THE IMMUNE RESPONSE

DATE 13/6/07

DR. ELAINE WILLIAMS

OUTLINE:

Definition
The Immune System
- Functional divisions
The Lymphoid System
- Divisions
Cells involved in the Immune response
Cytokines
Deranged immune responses

LEARNING OBJECTIVES:
At the end of this lecture students should be able to:

Define the immune response and discuss the mechanisms through which the
response is effected.
Describe the functional organization of the lymphoid system
List the cell types involved in the immune response and describe the
characteristics and function of each cell type
Describe the role of cytokines in the immune response
Discuss the effects of derangements of the immune system

IMMUNITY
Immunity refers to those physiologic mechanisms that enable an individual to recognize foreign antigens
and eliminate them without causing injury to its own tissues.
This is provided by the IMMUNE SYSTEM which is a complex and sophisticated network of cellular
and humoral (involving antibodies) elements, centered around the lymphoid system that promotes
defense against microbial agents and therefore prevention of disease.

IMMUNE SYSTEM
The immune system has two functional divisions INNATE & ACQUIRED
INNATE/ NATURAL IMMUNITY is present at birth, is non-specific and provides the first line of
defense against infection.
ACQUIRED/ ADAPTIVE/ NON-SPECIFIC IMMUNITY takes place after birth, after exposure to
antigen. It provides the second line of defense against infection.
Both divisions act together in concert throughout life and complement each other in the fight against
disease.
INNATE/NATURAL IMMUNITY:
This type of immunity is mediated through inflammatory cells, in particular polymorphs and
macrophages, which function as phagocytic cells, engulfing and destroying microorganisms and
clearing cellular debris generated during the inflammatory response. It acts in a non-specific manner
in that it does not involve previous exposure to antigen as is the case with acquired immune
responses.
Natural immunity is provided by:

The Skin:
The unbroken skin is perhaps the most effective barrier to environmental
substances. Most microorganisms are unable to penetrate intact skin. Breaches in the skin
following lacerations and abrasions are frequently followed by infection. Patients who
experience severe burns are prone to overwhelming infection which at times might be fatal.
Commensal Organisms:
These are non-pathogenic (do not normally cause disease) that
are present in the body as part of the normal bacterial flora or population. They are present
predominantly in the gastrointestinal tract and vagina. They play an important role in
immunity in that they compete with pathogenic (disease causing) organisms for nutrients. In
the absence of commensal organisms, pathogenic organisms flourish and disease sets in.
Enzymes:
A number of enzymes are present in body secretions that play a role in natural
immunity. Lysozyme present in tears and saliva is capable of splitting bacterial cell wall.
Mucus & Cilia:
Mucus and cilia present at epithelial surfaces, such as the respiratory
and genital tracts, are important in trapping and removing invading organisms. This is very
important in light of the fact that most infectious agents enter the body at epithelia surfaces.

ACQUIRED/SPECIFIC IMMUNITY:
This type of immunity is divided into two distinct types:

Cell mediated
Humoral

Cell Mediated Immunity(CMI): This type of immunity is mediated through a subset of

lymphocytes called T lymphocytes. These lymphocytes are developed during embryogenesis in the
thymus gland and have specific immune functions.
Humoral Immunity:
This type of immune response is mediated through antibodies
produced by another subset of lymphocytes called B lymphocytes. During embryogenesis, B
lymphocytes develop in the bone marrow.
These responses involving T & B lymphocytes are effected through the LYMPHOID SYSTEM which has
two main anatomical divisions:

The primary lymphoid organs

The secondary lymphoid organs

Primary Lymphoid Organs:

The primary lymphoid organs come into play during embryological
development and are the sites at which antigen independent ( does not require exposure to antigen)
differentiation of precursor cells occur leading to the development of immunocompetent lymphocytes, ie
lymphocytes capable of mediating immune responses.
Secondary Lymphoid Organs:
The secondary lymphoid organs are active throughout life and
represent sites of interaction of specific antigen with specific immunocompetent lymphocytes resulting in
specific immune responses directed against the specific antigen that initiated the response.
The Primary Lymphoid Organs are represented by the Thymus Gland in which there is differentiation of
precursor stem cells, originating in the bone marrow, to form immunocompetent T lymphocytes capable of
mediating cellular immune responses. The other primary lymphoid organ is the Bone Marrow in which
there is differentiation of precursor stem cells to form B lymphocytes capable of producing antibody and
mediating humoral responses.
These immunocompetent lymphocytes, once developed in the primary lymphoid organs, migrate from their
sites of development, to specific anatomical sites in the Secondary Lymphoid Organs. These are
represented by:

Lymph Nodes
Spleen
Mucosa Associated Lymphoid Tissues (MALT)

LYMPH NODES:
Lymph nodes are small organs found in groups or chains in anatomical
locations draining specific regions of the body eg- cervical, axilla and groin. They represent the sites of
generation of specific immune responses to specific antigens.
Within the lymph node, lymphocytes T and B occupy specific anatomical locations. The outermost part of
the lymph node (Cortex) is occupied predominantly by B lymphocytes, disposed as spherical structures
called germinal centres or follicles. T cells are found interspersed between these follicles. The area subjacent
to the cortex (Paracortex) is occupied predominantly by T lymphocytes.
The innermost part of the lymph node (Medulla) is occupied by a mixture of T lymphocyes, B lymphocytes
and plasma cells.

