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

EMBED PBrush

EMBED PBrush

EMBED PBrush

PAGE 10