· Human body is exposed, at all times, to a variety of disease-causing organisms - pathogens. Pathogenic organisms are- bacteria, viruses, fungi and parasites.
· Pathogenic organisms enter the body through the air we breathe, the fluids we drink, through body contact and ingested food items. Many of these organisms, if they manage to reach the deeper tissues, can produce diseases.
· Body possesses several mechanisms that combat these pathogens all the time and enable us to lead a normal life.
· Infectious diseases are the result of the absence or breakdown of these defence mechanisms.
· The defence mechanisms of the body provide us with resistance against the invading pathogenic organism.
· The ability of the body to withstand the harmful effects of pathogens is termed immunity and the defence mechanisms together constitute the immune system.
· The immune system is a collection of organs, cells and molecules whose complex interaction form an efficient system that protects the individual from invading pathogens and also from its own altered internal cells.
· Traditionally, the immune system is divided into two functionally distinct parts:
· The defence mechanisms of the body provide us with resistance against the invading pathogenic organism.
· The ability of the body to withstand the harmful effects of pathogens is termed immunity and the defence mechanisms together constitute the immune system.
· The immune system is a collection of organs, cells and molecules whose complex interaction form an efficient system that protects the individual from invading pathogens and also from its own altered internal cells.
· Traditionally, the immune system is divided into two functionally distinct parts:
(1) Innate immunity
(2) Adaptive immunity
· This is an arbitrary division and the two systems interact at various levels.
· Innate immunity or natural (non-adaptive) immunity refers to non-specific host defence mechanisms that distinguish foreign organisms and tissues but are unable to recognize a particular organism.
· They are operative all the time and do not require exposure to the foreign organism or tissue, but become more efficient on exposure to pathogens.
· Adaptive immunity or acquired immunity is the immune reaction that develops only after exposure to foreign organisms or tissues and takes some time to manifest the effects.
· Two important features of this system are:
· Innate immunity or natural (non-adaptive) immunity refers to non-specific host defence mechanisms that distinguish foreign organisms and tissues but are unable to recognize a particular organism.
· They are operative all the time and do not require exposure to the foreign organism or tissue, but become more efficient on exposure to pathogens.
· Adaptive immunity or acquired immunity is the immune reaction that develops only after exposure to foreign organisms or tissues and takes some time to manifest the effects.
· Two important features of this system are:
(1) specificity
(2) memory.
· Adaptive immune system is able to distinguish foreign cells from self and can distinguish one foreign pathogen from another.
· Adaptive immune system is able to distinguish foreign cells from self and can distinguish one foreign pathogen from another.
· Adaptive immunity can be passive or active.
· Passive immunity is a passive mechanism and involves the administration of a specific antibody to a particular pathogenic organism. The antibody combines with the pathogenic organism and neutralizes its harmful effects.
· For example, injection of serum containing specific antibodies to diphtheria causing organisms is an effective method of treating the disease.
· Active immunity is an active process involving many elements of the immune system and develops only after contact with foreign microbes or tissues.
· It is a complex process and two distinct active immune mechanisms are present - Cell-mediated immunity and Humoral immunity.
· The T-lymphocytes are the mediators of the cell-mediated immunity and is basically a cellular mechanism where specific groups of T-cells ultimately neutralize the invading microbes.
· Humoral immunity is carried out by the B-lymphocytes, by the secretion of specific antibodies, s which then interact with the particular invading organism and neutralize them.
· The two active immune mechanisms are interrelated and dependent on each other.
· It is a complex process and two distinct active immune mechanisms are present - Cell-mediated immunity and Humoral immunity.
· The T-lymphocytes are the mediators of the cell-mediated immunity and is basically a cellular mechanism where specific groups of T-cells ultimately neutralize the invading microbes.
· Humoral immunity is carried out by the B-lymphocytes, by the secretion of specific antibodies, s which then interact with the particular invading organism and neutralize them.
· The two active immune mechanisms are interrelated and dependent on each other.
A. INNATE IMMUNITY SYSTEM
· Innate immunity system comprises several diverse organs, cells and chemical factors and can be broadly grouped into two categories:1. Physiological barriers and bodily secretions
2. Non-specific immune responses.
1. Physiological barriers
· The physiological barriers are- the skin and the mucous membrane.
· The physiological barriers are- the skin and the mucous membrane.
· They provide defence at the body surface itself.
a. Skin:
· Skin covers the entire body except at the orifices.
a. Skin:
· Skin covers the entire body except at the orifices.
· The horny layer of the skin is an impermeable barrier and physically prevents the entry of foreign organisms.
· Sweat and sebum are acidic secretions containing bacteriostatic substances that neutralize microbes entering through the sweat glands or sebaceous glands.
· Skin harbours a large population of symbiotic microbes, referred to as commensal organisms.
· Sweat and sebum are acidic secretions containing bacteriostatic substances that neutralize microbes entering through the sweat glands or sebaceous glands.
· Skin harbours a large population of symbiotic microbes, referred to as commensal organisms.
· These microbes are resident on the skin surface and inhibit the growth of any pathogenic organisms on the skin, by competing with them for nutrients.
b. Mucous membrane :
· The systems in direct communication with the external environment within the body are lined with mucous membrane.