As illustrated in the above diagram, the lymph node is a kidney shaped structure which is surrounded by a
connective tissue capsule subjacent to which is a space called the Subcapsular Marginal Sinus. The capsule is
perforated by afferent lymphatics which empty into the sinus. Lymph from the sinus percolates through the
substance of the node in between the Medullary Cords (MC) and collecting in the Medullary Sinuses (MS)
eventually draining into the efferent lymphatic channel exiting the node at the hilum. The lymph node is
supplied by an artery and drained by a vein, both located at the hilum.
The outermost portion of the lymph node is the Cortex( pale blue area on diagram. This is the area in which
B cells are predominantly found. B lymphocytes are disposed in tightly packed spherical structures (Bright blue
structures) called Primary Lymphoid Follicles in the unstimulated node. On exposure to antigen, the primary
follicles become enlarged and less dense resulting in the formation of secondary follicles or germinal centres.
T lymphocytes are predominantly found in the area subjacent to the cortex, called the Paracortex. (Grey on
diagram). T lymphocytes are also found in the areas in between the follicles in the cortex.

THE SPLEEN:
The spleen is an encapsulated organ located just below the left costal margin. It is
composed of the red pulp and the white pulp. The white pulp represents the lymphoid area of the spleen and
encircles the splenic arterioles in the form of a periarteriolar sheath. Within the sheath, T lymphocytes are
found in the innermost portion (Blue area) and B lymphocytes peripherally in the outermost portion of the
sheath (Light blue area). In this area, in the stimulated node, B lymphocytes form follicles with germinal
centres. The red pulp is composed of intercommunicating splenic cords forming venous sinuses.

MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT):

The mucosa associated lymphoid tissue is
less organized than the lymph node and the spleen and is distributed along mucosal surfaces such as the
gastrointestinal tract where it is found beneath the epithelium within the connective tissue of the lamina propria.
B lymphocytes are found within follicles and T lymphocytes are interspersed in between the follicles.
Let us now consider the cells of the immune system in more detail.

Lymphoid cells T & B

Natural killer cells
Phagocytic cells

T LYMPHOCYTES:

T lymphocytes arise from progenitor precursor stem cells in the bone marrow, which early in
development, migrate to the thymus gland where they undergo differentiation to form immunocompetent
T lymphocytes capable of effecting cell mediated immune responses. They subsequently home to the
peripheral lymphoid organs where they occupy specific anatomical sites as discussed earlier.
They bear on their cell surface, a specific receptor for antigen the T cell receptor, composed of
polypeptide chains.
T lymphocytes are identical to B lymphocytes morhoplogically. They can however be
differentiated by utilizing immunohistiochemical techiques. The latter involves the use of
specific(monoclonal) antibodies that are restricted to surface antigens present on certain cell types. The
most common monoclonal antibodies used to identify T cells are UCHL1 & MT1.
T lymphocytes account for 60-70% of lymphocytes present in the peripheral blood.
T lymphocytes are sub-divided into various subsets which express specific surface markers and
also have specific effector functions. These are: 1) T helper/inducer bearing the so called cluster
differentiation antigen CD4. 2) T suppressor/cytotoxic- bearing the cluster differentiation antigen
CD8. The normal ratio of CD4:CD8 = 2:1
The T helper lymphocytes are important in initiating immune responses. This response is
controlled through the T suppressor subset which is important in terminating the response. Cytotoxic T
lymphocytes are important in destroying other cells, in particular, tumour cells and virally infected cells.

B LYMPHOCYTES:

B lymphocytes, like T lymphocytes, arise from progenitor stem cells in the bone marrow and migrate to
the peripheral lymphoid organs where they occupy specific anatomical sites as discussed earlier.
B lymphocytes carry IgM on the cell surface and this immunoglobulin bears an antigen specific binding
site.
B lymphocytes carry surface immunoglobulin as well as a receptor for the Fc portion of
immunoglobulin G. (IgG)
Like T lymphocytes, B lymphocytes can be identified by immunohistochemical tests using a variety of
monoclonal antibodies, in particular, 4KB5 and L26.
Activation of B lymphocytes following exposure to specific antigen results in morphological
transformation to a larger cell (lymphoblast) which ultimately transform to plasma cell which in turn
actively secretes antibody directed against the antigen that initiated the response. Interestingly, during
this process, there is production of so called memory lymphocytes. These lymphocytes are capable of
recalling exposure to the original antigen and react promptly and effectively upon subsequent exposure
to the same antigen.
Antibody production will therefore vary depending on the type of exposure to antigen and this is the
basis of vaccination. Antibody production is characterized by two types of responses primary and
secondary. The primary response follows the initial or first exposure to antigen and is different
qualitatively and quantitatively to the secondary response. The primary response is characterized by a
long period of time (latent period) before antibody can be detected. The antibody formed is of the IgM
type, the titre low and the level falls off rapidly. The secondary response follows re-exposure to the

original antigen. Here the antibody is formed after a relatively short latent period. The antibody is of the
IgG type, the titre high and remains elevated indefinitely. A small amount of Ig M is also formed.
This is illustrated in the diagram below.

