understanding the immunology

IMMUNITY

Everyday we are exposed to large number of infectious agents.

However, only a few of these exposures result in disease. Why?

This is due to the fact that the body is able to defend itself from most of these foreign agents.

This overall ability of the host to fight the disease-causing organisms, conferred by the immune system is called immunity.

The organs of the immune system includes primary lymphoid organs like bone marrow and Thymus where immature lymphocytes differentiate into antigen sensitive lymphocytes and secondary lymphoid organs like lymph nodes, spleen which provide sites of interaction of lymphocytes and antigens.

Lymphoid Organs:

Lymphoid organs are those organs where the maturation and proliferation of lymphocytes take place.

Types of Lymphoid Organs :

There are two types

(a) Primary Lymphoid' Organs (= Central lymphoid organs)

They are those organs where T -lymphocytes and B -lymphocytes mature and acquire their antigen -specific receptors.

Thymus and Bursa of fabricius of birds are primary lymphoid organs.

The bone marrow of mammals is considered equivalent to avian Bursa of fabricius.

All the cells of the immune system are initially derived from the bone marrow.

They form through a process called hematopoiesis.

During hematopoiesis, bone marrow -derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere.

The bone marrow produces B-cells, NK cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets.

Thymus is also called "Throne of immunity" or "Training school of T -lymphocytes".

The function of the thymus is to produce mature T cells.

Immature thymocytes / prothymocytes leave the bone marrow and migrate into the thymus.

Through a remarkable maturation process, sometimes referred to as thymic education, T -cells that are beneficial to the immune system are spread, while those T -cells that might evoke a detrimental auto-immune response are eliminated.

The mature Tcells are then released into the blood stream.

(b) Secondary Lymphoid Organs ( =Peripheral lymphoid organs)

After maturation, B -lymphocytes and T -lymphocytes migrate via blood vascular and lymphatic system to the secondary lymphoid organs where they undergo proliferation and differentiation.

The secondary lymphoid organs are lymph nodes, spleen, tonsils, peyer's patches of the small intestine, appendix and mucosal associated lymphoid tissues (MALT).

MALT is located within the lining of the major tracts (digestive, respiratory and urinogenital).

It constitutes about 50% of the lymphoid tissue in human body.

In secondary lymphoid organs like lymph nodes and spleen, there are two types of areas

(i) Thymus -dependent Area: Any part of peripheral lymphoid organs populated by T -lymphocytes. e.g. Paracortex of lymph nodes and centre of malpighian corpuscle of spleen.

(ii) Thymus -independent Area: It is rich is B -lymphocytes.

Spleen

The spleen is an immunologic filter of the blood.

It contains B cells, T cells, macrophages, natural killer cells and red blood cells.

In addition to capturing foreign materials (antigens) from the blood that passes through the spleen, migratory macrophages bring antigens to the spleen via the bloodstream.

An immune response is initiated when the macrophages present the antigen to the appropriate B or T cells.

This organ can be thought of as an immunological conference center.

In the spleen, B cells become activated and produce large amounts of antibody.

Also, old red blood cells are destroyed in the spleen.

Lymph Nodes

The lymph nodes function as an immunologic filter for the body fluid known as lymph.

Lymph nodes are found throughout the body.

Composed mostly of T cells, B cells, and macrophages, the nodes drain fluid from most of our tissues.

Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation.

In a similar fashion as the spleen, the macrophages that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response.

Lymphoid tissue located within the lining of major tracts (respiratory, digestive etc.) are called mucosal associated lymphoid tissue (MALT).

It constitutes 50% of the lymphoid tissue in the body.

Types of Immunity

There are two types of immunity against pathogens :

Non specific innate and Specific acquired immunity

A. Non-specific innate immunity:

It includes all those defense elements with which an individual is born i.e., always available to protect a living body. It can be further of four categories :

1. Anatomic barriers or Physical barriers :

(a) Skin:

The skin is physical barrier of body.

Its outer tough layer, the stratum corneum prevents the entry of bacteria and viruses.

(b) Mucous membrane:

Mucus secreted by mucous membrane traps the microorganisms and immobilises them.

Microorganisms and dust particles can enter the respiratory tract with air during breathing which are trapped in the mucus.

The cilia sweep the mucus loaded with microorganisms and dust particles into the pharynx (throat).

From the pharynx it is thrown out or swallowed for elimination with the faeces.