· The systems in direct communication with the external environment within the body are lined with mucous membrane.
· The mucous membrane contains several mechanisms that eliminate the microbes entering these passages.
· For example, the mucous lining of the respiratory tract secretes the sticky mucus. The suspended particles in the inspired air get deposited on the mucous lining, get periodically swept up by the ciliary movement and are expectorated by coughing.
· For example, the mucous lining of the respiratory tract secretes the sticky mucus. The suspended particles in the inspired air get deposited on the mucous lining, get periodically swept up by the ciliary movement and are expectorated by coughing.
· The epithelial cells secrete immunoglobins that combine with pathogens and are cleared from the tract.
· The alveoli contain large macrophages, which phagocytize microbes reaching the alveoli.
· Commensal microbes are present in the mucous membrane of the genital tract and digestive tract.
· In the vagina, lactobacilli maintain an acidic pH and inhibit the growth of harmful microbes.
· Commensals in the intestines play a role similar to that in the skin.
· Bodily secretions: Secretions of the body contain many bactericidal substances. Tear, saliva, gastric juice, semen, milk, and nasal secretions: all contain such substances.
· Bodily secretions: Secretions of the body contain many bactericidal substances. Tear, saliva, gastric juice, semen, milk, and nasal secretions: all contain such substances.
· The acid in the gastric juice is bactericidal and is important in making the ingesta sterile. Plasma cells secrete immunoglobulins (antibodies) into the blood.
· Immunoglobins work in the immune response of the body against antigens.
· Immunoglobulin A (IgA) is the major antibody present in the secretions of respiratory, gastrointestinal and genitourinary tracts.
· IgA binds with foreign antigens present at these sites and prevents their entry into the body.
CELLULAR ELEMENTS INVOLVED IN IMMUNITY
| Name of Cell | Description | Function |
|---|---|---|
| T-Lymphocyte (T-cells) |
A class of lymphocytes that undergo differentiation in the thymus gland | Cell-mediated immunity |
| 1. Cytotoxic T-cells (CTL) |
A sub-type of T-cells. | T-cells that attack and- destroy targeted antigenic microbes. |
| 2. Helper T-cells (Th) | A sub-type of T-cells. | T-cells are involved in cell-mediated immunity. Stimulate B-cells and initiate humoral immunity. |
| 3. Suppressor T-cells | A sub-type of T-cells. | T-cells inhibit immune response. |
| B-lymphocyte (B-cells) | A class of lymphocytes that differentiate in the bone marrow. | Humoral immunity Secrete antibodies |
| Antigen-presenting cells (APC) | Mononuclear phagocytes are present in lymphoid tissues Eg; Tissue macrophages. | Ingest invading microbes and present a part of them along with MHC Class II molecules on their membrane. |
| Natural killer cells | A sub-type of lymphocyte that does not undergo differentiation in the thymus. | Similar to cytotoxic T-cells; destroy pathogenic microbes. |
In addition to the above cells, the granulocytes and monocytes have an important role in immune responses.
CLINICAL FACTORS INVOLVED IN IMMUNITY
| Name of cell | Description | Function |
|---|---|---|
| Antigen | Proteins or polysaccharides that provoke an immune response. The epitope is the part of the antigen that binds with the antibody. An antigen can possess several epitopes. |
Activate immune response in the host. |
| Antibody | Specific proteins produced on exposure to antigens. Antibodies are termed Immunoglobulins (Ig). IgA, IgD, IgE, IgG & IgM are the different types of Ig. |
Antibodies combine with antigens and inactivate them by several mechanisms. |
| Complement system | A group of proteins synthesized by the liver and phagocytes | Complement proteins facilitate antigen-antibody reactions. |
| Cytokines | Hormone-like substances secreted by activated T-cells and phagocytes. Interleukins, Lymphokines, Interferons and Growth factors are different types of cytokines. |
Mediate immune responses. |
| Major histocompatibility complex (MHC) | Adhesion molecules on cell membranes. Class 1 MHC—expressed in all living cells. Class II MHC—expressed by macrophages, B-cells and APCs. |
Important for “Self-recognition during an immune response. |
| Clustering of Determinants (CD) | Membrane proteins of T-cells The sub-types of T-cells carry different types of CD groups: Helper T-cells express CD4, Cytotoxic T-cells express CD8. |
Recognition of specific antigens |
| Opsonins | Substances facilitating phagocytosis eg; Complements | Coat the cell surface and attract the phagocytes. |
| T-cell receptor (TCR) | Integral proteins of the T-cell membrane | Mediate antigen recognition in cell-mediated immunity. |
| B-cell receptor (BCR) | Integral proteins of B-cell membrane | Ig molecules mediate antigen recognition in humoral immunity. |
Non-specific Immune Responses
· Non-specific immune responses include the following:
a. Phagocytosis
b. Reticuloendothelial system
c. Inflammatory response
· Non-specific immune responses include the following:
a. Phagocytosis
b. Reticuloendothelial system
c. Inflammatory response
a. Phagocytosis
· Neutrophils and the macrophages are phagocytic cells.
· Neutrophils and the macrophages are phagocytic cells.
· The phagocytic cells ingest and destroy bacteria, viruses and other particulate matter.