NATURAL KILLER (NK) CELLS/ NULL CELLS

These cells are devoid of the charcteristics that define T cells or B cells as described above.
They, however, have on their surface, a receptor for the Fc portion of IgG, which is important
for effector function of these cells
These cells are responsible for mediating Antibody-Dependent-Cell-Mediated Cytotoxicity
(ADCC) reactions. These interactions require that target cells be coated with IgG antibody.
Natural Killer cells will bind to these coated cells through the receptor for the Fc portion of IgG
that is present on its cell surface. This cell-cell interaction results in destruction of the target cell
coated with antibody.

This interaction is represented in the diagram below:

THE MONONUCLEAR PHAGOCYTIC SYSTEM

This system plays an important role in eliciting effective immune responses

Macrophages are derived from haematopoetic precursor stem cells in bone marrow
They circulate in the blood as monocytes and are distributed in various tissues where they are
called macrophages
These cells augment the immune response through a number of mechanisms.
They process and present antigen to T cells during the induction phase of the immune
response.
They produce soluble factors eg Interleukin 1, that promote the differentiation of T & B cells
therby amplifying the immune response
They are capable of destroying tumour cells and are therefore are important in tumour
immunology.

They engulf and destroy particulate matter and are therefore important in removing debris
formed during inflammation

POLYMORPHS

These cells are important in destroying bacteria. In order to facilitate this, these cells are armed
with receptors,such as the receptor for C3b, that interact with bacteria after which follows the
process of phagocytosis and ultimately destruction of the bacteria.

CYTOKINES

Another important participant in the immune response is a family of biologically active

substances secreted by a variety of cell types collectively called cytokines. These can be regarded
as messenger molecules of the immune response which function together to amplify the immune
response. They are secreted by a number of cells including lymphocytes, monocytes and
endothelial cells. A large number of cytokines have been described over the years which have a
wide spectrum of overlapping properties which can be categorized as follows:
1) Cytokines that mediate natural immunity. Included in this group are Interleukin 2, Tumour
Necrosis Factor , Interferon and Interleukin 6. Interferon is important in the protection
against viral infection.
2) Cytokines that regulate lymphocyte growth, activation and differentiation Interleukin 2,
4, 5, 13, 15 and transforming growth factor .
3) Cytokines that activate inflammatory cells Interferon & TNF .
4) Cytokines that affect leukocyte movement and are therefore important for chemotaxis
during
inflammation.
5) Cytokines that stimulate haematopoeisis by inducing haematopoetic stem cells in the bone
marrow to differentiate into mature cells eg Colony Stimulating Facor.

In Summary, these are the features of the immune system that is designed and structured to effect
immune responses and prevention of disease. It is a highly sophisticated system that functions
effectively under normal circumstances. Not surprising, however, is malfunctioning of the system at
various levels resulting in disease.
The derangements include:
Exaggerated responses resulting in hypersensitivity disordera such as the allergic type of
bronchial asthma
Immune responses directed against self antigens and the development of a wide spectrum
of autoimmune diseases
Loss of immune function and the development of Immunodeficiency Disorders either
primary or secondary (acquired)

These derangements will be discussed in detail in the later lectures

Questions:
1.

Which of the following is a function of T lymphocytes?

a.
b.
c.
d.

2.

Induction of the immune response

Secretion of antibodies and cytokines
Processing of antigen
Antibody dependent cytotoxicity

Which of the following is NOT involved in Innate (Natural Immunity)?

a.
b.
c.
d.

Lysozyme present in saliva

Commensal organisms in the gut
Cilia lining the respiratory tract
Memory B lymphocytes*

Answers & Explanations:

1.

The answer is a). T lymphocytes, particularly the T helper subset, is important in inducing or
initiating immune response. They also secrete a variety of cytokines but they do not secrete anitbody.
Antibodies are secreted by plasma cells which are differentiated from B lymphocytes. Macrophages
process and present antigens to T and B cells during the immune response.
Natural killer cells mediate antibody dependent cytotoxicity by virtue of the presence of a receptor
for IgG on its cell surface. The interaction requires that the target cell be coated with IgG antibody.

2.

The answer is d). Memory B lymphocytes are generated during acquired immune reponses. They
form a pool of lymphocyes that are capable of remembering prior exposure to antigen. On reexposure to that antigen there is a more rapid and effective immune response. This is the basis of
vaccination. Lysozyme present in saliva and tears is capable of non-specifically splitting bacterial
cell wall. Commensal organisms compete with pathogenic bacteria for nutrients and are therefore
important in the prevention of disease. Cilia and mucus at epithelial surfaces aid in the removal of
invading microorganism.

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