Mucous membrane over mucosa of stomach protects it from corrosive action of HCl.

2. Physiological barrier :

(a) Oil secreted by the oil glands and sweat secreted by sweat glands make the surface of the skin acidic (pH 3-5). This does not allow the microorganisms to establish on the skin. Some friendly bacteria also occur on the skin which releases acids and other metabolic wastes that check the growth of pathogens. The sweat also contains an enzyme named lysozyme that destroys the cell walls of many bacteria.

(b) Lysozyme is also present in tears and checks eye infections.

(c) Lysozyme is also present in the saliva which kills bacteria present in food.

(d) Highly acidic gastric juice also kills harmful bacteria in the stomach.

(e) Bile checks the growth of foreign bacteria in the intestine.

(f) The mesh of fine hair in our nostrils filters out particles which may carry pathogens. Nasal secretions also destroy the harmful foreign germs with their lysozyme.

(g) Certain bacteria normally live in vagina. These bacteria produce lactic acid. Lactic acid kills the foreign bacteria.

(h) Interferon:

These are the glycoproteins released by the cells in response to a viral infection which they help to combat.

These interferons do not kill/inactivate the virus, but they make the unattacked cells less susceptible so they are prevented from the attack of virus.

Interferons were discovered by Isaac and Lindemann.

They also prevent the viruses from taking over the cellular machinery.

Interferon proteins have proved to be effective in treating influenza and hepatitis, but their role in cancer treatment is doubtful. (Interferons are now included in cytokine barrier.)

Concept Builder

The interferon treatment known as interferon alpha is used to treat a variety of cancers, including two different types of leukemia and AIDS-related Kaposi's sarcoma.

Hairy cell leukemia is a type of cancer that affects the bone marrow as well as the blood.

Chronic myelogenous leukemia tends to only affect the bone marrow.

AIDS-related Kaposi's sarcoma is a type of cancer that attacks the soft tissue of the body.

Interferon beta is another type of interferon treatment.

This class of medication is used to treat multiple sclerosis, a degenerative disease that affects the brain as well as the spinal cord.

Still another type of treatment is interferon gamma.

This is used to treat a condition known as chronic granulomatous disease, which is marked by masses that resemble tumors that develop in various tissues of the body.

3. Phagocytic barrier :

The internal defence is carried on by white blood corpuscles, macrophages, inflammatory reaction, fever.

(a) White blood corpuscles (Leucocytes) :

The leucocytes in general and lymphocytes in particular are capable of squeezing out through the wall of the blood capillaries into the extravascular regions.

This phenomenon is called diapedesis.

The leucocytes protect in different ways.

(i) Lymphocytes: Lymphocytes can produce plasma cells which secrete antibodies to provide immunity.

(ii) Monocytes: They are phagocytic in action.

(iii) Eosinophils : Eosinophils can attach themselves to parasitic forms (mostly in case of helminths) and cause their destruction by liberating lysosomal enzymes on their surface.

(iv) Neutrophils : They eat up harmful germs and are, therefore phagocytic in nature.

(b) Macrophages:

The macrophages are formed by enlargement of monocytes. They are large cells which are phagocytic in nature.

4. Inflammatory barrier:

When the micro-organisms like bacteria, viruses, etc. enter the body tissue through some injury, these produce some toxic substances which kill more cells.

These broken cells also release some material which attract the mast cells.

The mast cells release histamine.

Histamine causes dilation of capillaries and small blood vessels surrounding the injury and increases the permeability of the capillary walls.

The more blood flows to area making it red and warm.

The fluid (plasma) leaks out into the tissue spaces, causing its swelling.

This reaction of the body is known as inflammatory response.

The plasma that accumulates at the injured site dilutes the toxins secreted by bacteria and decreases their effect.

Fever:

The inflammatory response may be in the region of the wound (localized), or it may spread all over the body (systemic).

In systemic inflammatory response, the number of WBC increases generally, the fever is caused by the toxins released by the pathogens or by compounds called pyrogens (fever producing substances).

These compounds are released by W.B.C. in order to regulate temperature of the body.

Moderate fever stimulates the phagocytes and inhibits growth of microorganism.

However, a very high fever is dangerous.

It is necessary to bring down fever by giving antipyretics (fever-reducing drug) and by applying cold packs.

Thus the interferons leucocytes, macrophages, inflammatory response and fever form second line of defence.