· They are the first line of defence against invading organisms and prevent them from multiplying in the body.
· The ingestion process is termed phagocytosis.
· The phagocytic cells are attracted to the site of infection by chemicals secreted during the inflammatory response.
· The phagocytic cells are attracted to the site of infection by chemicals secreted during the inflammatory response.
· The spread of infection can be controlled at an early stage by their migration and phagocytosis, at the site of infection.
· Phagocytosis is facilitated by the presence of opsonins—opsonization—on the target cells.
· Phagocytosis is facilitated by the presence of opsonins—opsonization—on the target cells.
· The opsonins are the complement proteins or antibodies.
b. Reticuloendothelial system
· Reticuloendothelial system is a composite group of cells in various tissues, which filter the microbes from the bloodstream or lymph and phagocytize them.
· Monocytes, macrophages, tissue macrophages, specialized endothelial cells present in the blood, lymphoid tissues, liver, spleen, bone marrow, lung and other tissues constitute the reticuloendothelial system.
· Kupffer cells present in the liver sinusoids are the typical cells of this system.
· They are tissue macrophages and form an effective filtration system. Portal blood from the intestinal tract contains bacteria from the GI tract, the Kupffer cells filter out the bacteria and the blood flowing into the systemic vessels is sterile.
· The filtered organisms are phagocytized by the Kupffer cells.
· Similar functions are carried out by the tissue macrophages present in the spleen, lymph nodes and bone marrow.
· The fixed phagocytic cells in these organs can become mobile in response to chemotactic stimuli, and migrate to other sites in the body.
· Similar functions are carried out by the tissue macrophages present in the spleen, lymph nodes and bone marrow.
· The fixed phagocytic cells in these organs can become mobile in response to chemotactic stimuli, and migrate to other sites in the body.
c. Inflammatory response
· Inflammatory response is induced by injury/infection to the tissues.
· It is a non-specific immune response and presents four cardinal signs— rubor (redness), calor (warm), dolor (pain) and turgor (stiffness).
· It isolates the area of injury, delays the spread of microbes or toxins and attracts the phagocytes to the site of injury.
Inflammation begins with
a. The dilatation of the local arterioles and capillaries from which, plasma constituents escape to the extravascular spaces.
b. Tissue fluid accumulates at the site of injury, and a fibrin network is formed and blocks the lymphatic channels.
c. The site of injury is isolated and the movement of microbes is restricted. The injured cells secrete chemoattractants, and the phagocytic cells - neutrophils, monocytes, and eosinophils migrate to the site.
d. Phagocytes engulf the microbes and digest them. pH of the inflamed area becomes acidic and cellular proteases lyse the leucocytes.
e. Larger macrophages migrate to the inflamed area, engulf the leucocytic debris and the microbes, and initiate resolution of the inflammation.
The inflammatory response involves several cytokines, some of them are:
a. Interleukin-1
b. Tumour necrosis factor
c. Granulocyte/Monocyte Colony-stimulating factor
d. Granulocyte Colony-stimulating factor
e. Monocyte Colony-stimulating factor.
a. Interleukin-1
b. Tumour necrosis factor
c. Granulocyte/Monocyte Colony-stimulating factor
d. Granulocyte Colony-stimulating factor
e. Monocyte Colony-stimulating factor.
· These cytokines are secreted by activated macrophages and leucocytes at the site of inflammation.
· Increased production of granulocytes and monocytes is due to the secretion of colony-stimulating factors.
· The factors listed above are responsible for the entire sequence of changes during an inflammatory response and its subsequent resolution.
a. Antigens are macromolecules that evoke an immune response in the body. Chemically antigens can be proteins, polysaccharides, and conjugates of lipids with proteins (lipoproteins) or polysaccharides (glycolipids). Antigens exhibit chemical complexity and have a molecular weight of more than 10,000.
b. Every antigen displays regularly occurring chemical groups on their surface, termed epitopes or antigenic determinants. Epitopes are the smallest unit of the antigen that evokes an immune response. An antigen may possess one or more such epitopes.
c. Antigens are an integral part of a foreign organism or tissue, and such antigens are termed exogenous antigens.
d. Antigens that arise from cells within the body are the endogenous antigens—eg., proteins produced by virus-infected cells, cancerous cells.
Exogenous antigens
· The exogenous antigens are taken up by the antigen-presenting cells (APCs).
· APCs are the phagocytic cells, viz., the dendritic cells, macrophages and B-lymphocytes.
· APCs express class II major histocompatibility complex molecules (MHC) on their membrane surface. These are glycoproteins, which confer chemical identity to the host cells.
· APCs engulf the antigen containing pathogen or foreign tissue by endocytosis, degrade the organism/tissue and break up the antigenic protein into short peptides.
· These peptides (epitopes) are displayed on the surface of the APC along with MHC molecules, for recognition by the helper T-lymphocytes.
Endogenous antigens
· The endogenous antigens that are generated within the host body cells are degraded into peptide fragments within the cell and displayed at the surface of the cell along with class I MHC molecules.
· Class I MHC molecules are expressed by all the cells of the body and present the antigen-MHC complex to the cytotoxic lymphocytes.
· B-lymphocytes: present the antigen by a different process.
