapter 2- cells and tissues of the immune system
Cells in the immune system are produced in the bone marrow, then circulate in the blood to reach the tissues.
Although, some cells need further differentiation after they leave the bone marrow. White blood cells include:
1. Neutrophils
2. Eosinophils
3. Basophils
4. Monocytes – which can differentiate into macrophages and dendritic cells after bone marrow
5. Lymphocytes – proliferate and differentiate in lymphoid tissues in response to antigenic stimulus
Also, tissue mast cells are important immune cells, which are capable of triggering and inflammatory response
(particularly in the presence of helminth parasites).
, Primary lymphoid tissues
The sites where lymphocyte development occurs. In here cells undergo initial maturation to a naïve phenotype
that are capable of engaging in immune surveillance.
- The development of B and T lymphocytes, independent of exposure to specific antigens
- Within the bone marrow is a population of pluripotent stem cells, which give rise to precursors
responsible for production of the various haematopoietic lineages: erythroid, platelet, myeloid and
lymphoid cells
Lymphoid precursor commit to innate lymphocyte lineages B cell or T cell lineages in the bone marrow
(including NK cells).
1. Immature B cells leave the bone marrow into peripheral lymphoid tissues under influence of cytokines
such as BAFF and the intestinal microbiome
2. The location and extent of B cell development in the peripheral lymphoid tissues varies by species
3. the final maturation phase of B cells occurs in secondary lymphoid tissues including the spleen and
lymph nodes
The thymus, an organ found in the cranial mediastinum of the thoracic cavity, is the primary lymphoid organ for
T cell development. The thymus is of maximal size during the first few months after birth and involutes during
puberty to become difficult to identify in adult animals, since it is replaced by adipose tissue. It is an
encapsulated organ consisting of lobules; outer cortex and inner medulla.
- Has a network formed by cortical and medullary epithelial cells that is closely packed with immature T
lymphocytes, with fewer interspersed macrophages and dendritic cells.
- Hassall’s corpuscles, made up of clusters of concentrically arranged epithelial cells in the medulla,
are thought to produce growth factors that influence T cell development.
1. Precursor cells are exported from the bone marrow to the thymus to undergo development into mature
T cells
2. The precursor T cells enter the subcapsular region of the thymus from the blood and initiate their
development into functional naïve T cells, while they migrate through the outer cortex into the medulla
3. they enter the general circulation as functional naïve T cells
4. naïve T cells continue to be produced from the thymus, even into relatively old age. In congenitally
athymic animals there is a total lack of cell-mediated immunity (CMI), for which T cells are necessary