5. Natural Killer (NK) Cells:

NK cells are another population of large granular lymphocytes that destroys wide variety of infectious microbes and certain spontaneously arising tumor cells.

Unlike T-cell, these do not mature in the thymus and unlike both Band T-cells, they lack surface molecules/antigen receptors.

NK cells are present in the spleen, lymph nodes, red bone marrow and blood.

NK cells release g-interferon which stimulates their cytolytic activity.

NK cells may release chemical-perforins which cause cytolysis of the microbe or may bind to a target cell to inflict damage by direct contact.

NK cells probably attack cells that do not display major histocompatibility complex (MHC) antigens.

NK cells are defective or decreases in number in some cancer patients and in patients with AIDS.

6. Complement System :

The complement system is a set of 30 different protein molecules always found in the blood.

There are no cells in the system.

With an infection, this system of molecules is activated, leading to a sequence of events on the surface of the pathogen that helps destroy the pathogen and eliminate the infection.

The complement system can be activated in two main ways.

The first and most potent way known as Classical Pathway occurs when IgG (or IgM) binds to antigen at the surface of a cell.

This exposes the Fc region of the antibody such that the first complement protein (C₁) binds.

The second means of activation known as Alternate Pathway is part of the natural (innate) immune response. (i.e. neither antibodies nor T cell receptors are involved.)

Here certain polysaccharides found on the surface of bacteria activate the system.

This can occur immediately and does not require prior exposure to the molecules.

But in either case, a cascade of events follows, in which each step leads to the next.

At the centre of the cascade are steps in which the proteolysis of a complement protein leads to a smaller protein and a peptide.

The smaller protein remains bound to the complex at the surface of the microorganism, while the peptide diffuses away.

As a result, the membrane loses all its regulatory properties; that is to say, the cell swells and bursts.

This final complex of molecules that causes the cell lysis is termed the membrane attack complex (MAC).

Thus the complement system triggers a constellation of effects that helps deal with an infection:

(a) Opsonization

(b) Chemotaxis (attracting macrophages and neutrophils)

(c) Inflammation

(d) Lysis (rupturing membranes of foreign cells)

The present classification of Innate Immunity is as follows:

Innate immunity is non-specific type of defence, that is present at the time of birth. This is accomplished by providing different types of barriers to the entry of the foreign agents into our body. Innate immunity consist of four types of barriers.

These are :

(i) Physical barriers: Skin on our body is the main barrier which prevents entry of the microorganisms. Mucus coating of the epithelium lining the respiratory, gastrointestinal and urogenital tracts also help in trapping microbes entering our body.

(ii) Physiological barriers: Acid in the stomach, saliva in the mouth, tears from eyes-all prevent microbial growth.

(iii) Cellular barriers: Certain types of leukocytes (WBC) of our body like polymorpho-nuclear leukocytes (PMNL-neutrophils) and monocytes and natural killer (type of lymphocytes) in the blood as well as macrophages in tissues can phagocytose and destroy microbes.

(iv) Cytokine barriers: Virus-infected cells secrete glycoproteins called interferons which protect non-infected cells from viral infection.

B. Acquired or Adaptive or Specific Immunity

Immune system forms third line of defence.

There are two components of immune system in body :

Humoral immune system and cell-mediated immune system. The important characteristics of the immune systems are

1. Specificity: Ability to differentiate between foreign molecules.

2. Diversity: To recognize enormous variety of foreign molecules.

3. Discrimination: Ability to differentiate between foreign and self i.e., will respond to foreign compound and avoid response to self molecules.

4. Memory: After encountering any foreign agent or microbe, immune response is evoked. It results in the formation of memory cells responsible for retaining memory. This is the basis of vaccination as the second response to the same microbe will evoke hightened immune response due to memory cells.

Specific Immunity Involves two types of Cells

1. Lymphocytes and

2. Antigen presenting cells

1. Lymphocytes:

Lymphocytes (a type of WBCS) are the main cells of immune system of the body.

Lymphocytes, meant for immune system, are of two types: T-cells and B-cells.

Both types of cells develop from the stem cells found in the liver of the foetus and in the bone marrow cells of the adult.

Those lymphocytes that migrate to the thymus and differentiate under its influence are called 'T-cells', while those cells that continue to be in the bone marrow for differentiation are known as 'B-cells'.

The final maturation of young lymphocytes occur in lymphoid tissues like lymph nodes, spleen and tonsils.