· B-cells engulf the antigen by receptor-mediated endocytosis.
· The B-cell receptors (BCR) for antigens are present on the cell membrane.
· BCRs (antibody) have a high affinity for the antigens and are engulfed even when they are present in very small concentrations in the body fluids.
· The engulfed antigen is degraded to small peptides and the peptide fragments are displayed along with class II MHC molecules on the surface, for recognition by helper T-cells.
· The naive T-cell groups are of three categories:
a. Helper T-cells (Th)
b. Cytotoxic T-cells (CTL)
c. Suppressor T-cells
a. Helper T-cells are of two types: Th1 and Th2.
b. Cytotoxic T-cells (CTL) express the cell marker, CD8, usually denoted as CD+8 cells.
· Even after the removal of the antigen from the body, some of the activated Th1 cells remain as memory cells and are activated on subsequent exposure to the same antigen. (If reinfection is caused by the same microbes later in life.) Then these memory T-cells proliferate rapidly and trigger the immune response. This is referred to as a secondary immune response.
· The endogenous antigens are recognized by CTLs. A particular CTL group with a specific TCR recognizes a specific antigen displayed along with the class I MHC molecule on the APCs.
a. This CTL group is activated, undergoes mitotic divisions and differentiates into a clone of effector cells.
b. These cells now exhibit numerous lysosomes containing pore-forming proteins called perforins and several types of granzyme.
· The effector CTLs destroys the antigen containing cells by two mechanisms:
1. Perforins secreted by CTLs form pores on the target cells and allow the entry of granzymes into the cells. Granzytnes activate the apoptosis mechanism and the cells self-destruct themselves.
2. CTLs express the death activator Fas ligand (FasL). FasL binds with the Fas receptor on the target cells and induces apoptosis.
· As in the case of Th1 cells, some of the activated CTLs remain as memory cells and mediate the secondary immune responses.
The suppressor T-cells inhibit the immune response. Suppressor T-cells express lymphokines and inhibit the activity of Thl and CTL cells. In this way, these cells ensure an effective immune response.
Antibody-Antigen reactions
· Antibodies secreted by the plasma cells are specific to a particular antigen.
Complement system
· Complement is a generic term for a group of 20 proteins involved in facilitating immune responses.
1. They are synthesized in the liver and the phagocytes. They are present in the plasma and expressed on the cell membranes.
2. Complement proteins, like clotting factors, are present in the inactive form. They are designated as Cl to C9, B and D.
3. The complement system is activated by two pathways:
1. Anaphylactic (Immediate) Hypersensitivity
· Allergic reactions belong to this category, caused by excessive production of IgE antibodies in response to common environmental antigens such as pollens, house dust, mite and certain drugs.
· Antigens that produce allergies are called allergens.
2. Cytotoxic Hypersensitivity
· Autoimmune diseases are examples of this type.
3. Complex-mediated Hypersensitivity
· Antibodies bind with antigen and form immune complexes.
4. Cell-mediated (delayed) Hypersensitivity
· Rejection of transplants is due to this type of hypersensitivity.
MICROCIRCULATION
· Blood flow through the spleen has been demonstrated to have three distinct velocity patterns - fast, intermediate and slow.
FUNCTIONS
· Spleen has two major functions:
Immunity
· Spleen is a secondary lymphoid tissue and plays an important role in immune responses.
Haematopoiesis
· In the foetal stage, the spleen is the site of haematopoiesis.
B. ADAPTIVE (ACQUIRED) IMMUNITY SYSTEM
· The adaptive immune system is activated on exposure to specific antigens and the effects are manifest after 4 to 7 days.a. Antigens are macromolecules that evoke an immune response in the body. Chemically antigens can be proteins, polysaccharides, and conjugates of lipids with proteins (lipoproteins) or polysaccharides (glycolipids). Antigens exhibit chemical complexity and have a molecular weight of more than 10,000.
b. Every antigen displays regularly occurring chemical groups on their surface, termed epitopes or antigenic determinants. Epitopes are the smallest unit of the antigen that evokes an immune response. An antigen may possess one or more such epitopes.
c. Antigens are an integral part of a foreign organism or tissue, and such antigens are termed exogenous antigens.
d. Antigens that arise from cells within the body are the endogenous antigens—eg., proteins produced by virus-infected cells, cancerous cells.
Antigen Presentation
· An absolute requirement in any type of adaptive immune response is the recognition of the antigen by a T-lymphocyte.
· An absolute requirement in any type of adaptive immune response is the recognition of the antigen by a T-lymphocyte.
· The two categories of antigens are processed and presented to T-cells by different mechanisms.
Exogenous antigens
· The exogenous antigens are taken up by the antigen-presenting cells (APCs).
· APCs are the phagocytic cells, viz., the dendritic cells, macrophages and B-lymphocytes.
· APCs express class II major histocompatibility complex molecules (MHC) on their membrane surface. These are glycoproteins, which confer chemical identity to the host cells.
· APCs engulf the antigen containing pathogen or foreign tissue by endocytosis, degrade the organism/tissue and break up the antigenic protein into short peptides.
· These peptides (epitopes) are displayed on the surface of the APC along with MHC molecules, for recognition by the helper T-lymphocytes.
