FDT - ONLINE - IMMUNOLOGY
THE IMMUNE RESPONSE
DATE 13/6/07DR. 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
IMMUNITYImmunity 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 HumoralCell 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 organsPrimary
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 thesubstance 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
lecturesQuestions:1. Which of the following is a function of T
lymphocytes?
a. Induction of the immune responseb. Secretion of antibodies
and cytokines
c. Processing of antigen
d. Antibody dependent cytotoxicity
2. Which of the following is NOT involved in Innate (Natural
Immunity)?
a. Lysozyme present in saliva
b. Commensal organisms in the gut
c. Cilia lining the respiratory tract
d. 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
re-exposure 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. EMBED PBrush
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