T-cells are responsible for cellular immunity, however, B-lymphocytes produce antibodies that take part in the humoral immunity.

Both T-cells and B-cells require antigens to trigger them into action but they respond differently.

B-lymphocytes are independent of the thymus and in man probably complete their early maturation within the bone marrow.

They are called B-cells because they mature within the Bursa of Fabricius found in the cloaca of birds.

2. Antigen presenting cells:

Antigen presenting cells (APCs) are a special class of cells which process and present exogenous antigens.

APCs include macrophages, B-cells, and dendritic cells.

APCs are strategically located in places where antigens are likely to penetrate non specific defenses and enter the body.

These are the epidermis and dermis of the skin, mucus membranes that line the respiratory, urinary, reproductive tracts.

The steps in processing and presenting an exogenous antigen by an APC include

(a) Ingestion of antigen

(b) Digestion of antigen into peptide fragments

(c) Fusion of peptide fragments to MHC and its insertion into the plasma membrane. This triggers either a cell mediated immune response (CMI) or Humoral mediated immune (HMI) response.

Antigens:

The antigens are foreign 'molecules' that invade the body of an organism.

The word 'antigen' is a shortened form of 'antibody generating' because they stimulate the production of antibodies in response to infection.

Antigens are generally large molecules.

The majority of them are made of proteins or polysaccharides found on the cell walls of bacteria and other cells or on the coats of viruses.

All antigens are not the parts of microorganism.

Other structures like pollen grains, white of an egg, shell fish, certain fruits and vegetables, chicken, feathers of birds, blood cells from other persons or animals, drugs, chemicals, etc. can also induce the immune system to produce antibodies.

Antibodies are an army of proteins produced by plasma cells.

Structure of Antibody (Ig)

Antibodies (Immunoglobulins, abbreviated Ig) are glycoproteins of molecular weight 150,000-900,000 kd.

One end of the Ig binds to antigens (the Fab portion, so called because it is the fragment of the molecule which is antigen binding), and the other end which is crystallizable, and therefore called Fc, is responsible for effector functions.

There are 5 classes ('Isotypes') of Ig; IgM, IgG, IgA, IgD and IgE.

Light chains exist in two classes, lambda and kappa.

Each antibody molecule has either lambda or kappa light chains, not both.

Immunoglobulins are found in serum and in secretions from mucosal surfaces.

They are produced and secreted by plasma cells which are found mainly within lymph nodes and connective tissues and do not circulate.

Plasma cells are derived from B lymphocytes.

These cells are responsible to secrete antibodies i.e. Immunoglobulins.

The immunoglobulin molecule consists of two light chains, each of approximate molecular weight 25,000, and two heavy chains, each of approximate molecular weight 50,000.

IgA exists in monomeric and dimeric form, IgM in pentameric form.

The links between monomers are made by a J chain.

Additionally, IgA molecules receive a secretory component from the epithelial cells into which they pass.

This is used to transport them through the cell and remains attached to the IgA molecule within secretions at the mucosal surface.

The heavy and light chains consist of amino acid sequences.

In the regions concerned with antigen binding, these regions are extremely variable, whereas in other regions of the molecule, they are relatively constant.

Thus each heavy and each light chain possesses a variable and a constant region.

The isotype of an Ig is determined by the constant region.

L-chains are linked from H-chains by disulphide (S-S) links. Intrachain S-S links divide H and L chains into domains which are separately folded.

Antibodies are synthesized by B lymphocytes and exist in 2 forms -either membrane bound or secreted.

B lymphocytes use membrane bound antibody to interact with antigens.

B cells makes antibodies all of the same specificity i.e. able to react with the same antigenic determinants, and its progeny (as a consequence of mitotic division) are referred to as a clone.

The clone will continue making antibody of the same specificity.

Simultaneously, there will be lots of other clones of different specificity.

This is known as a polyclonal response.

Antigens have determinants called epitopes.

Epitopes are molecular shapes recognized by antibodies, which recognise 1 epitope rather than whole antigen.

Antigens may be proteins, lipids or carbohydrates, and an antigen may consist of many different epitopes, and/or may have many repeated epitopes.

B-Iymphocytes evolve into plasma cells under the influence of T cell released cytokines.

Plasma cells secrete antibodies in greater amounts, but do not divide.

They exist in lymphoid tissues, not blood.

Other B cells circulate as memory cells.

B cells divide, forming plasma cells and B memory cells.