Endogenous antigens
· The endogenous antigens that are generated within the host body cells are degraded into peptide fragments within the cell and displayed at the surface of the cell along with class I MHC molecules.
· Class I MHC molecules are expressed by all the cells of the body and present the antigen-MHC complex to the cytotoxic lymphocytes.
· B-lymphocytes: present the antigen by a different process.
· B-cells engulf the antigen by receptor-mediated endocytosis.
· The B-cell receptors (BCR) for antigens are present on the cell membrane.
· BCRs (antibody) have a high affinity for the antigens and are engulfed even when they are present in very small concentrations in the body fluids.
· The engulfed antigen is degraded to small peptides and the peptide fragments are displayed along with class II MHC molecules on the surface, for recognition by helper T-cells.
Cell-mediated Immunity
· Cell-mediated immunity is the function of T-lymphocytes.
· Cell-mediated immunity is the function of T-lymphocytes.
· An important requisite of this process is the production of immunologically competent T-cells by the thymus.
· Groups of T-cells with identical T-cell receptors (TCR) for a particular antigen are formed in the thymus, from bone marrow-derived precursor lymphocytes.
· Each group of mature T-cells that are formed, recognize a particular epitope of an antigen, even though the epitope may never be present in the body.
· Groups of T-cells with identical T-cell receptors (TCR) for a particular antigen are formed in the thymus, from bone marrow-derived precursor lymphocytes.
· Each group of mature T-cells that are formed, recognize a particular epitope of an antigen, even though the epitope may never be present in the body.
· Groups of antigen-specific naive T-cells provide the basis for cell-mediated immunity.
· Naive T-cell groups with low affinity for MHC molecules are selected and those with strong affinity undergo apoptosis.
· Naive T-cell groups with low affinity for MHC molecules are selected and those with strong affinity undergo apoptosis.
· This process is called negative selection and eliminates T-cells that may destroy the host cells.
· The population of naive T-cells initiate the cell-mediated immune responses against foreign antigens.
· The population of naive T-cells initiate the cell-mediated immune responses against foreign antigens.
· The naive T-cell groups are of three categories:
a. Helper T-cells (Th)
b. Cytotoxic T-cells (CTL)
c. Suppressor T-cells
a. Helper T-cells are of two types: Th1 and Th2.
· Both of them express the cell marker, termed CD4 on their membrane, and are denoted as CD+4 cells.
· Th1 cells are involved in cell-mediated immunity, while Th2 cells are concerned with humoral immunity.
· Th1 cells are involved in cell-mediated immunity, while Th2 cells are concerned with humoral immunity.
b. Cytotoxic T-cells (CTL) express the cell marker, CD8, usually denoted as CD+8 cells.
· CTLs target endogenous antigens presented along with class I MHC molecules.
· Suppressor T-cells are regulatory T-cells and maintain the immune response within limits.
· All types of T-cells secrete several stimulatory or inhibitory factors collectively known as lymphokines. The lymphokines are the mediators of an effective immune response.
· Cell-mediated immunity is effective against exogenous antigens derived from protozoal infections, fungi, virus-infected cells, tumour cells and transplanted organs or tissues.
1. The APCs (with epitopes and MHC molecules displayed on their membrane surface) come in contact with naive T-cell groups in lymph nodes and spleen, where they may be present adjacent to each other.
2. A particular group of helper T-cells (Th1 ) containing the specific TCR for the epitope of the exogenous antigen is recognized.
3. These cells get activated by interleukin-12 and interferon-y secreted by APCs, in presence of co-stimulatory molecules - B7 present on APC and CD28 is present on the T-cells. The activated Th1 cells secrete the lymphokines—tumour-necrosis factor- and interferon-y.
· The Th1 cells multiply and proliferate forming a clone, in presence of the lymphokines and producing two important immune responses:
· They stimulate macrophages to kill the pathogen they have engulfed
· Recruit other leucocytes to the site producing an inflammatory response.
· Suppressor T-cells are regulatory T-cells and maintain the immune response within limits.
· All types of T-cells secrete several stimulatory or inhibitory factors collectively known as lymphokines. The lymphokines are the mediators of an effective immune response.
· Cell-mediated immunity is effective against exogenous antigens derived from protozoal infections, fungi, virus-infected cells, tumour cells and transplanted organs or tissues.
1. The APCs (with epitopes and MHC molecules displayed on their membrane surface) come in contact with naive T-cell groups in lymph nodes and spleen, where they may be present adjacent to each other.
2. A particular group of helper T-cells (Th1 ) containing the specific TCR for the epitope of the exogenous antigen is recognized.
3. These cells get activated by interleukin-12 and interferon-y secreted by APCs, in presence of co-stimulatory molecules - B7 present on APC and CD28 is present on the T-cells. The activated Th1 cells secrete the lymphokines—tumour-necrosis factor- and interferon-y.
· The Th1 cells multiply and proliferate forming a clone, in presence of the lymphokines and producing two important immune responses:
· They stimulate macrophages to kill the pathogen they have engulfed
· Recruit other leucocytes to the site producing an inflammatory response.
· Even after the removal of the antigen from the body, some of the activated Th1 cells remain as memory cells and are activated on subsequent exposure to the same antigen. (If reinfection is caused by the same microbes later in life.) Then these memory T-cells proliferate rapidly and trigger the immune response. This is referred to as a secondary immune response.
· The endogenous antigens are recognized by CTLs. A particular CTL group with a specific TCR recognizes a specific antigen displayed along with the class I MHC molecule on the APCs.
a. This CTL group is activated, undergoes mitotic divisions and differentiates into a clone of effector cells.
b. These cells now exhibit numerous lysosomes containing pore-forming proteins called perforins and several types of granzyme.
· The effector CTLs destroys the antigen containing cells by two mechanisms:
1. Perforins secreted by CTLs form pores on the target cells and allow the entry of granzymes into the cells. Granzytnes activate the apoptosis mechanism and the cells self-destruct themselves.
2. CTLs express the death activator Fas ligand (FasL). FasL binds with the Fas receptor on the target cells and induces apoptosis.
· As in the case of Th1 cells, some of the activated CTLs remain as memory cells and mediate the secondary immune responses.
The suppressor T-cells inhibit the immune response. Suppressor T-cells express lymphokines and inhibit the activity of Thl and CTL cells. In this way, these cells ensure an effective immune response.
· Natural Killer cells (NK cells): Natural killer cells are a subtype of T-cells that do not undergo processing in the thymus and take part in cell-mediated immunity.
3. They do not require the presence of MHC molecules or antibodies.
4. They are non-specific and resemble CTLs in their actions.
5. They destroy virus-infected cells, protozoa and pathogenic cells and tissues.
3. They do not require the presence of MHC molecules or antibodies.
4. They are non-specific and resemble CTLs in their actions.
5. They destroy virus-infected cells, protozoa and pathogenic cells and tissues.
Humoral Immunity
· Humoral immunity is mediated by B-cells.
· Humoral immunity is mediated by B-cells.
· B-cells undergo a selection process very much like the T-cells in the bone marrow.
a. This negative selection process results in a number of B-cells with specific B-cell receptors (BCR) for particular antigens.
b. BCRs are immunoglobulins that bind soluble antigens.
c. Antgenic foreign organisms come into contact with B-cells in the lymphoid tissues.
d. A particular group of B-cells recognizes the foreign antigen and engulfs it by receptor-mediated endocytosis. The BCR present on the B-cells is the receptors, which mediate this process.
e. The internalized organism is degraded into small fragments, and a specific epitope is displayed by the B-cells along with class II MHC molecules for recognition by T(i2 lymphocytes.
f. A Th2 clone with a specific TCR for the displayed epitope is activated in presence of co-stimulatory molecules and secretes lymphokines.
g. The lymphokines stimulate the B-cells to undergo mitotic divisions into a clone with identical BCRs.
h. The activated clone of B-cells differentiate into large secretory cells, called plasma cells.
i. The plasma cells secrete soluble antibodies (immunoglobulins).
a. This negative selection process results in a number of B-cells with specific B-cell receptors (BCR) for particular antigens.
b. BCRs are immunoglobulins that bind soluble antigens.
c. Antgenic foreign organisms come into contact with B-cells in the lymphoid tissues.
d. A particular group of B-cells recognizes the foreign antigen and engulfs it by receptor-mediated endocytosis. The BCR present on the B-cells is the receptors, which mediate this process.
e. The internalized organism is degraded into small fragments, and a specific epitope is displayed by the B-cells along with class II MHC molecules for recognition by T(i2 lymphocytes.
f. A Th2 clone with a specific TCR for the displayed epitope is activated in presence of co-stimulatory molecules and secretes lymphokines.
g. The lymphokines stimulate the B-cells to undergo mitotic divisions into a clone with identical BCRs.
h. The activated clone of B-cells differentiate into large secretory cells, called plasma cells.
i. The plasma cells secrete soluble antibodies (immunoglobulins).
Antibody-Antigen reactions
· Antibodies secreted by the plasma cells are specific to a particular antigen.
· The antibodies mediate immune responses in two ways :
1. Antibodies directly combine with the antigen and neutralize the pathogen
2. Antibodies activate the complement system and cause lysis of the pathogen
Direct binding of the antibodies with the antigen can produce the following effects :
3. Agglutination - antibodies combine with antigens on the pathogens, cause clumping, and the clumps are cleared by phagocytes.
4. Precipitation - antibody-antigen complex form an insoluble compound, precipitate and are engulfed by phagocytes.
5. Neutralization - antibodies cover up the toxic parts of the antigenic organism and render them harmless.
6. Lysis-antibodies attack the antigen containing cell membrane, rupture the cell and are ingested by the phagocytes.
· The direct antibody-antigen reactions are not potent enough to provide adequate protection against pathogens.
· The most effective way the antibodies immunize the body is by activating the complement system.
1. Antibodies directly combine with the antigen and neutralize the pathogen
2. Antibodies activate the complement system and cause lysis of the pathogen
Direct binding of the antibodies with the antigen can produce the following effects :
3. Agglutination - antibodies combine with antigens on the pathogens, cause clumping, and the clumps are cleared by phagocytes.