Plasma cells make and release between 2000 and 20,000 antibody molecules per second into the blood for the next four or five days.

B memory cells live for months or years, and are part of the immune memory system.

B-Iymphocytes are formed within the bone marrow and undergo their development.

They have the following functions:

(i) To interact with antigenic epitopes, using their immunoglobulin receptors.

(ii) To subsequently develop into plasma cells, secreting large amounts of specific antibody

(iii) To circulate as memory cells.

(iv) To present antigenic peptides to T cells (as antigen presenting cells).

Main functions of free (Soluble) Antibodies:

Antibodies exist free in body fluids, e.g. serum, and membrane bound to B lymphocytes.

Their function, when membrane bound is to capture antigen for which they have specificity, after which the B lymphocytes will take the antigen into its cytoplasm for further processing.

Free antibodies cause agglutination of particulate matter, including bacteria and viruses.

IgM is particularly suitable for this, as it is able to change its shape.

Opsonization i.e. coating of antigen by molecules known as opsonins for which the antibody's Fab region has specificity (especially IgG).

Even complement system takes part in opsonisation specially C3B molecule.

This facilitates subsequent phagocytosis by cells possessing an Fc receptor, e.g. neutrophil (polymorphonuclear leucocytes or polymorphs).

Hence, opsonisation is the process that facilitates the phagocytosis of antigen.

Thus it can be seen that in opsonization and phagocytosis, both, the Fab and the Fc portions of the immunoglobulin molecule are involved.

Neutralization of toxins released by bacteria e.g. tetanus toxin is neutralized when specific IgG antibody binds, thus preventing the toxin binding to motor end plates and causing persistent stimulation, manifest as sustained muscular contraction which is the hallmark of tetanic spasms.

This applies particularly to IgG.

In the case of viruses, antibodies can hinder their ability to attach to receptors on host cells. Here, only Fab is involved.

Antibodies against bacterial cilia or flagella will hinder their movement and ability to escape the attentions of phagocytic cells.

Mucosal protection is provided mainly by IgA, and to a lesser degree by IgG.

IgA acts chiefly by inhibiting pathogens from gaining attachment to mucosal surfaces.

As a consequence of antigen e.g. parasitic worms, binding to specific IgE attached to mast cells by their receptor for IgE, there is release of mediators from the mast cell.

This leads to contraction of smooth muscle, which can result in diarrhoea, and expulsion of parasites.

Precipitation of soluble antigens by immune complex formation.

Consist of antigen linked to antibody.

Depending on ratio of antigen to antibody, these can be of varying size.

When fixed at one site, they can be removed by phagocytic cells.

They may also circulate prior to localization and removal, and can fix complement.

Antibodies bind to organisms via their Fab region.

Large granular lymphocytes (Natural Killer cells -abbreviated NK cells), attach via Fc receptors, and kill these organisms not by phagocytosis but by release of toxic substances called perforins.

Concept Builder

Clonal Selection Theory : A theory explaining how the cells of the immune system produce large quantities of the right antibody at the right time, i.e., when the appropriate angtigen is encountered.

It proposes that there is a pre-existing pool of lymphocytes (B-cells) consisting of numerous small subsets.

Each subset carries a unique set of surface antibody molecules with its own particular binding characteristics.

If a cell encounters and binds the corresponding antigen it is selected stimulated to divide repeatedly and produce a large clone of identical cells, all secreting the antibody.

The involvement of helper T cells (see T-cell) is essential for activation of the B cell.

A form of clonal selection is also invoked to explain the development of immunological tolerance.

Five classes (Isotypes) of Antibodies

(i) IgA forms 15% of total antibody count. It is found in mucous secretions of the respiratory tract and the upper part of the digestive tract and the vagina. It is also found in colostrum. Colostrum is a golden liquid substance that a nursing mother expels from her breasts 24-48 hours after delivery. This substance is produced before the milk and is very important in the transfer of antibodies to a newborn infant. IgA given by the mother in the colostrum will protect the baby for about six months. Oimeric IgA has four paratopes.

(ii) IgD forms less than 1% of the total antibodies appears to have a role in activating and suppressing lymphocyte activity found in large quantities in the cell walls of many B-cells. IgO has two paratopes.

(iii) IgE is less than 1% of total antibodies. Mediator in allergic responses. Most importantly activates histamine secreting cells. Also appears to playa role in parasitic infection. IgE has two paratopes.