4. Precipitation - antibody-antigen complex form an insoluble compound, precipitate and are engulfed by phagocytes.
5. Neutralization - antibodies cover up the toxic parts of the antigenic organism and render them harmless.
6. Lysis-antibodies attack the antigen containing cell membrane, rupture the cell and are ingested by the phagocytes.
· The direct antibody-antigen reactions are not potent enough to provide adequate protection against pathogens.
· The most effective way the antibodies immunize the body is by activating the complement system.
Complement system
· Complement is a generic term for a group of 20 proteins involved in facilitating immune responses.
1. They are synthesized in the liver and the phagocytes. They are present in the plasma and expressed on the cell membranes.
2. Complement proteins, like clotting factors, are present in the inactive form. They are designated as Cl to C9, B and D.
3. The complement system is activated by two pathways:
(a) Classical pathway
(b) Alternative pathway
· The classical pathway occurs when an antibody binds with an antigen, a specific reactive site of the antibody is activated which initiates a 'cascade', and the endproducts of this chain of reactions lyse the pathogens.
1. The alternative pathway is activated in the absence of antigen-antibody reactions, especially by pathogens containing large polysaccharide groups.
2. These antigenic substances react with B and D complement proteins and activate the protein, C3. The endproducts lyse the pathogens.
The complement system has manifold functions :
a. Lyse pathogenic organisms.
b. Generate mediators for inflammatory response and attract phagocytes.
c. Coat the pathogens for efficient phagocytosis— Opsonization.
d. Enhance antibody-antigen immune response.
· The classical pathway occurs when an antibody binds with an antigen, a specific reactive site of the antibody is activated which initiates a 'cascade', and the endproducts of this chain of reactions lyse the pathogens.
1. The alternative pathway is activated in the absence of antigen-antibody reactions, especially by pathogens containing large polysaccharide groups.
2. These antigenic substances react with B and D complement proteins and activate the protein, C3. The endproducts lyse the pathogens.
The complement system has manifold functions :
a. Lyse pathogenic organisms.
b. Generate mediators for inflammatory response and attract phagocytes.
c. Coat the pathogens for efficient phagocytosis— Opsonization.
d. Enhance antibody-antigen immune response.
DISORDERS OF THE IMMUNE SYSTEM
· Immune mechanisms of the body target foreign antigens and defend the body against their harmful effects.· In certain circumstances, the immune response may become excessive. If the immune response persists over a longer period than necessary, gross tissue damage may occur.
· Abnormal immune responses to an antigen are termed hypersensitivity reactions or allergies.
· Abnormal immune responses to an antigen are termed hypersensitivity reactions or allergies.
· Four types of hypersensitivity reactions are seen.
1. Anaphylactic (Immediate) Hypersensitivity
· Allergic reactions belong to this category, caused by excessive production of IgE antibodies in response to common environmental antigens such as pollens, house dust, mite and certain drugs.
· Antigens that produce allergies are called allergens.
· IgE antibodies bind with mast cells and basophils, which contains vasoactive substances stored in their granules.
· On continued exposure, IgE ruptures these cells and release the vasoactive substances from their granules. Histamine, slow-reacting substance-A and eosinophil chemotactic substance are released.
· Massive release of histamine, in severe cases, results in circulatory shock due to vasodilatation and hypotension.
· Massive release of histamine, in severe cases, results in circulatory shock due to vasodilatation and hypotension.
· Bronchospasm, dyspnoea aggravate this condition and may become fatal due to anaphylactic shock.
· Milder forms of this type of hypersensitivity produce—urticaria, bronchial asthma and hay fever.
· Milder forms of this type of hypersensitivity produce—urticaria, bronchial asthma and hay fever.
2. Cytotoxic Hypersensitivity
· Autoimmune diseases are examples of this type.
· The immune system does not target the host cells.
· Genetic mutations, infections or drugs alter the host cell membrane and expose new antigens on their surface.
· This will lead to the production of antibodies against the host cells, and such antibodies are termed autoantibodies.
· Genetic mutations, infections or drugs alter the host cell membrane and expose new antigens on their surface.
· This will lead to the production of antibodies against the host cells, and such antibodies are termed autoantibodies.
· Auto-antibodies target the host cells.
· Rheumatoid arthritis, autoimmune haemolytic anaemia, idiopathic thrombo- cytopenia purpura (ITP), DiGeorge's disease, autoimmune thyroiditis (Hashimoto's disease) - are the result of such autoimmune reactions.
· Rheumatoid arthritis, autoimmune haemolytic anaemia, idiopathic thrombo- cytopenia purpura (ITP), DiGeorge's disease, autoimmune thyroiditis (Hashimoto's disease) - are the result of such autoimmune reactions.
3. Complex-mediated Hypersensitivity
· Antibodies bind with antigen and form immune complexes.
· The immune complexes are usually removed by phagocytes, but occasionally, persist and are deposited in the tissues.
· Immune complexes activate the complement system and release chemotactic factors attracting neutrophils.
· Immune complexes activate the complement system and release chemotactic factors attracting neutrophils.
· Neutrophils release their granular contents and damage the tissue harbouring such immune complexes.
· Serum sickness is a good illustration. Murine sera for treating tetanus or diphtheria produce skin rashes, joint pain and renal damage, few days after administration of the sera to some people.