(iv) IgG-composes 75% of our immunoglobulin pool. IgG stimulates phagocytic cells, activates the complement system , binds neutrophils, opsonizes and can neutralise toxins. Most importantly, it is the only antibody that can cross the placenta and confer immunity on the foetus. IgG also has two paratopes.

(v) IgM-makes up 7-10% of our total antibodies. This is the predominant early antibody; the one that first activates in an initial attack of antigen. Because of its high number of antigen binding sites (10), it is an effective agglutinator of antigen. This is important in the initial activation of B-cells, macrophages, and the complement system.

Table : Functions of Different Immunoglobulin Classes

*Most abundant Ig (about 75 percent of human antibodies) ; only antibody that can cross placenta.

Mode of Action of T-cells to Antigens or cell mediated immunity (CMI) :

T-cells are the major cells that drive cellular immunity whereas an another type of lymphocyte, called as B cells, is the principle cell involved with antibody-mediated immunity.

T-cells are so-called because they are matured in an organ called the thymus.

The surface of a T-cell contains thousands of T cell receptors (TCR) but, for anyone T-cell, all the receptors are identical (monoclonal).

This means that anyone T-cell is only able to recognize a small group of related antigens i.e. each T-cell is specific only to those antigens and is not effective against any others.

The receptor rarely binds with an entire antigen but with a sub-section of it called an epitope.

The function of T-cells is to detect cells in the body that are internally infected with viruses and bacteria.

Intra cellular pathogen do this by sampling the contents of cells.

Two types of T-cells sample different populations of cells and take diferent action when they detect a antigen.

These are the "killer" or cytotoxic (CD8+) T cells and the "helper" (CD4+) T-cells.

The CD8+ and CD4+ describe the types of receptors that each carries.

A third type of T-cell called a "suppressor" T-cells also uses the CD8+receptor.

Almost all the cells in the body express a protein called the major histocompatibility complex protein.

The function of MHC is to present antigens to T-cells.

MHC has a slit in it, shaped like a letter box and the cell pushes antigens through this slit.

T-cell receptors plug onto the MHC molecule and try to bind with the presented antigen.

MHC comes in two major varieties: MHC class I and MHC class II.

MHC class I is present on almost all nucleated cells and it is the job of killer T-cells to bind to antigens presented in this way.

When a match is found, the killer T-cell latches onto the infected cell and destroys it.

MHC class II is present only on a population of cells known as antigen presenting cells (APC).

These include macrophages, B cells and dendritic cells. It is the job of helper T-cells to bind to antigens presented in this way.

When this happens, a helper T-cell can do several things:

(a) It produces special messenger molecules called cytokines. Various different cytokines send different complex signals to other cells including : attracting immune system cells to the site of the infection, causing endothelial (blood vessel lining) cells to let these other cells through and causing the immune system cells to activate themselves.

(b) Cooperate with complementary B-cells to get them to clone themselves and to release antibodies.

(c) Clone themselves to increase the number of this type of T-cell.

Helper T-cells are strongly implicated in the process of demyelination in multiple sclerosis.

The third type of T-cell, the suppressor T-cell, is involved with suppressing an immune response.

It is not well understood how they do but they probably use several mechanisms including "programmed cell deatft' (apoptosis) which involves sending cytokines to other immune system cells telling them to commit suicide.

T-cells are manufactured in the bone marrow but migrate to an organ called the thymus where they are matured via a process called affinity maturation which removes those which are active against the body's own antigens (autoreactive).

Selection for particular T-cells is dealt with in the entry on the thymus.

Helper T cells are CD4 cells that become activated when they encounter the antigens now displayed on the macrophage surface.

Activated T cells identify and activate B cells.

Clonal Selection and Primary and Secondary Immune Responses

Each Band T lymphocyte displays on its surface a specific receptor; the number of cells expressing a given receptor is rather small.

In case of a B cell, this receptor is the antibody produced by that cell.

When this receptor interacts with the antigenic determinant specific to it, the lymphocyte becomes activated and divides to form a clone of cells.

These cells are also transformed into effector cells, i.e., antibody producing B cells and T cytotoxic cells.

This phenomenon is called clonal selection, where all the cells in a given T or B cell clone are derived from a single parental cell, and exhibit the same specificity for antigenic determinant.

But some of the activated lymphocytes develop into long-lived memory cells, and do not produce antibodies or kill infected cells.