· Serum sickness is a good illustration. Murine sera for treating tetanus or diphtheria produce skin rashes, joint pain and renal damage, few days after administration of the sera to some people.
· The persistence of immune complexes is said to be the cause of this condition.
4. Cell-mediated (delayed) Hypersensitivity
· Rejection of transplants is due to this type of hypersensitivity.
· This type of delayed hypersensitivity is mediated by a subset of T-cells.
· These T-cells secrete several lymphokines in response to the presence of antigens located on the transplanted tissue.
· These T-cells secrete several lymphokines in response to the presence of antigens located on the transplanted tissue.
· The lymphokines attract macrophages and other phagocytic cells to the transplant and initiate the rejection process.
· This is a type of cell-mediated immune reaction and is also seen in certain conditions of chronic contact with certain chemicals (contact dermatitis).
· This is a type of cell-mediated immune reaction and is also seen in certain conditions of chronic contact with certain chemicals (contact dermatitis).
SPLEEN STRUCTURE
· Spleen is a secondary lymphoid organ.
· Spleen is a secondary lymphoid organ.
· It consists of a mass of vascular and lymphoid tissue encased in a capsule. Spleen is made of two important components are: the white pulp and the red pulp, with the intervening marginal zone.
· The white pulp contains the lymphoid tissue in which T- and B-lymphocytes mature, proliferate under antigenic stimulation.
· The white pulp contains the lymphoid tissue in which T- and B-lymphocytes mature, proliferate under antigenic stimulation.
· The red pulp is a complex system of interconnected spaces harbouring a large population of phagocytic macrophages.
· The structure of the red pulp is such that the resident macrophages are able to remove particulates from the blood as it flows through this region.
· The structure of the red pulp is such that the resident macrophages are able to remove particulates from the blood as it flows through this region.
· The red pulp is an ultrafiltration device and removes the aged red cells, microbes, cellular debris and other particulate matter from the circulation.
· At the junction between the white pulp and red pulp, is the marginal zone, an area important in establishing immune responses.
· At the junction between the white pulp and red pulp, is the marginal zone, an area important in establishing immune responses.
MICROCIRCULATION
· Blood flow through the spleen has been demonstrated to have three distinct velocity patterns - fast, intermediate and slow.
· The bulk of the splenic blood (90%) is very rapid, 8% takes minutes to flow through and 2% takes an hour or more.
· Rapid blood flow occurs through a proportion of arterioles, which drain directly into the sinuses without much resistance to the passage of blood.
· Intermediate velocity is the result of 'open' circulation by which blood percolates slowly through the reticular tissue, permitting maximum contact with splenic macrophages and enhancing the removal of particulates and ageing red cells.
· Slow circulation probably involves adhesion between blood cells and splenic cells for a considerable period of time.
· The total volume of blood in the intermediate and slow circulation exceeds that of the rapid blood flow.
· Rapid blood flow occurs through a proportion of arterioles, which drain directly into the sinuses without much resistance to the passage of blood.
· Intermediate velocity is the result of 'open' circulation by which blood percolates slowly through the reticular tissue, permitting maximum contact with splenic macrophages and enhancing the removal of particulates and ageing red cells.
· Slow circulation probably involves adhesion between blood cells and splenic cells for a considerable period of time.
· The total volume of blood in the intermediate and slow circulation exceeds that of the rapid blood flow.
· The net effect is an increase in haematocrit within the spleen compared to the rest of the general circulation.
FUNCTIONS
· Spleen has two major functions:
(1) removal of particulate material including ageing red cells from the circulation and
(2) supply of lymphocytes and antibodies as part of the body's immune system.
· These activities are carried out in conjunction with the rest of the body.
· Spleen is not essential for life, even though its removal hampers the immune responses.
Removal and destruction
· The splenic macrophages remove and destroy particulate materials, cell debris, aged red cells and microbes.
Removal and destruction
· The splenic macrophages remove and destroy particulate materials, cell debris, aged red cells and microbes.
· Macrophages are highly phagocytic, ingest these materials and digest them.
· Spleen is the major site of destruction of aged or damaged red cells and platelets. The structure of the red pulp and pattern of blood flow through this region facilitates the phagocytic activity of the macrophages.
· Spleen is the major site of destruction of aged or damaged red cells and platelets. The structure of the red pulp and pattern of blood flow through this region facilitates the phagocytic activity of the macrophages.
Immunity
· Spleen is a secondary lymphoid tissue and plays an important role in immune responses.
· Macrophages and lymphocytes are normally resident in the spleen.
· The blood flow pattern through the white pulp facilitates various aspects of immune responses.
· Antigen presentation, recognition by T-cells, activation and proliferation of lymphocytes, cell-mediated immune reactions, antibody-mediated immune reactions - largely occur in the spleen.
· The proliferation of T-cell clones and maturation of B-cell clones take place in the marginal zone of the spleen.
Haematopoiesis
· In the foetal stage, the spleen is the site of haematopoiesis.
· The red pulp houses committed precursors of blood cells.
· In the adult, lymphopoiesis in the white pulp contributes to the circulating reserve of T-cell and B-cell clones.
· In certain pathological states, the red pulp may resume haematopoiesis.