The immune response mounted as a result of the first encounter of an animal with an antigen takes relatively longer, is feeble, and declines rapidly.

This is known as primary immune response.

But a subsequent encounter of this animal with the same antigen results in a hightened immune response much more rapidly.

This is referred to as the secondary immune response or anamnestic response.

The secondary response is due to the memory cells that were produced during the primary response; it lasts much longer than primary response.

This is why a person surviving a disease like chicken pox or measles becomes immune to subsequent attacks of the same disease.

Development of Immunity

A person may develop immunity in three ways.

(i) Vaccination: It is a technique to develop immunity without infection. Weakened or dead pathogens (attenuated) or parts of pathogens are injected into a person who is required to be made immune. The pathogens given in a vaccine are unable to cause the disease but are sufficient to stimulate the formation of antibodies by the host's immune system. Often 2 or 3 additional doses are needed to generate adequate immunity. These doses are called booster doses.

(ii) Antitoxins: Antibodies that neutralize toxins produced in the body or introduced from outside are called antitoxins. Bacterial toxins are produced in the body, however antitoxins produced from outside are prepared from snake venom and is used as a remedy for snake bite.

(iii) Immunity through diseases: Some diseases such as mumps, measles, small pox produce a life long immunity. Hence these diseases do not appear again.

Types of Immunity: There are two main types of immunity : Inborn or innate and acquired or adaptive.

(i) Inborn or innate immunity: This type of immunity is inherited by the organism from their parents and protects it from birth throughout life. Example : Human beings have inborn immunity against distemper (a fatal disease of dogs).

(ii) Acquired or adaptive immunity: This immunity is acquired in life time. The acquired immunity is of two types: Active or natural and passive or artificial.

(a) Active immunity: When an organism's own cells produce antibodies it is called active immunity. It develops when a person suffers from a disease or gets vaccination for a disease.

(b) Passive immunity: In passive immunity, the antibodies are produced in some other organisms (e.g., vertebrates) in response to the given antigen. These antibodies are then injected into the human body at the time of need. This is known as inoculation. For example, persons infected by rabies, tetanus, Salmonella (causes food poisoning) and snake venom are given the sufficient amount of antibodies so that they can survive.

Passive immunity provides immediate relief, however, active immunity requires some time for the formation of antibodies.

There is another form of passive immunity. Nursing mothers transfer antibodies prepared in their body to the infants in their milk. Bottle-fed infants do not get this benefit. After a few weeks, infants own immunity system starts working.

Table : Differences between Active Immunity and Passive Immunity

History of Vaccination and Immunisation

In vaccination weakened or dead pathogens, or portions of pathogens, are injected into a person who is required to be made immune.

The pathogens given in a vaccine are unable to cause the disease, but are sufficient to stimulate the formation of antibodies by host's cells.

The process of vaccination was initiated by Edward Jenner in 1790.

He observed that milkmaids did not contract smallpox apparently because they were exposed to a similar but milder form of disease called cowpox.

Edward Jenner infected first James Phipps, a healthy boy of about 8 years with cowpox and two months later he infected the boy with smallpox.

The boy did not suffer from small pox.

Jenner proposed that an induced mild form of a disease would protect a person from a virulent form (which has ability to damage the host).

He used the term vaccine (in Latin Vacca means 'cow') and the term vaccination for protective inoculation.

Edward Jenner was the first to discover a safe and effective means of producing artificial immunity against small pox.

Thus once vaccination is done the individual is protected from the disease.

Vaccination develops acquired immunity.

Pasteur confirmed Jenner's findings and produced vaccines for other diseases like anthrax, rabies and chicken cholera.

In 1891, another daring step was taken which added to the growing understanding of immunology.

A little girl lay dying of diphtheria.

Her physician, Emil von Behring, decided to gamble on her life.

He infected sheep with diphtheria bacteria and waited for some time.

He then withdrew some blood from the sheep, and separated the serum by allowing it to clot.

He injected the serum into the patient.

Within a few hours she began to recover dramatically.

A new method of treatment had been discovered -passive immunity.

Von Behring was awarded the Nobel prize for this work.

Passive immunisation is the practice of taking antibodies produced by a vertebrate, in response to deliberate infection, and transferring them to a different organism by injection.

For instance, persons infected by rabies or Salmonella (that causes food poisoning) are likely to succumb to the disease as they would not be able to produce sufficient amounts of antibodies quickly.

To avert death, such persons are inoculated with antibodies produced in plasma of horses or cow.

This provides passive immunity.

IMMUNE SYSTEM DISORDER

Improper functioning of immune system can cause, discomfort, disease or even death. These disorders may involve :

1. Hypersensitivity or Allergy :

Allergy means inappropriate and excessive response to common antigens.

Substance causing allergic reaction are called allergens.

The common allergens are dust, pollen, mould, spores, fabrics, feathers, fur, plants, bacteria, foods, heat, cold, sunlight.

Parthenium flower is a common allergen in India.

Allergy mostly affects the skin and the mucous membrane.

Hay fever affects the mucous membranes of the nose, eyes and upper respiratory tracts.

In asthma, the lower portions of the respiratory system are severely affected.

In eczema, the skin becomes red, followed by the appearance of minute blisters.

During allergic reaction there is increased release of histamine from mast cells.

It causes marked dilation of all the peripheral blood vessels and the capillaries become highly permeable so that large amounts of fluid leak out from the blood into the tissues.

The blood pressure decreases drastically often resulting in the death of the individual within a short time.

Spleen is called the shock organ of allergy.

The exact nature of the substance of which a person is hypersensitive must be known before he can be properly treated.

Some forms of allergy are mentioned below:

(i) Hay fever: In this allergic form, there is swollen, reddened, running eyes and nose. The drugs called antihistamines are of major importance in the treatment of this allergic disorder.

(ii) Asthma: It is the sudden spasm of tissue surrounding respiratory tract causing narrowing of respiratory tract. The tissue surrounding the respiratory tubes in the lungs swell up and compress the tubes. Hence there is difficulty in breathing.

(iii) Anaphylactic shock : It is an allergic reaction involving all the tissues of the body and occurs in a few minutes after the injection of an antigen such as penicillin. Such a reaction is very serious. Histamine released from ruptured mast cells causes marked dilation of all the arteries so that a large amount of fluid is passed from the blood to the tissues and there is a drastic fall in blood pressure. The affected person may become unconscious and the individual may die within a short time.

2. Autoimmunity:

Andibodies are produced against antigens but sometimes it may also happen that the immune system of the body goes off the track and starts behaving against the 'own body' or 'self'.

This leads to a variety of diseases known as autoimmune diseases.

This type of diseases depends on which type of 'self-antigen' is involved.

When the cells acting as antigens in the same body, they are called autoantigens.

The nature of autoimmune diseases depends on the autoantigens involved.

For example, if the autoantigens are RBCs then the body destroys its own RBC resulting in chronic anaemia; if the autoantigens are produced against acetylcholine receptors (Myasthenia gravis); if the autoantigens are liver cells, then it results in chronic hepatitis, etc. Other autoimmune diseases are insulin-dependent diabetes, Addison's disease, ulcerative colitis and rheumatoid arthritis.

3. Immuno deficiencies

(i) Severe combined immuno deficiency (SCID) :

Sometimes new born children are without T-cells and B-cells.

These children are highly susceptible to various infections.

The most serious disorder of this type is a congenital disease known as severe combined immuno deficiency (SCID) in which both B-cells and T-cells are not present in the body.

Such children are highly susceptible even to minor infections.

In developed countries like U.S.A. such children are kept alive by keeping them in germ-free environments called isolation suits.

(ii) Acquired immune deficiency syndrome (AIDS) :

It is a disorder of cell mediated immune system of the body.

There is a reduction in the number of helper T-cells which stimulate antibody production by B-cells.

This results in the loss of natural defence against viral infection.

4. Graft rejection:

Grafts of a kidney, heart, lung, liver, etc. from one human to another always (unless donated by an identical twin) are seen by the recipient's immune system as antigenic and elicit an immune response.

If unchecked, this response will eventually lead to destruction of the graft. Both CD4+ and CD8+ T cells participate in graft rejection.

They are responding to differences between donor and host of their class II and class I histocompatibility molecules (respectively).

5. Graft-versus-host disease:

Grafts of bone marrow are used to provide, or restore, a source of blood cells for the recipient.

If there is any histocompatibility differences between donor and recipient (and there always are some, unless the patient's own marrow is used or that of an identical twin), then the T cells of the donor will mount an immune response against the tissues of the recipient.

Fortunately, graft-versus-host disease can usually be controlled with immunosuppressive drugs.