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Immunology

Immunology, the study of the immune system, grew out of the common experience that people who recover from certain infections become there-after ‘immune’ to the disease again. Immunity is highly specific; an individual who recovers from measles is protected against the measles virus, but not against other common viruses such as cold, chicken-pox or mumps. The immune system initiate the destruction and elimination of the invading organisms. Hence it becomes necessary that they may be made in response only to molecules that are foreign to the host and not to those of the host itself. This ability to distinguish foreign molecules from self molecules is another fundamental feature of the immune system. Definition: Immunity may be defined as those effective defense mechanisms that are acquired by an individual to protect himself from potentially harmful micro-organisms in the environment.

Primary and secondary lymphoid organs The cells responsible for immune specificity are a class of white blood cells known as lymphocytes. Lymphocytes occur in large numbers in the blood, lymph and lymphoid organs such as thymus, lymph nodes, spleen and appendix. There are two major classes of immune responses mediated by different class of lymphocytes: B lymphocytes and T lymphocytes. In mammals, B lymphocytes originate from the haemopoietic tissue of the bone marrow or foetal liver, both of which are called primary lymphoid organs. In birds, the primary lymphoid organ includes a gut-associated lymphoid organ called bursa of Fabricius. In both mammals and birds, most of the B-lymphocytes die but a few migrate via blood to the lymph nodes, spleen, and gut-associated lymphoid tissues such as appendix, adenoids and Payer’s patches in the small intestine. These organs are called secondary lymphoid organs and in them the B-lymphocytes proliferate into antibody producing plasma cells.

Thymus: It is a bilobed structure which lies in the thorax just above the heart. It consists of actively proliferating lymphocytes. In man thymus begins to function in the embryo and is active during and just after birth. It continues to grow till puberty after which it atrophies although it is readily recognizable in the adults. The stem cells enter the thymus and produce thymocytes which differentiate in to T-lymphocytes which are morphologically similar to blood lymphocytes and hence called T-lymphocytes.

Bursa of Fabricius: this is a branch of the gut in birds in to which the stem cells from the bone marrow enter and differentiate in to B-lymphocytes. The bursae is absent in mammals, so it is believed that they are pre-processed in an unknown area of the body probably in the liver during mid-foetal life and then in the bone marrow during late foetal life and after birth. Hence, the liver and bone marrow are considered as bursa equivalents.

Payer’s patches: The gut associated lymphoid tissues (GALT) include tonsils, Payer’s patches and appendix. The Payer’s patches are the aggregations of lymphoid tissues present in the lamina propria of the ileum of the alimentary canal.

Lymph nodes: They are bean shaped bodies which lie along the lymphatic ducts which are rich in phagocytes. The node acts as a reticular mesh filtering the foreign bodies from the lymph. These foreign bodies are then destroyed by phagocytosis.

Spleen: It is the largest lymphoid organ. It is present in the upper part of the abdominal cavity, behind the stomach and close to the diaphragm. It plays an important role in the production and destruction of RBC and also acts as a filter, filtering the foreign bodies ( antigens ) from the blood stream. These antigens stimulate the humoral or cell mediated immune response in the spleen.

T Lymphocytes and Cell Mediated Immunity: •	T lymphocytes are processed by the thymus gland with the help of the hormone thymosin to form functional mature T lymphocyte. •	Thymus gland lies between the heart an •	The mature T lymphocytes are released in to the circulation. •	The antigen presenting cell mostly macrophages present the antigenic fragments on their cell membrane to the T-lymphocyte. •	The T-lymphocytes get stimulated and start clonal expansion by division and proliferation •	Thus four main types of specialized T-lymphocytes are produced. They are Cytotoxic T cells (Killer T cells), Helper T cells, Suppressor T cells and Memory T cells. 1.	Cytotoxic T cells (Killer T cells) : They attach themselves to the target cell and release powerful toxins and inactivate them or kill them by destroying their walls. 2.	Helper T cells: They help in the production of cytokines ex: inter-leukins and interferons which support and promote cytotoxic T cells and macrophages. 3.	Suppressor T cells : They inhibit the immune response of both T and B lymphocytes when the infection is controlled. 4.	Memory T cells: These provide cell mediated immunity by responding rapidly to another encounter with the same antigen.

B Lymphocytes and Antibody Mediated ( Humoral ) Immunity. •	 B lymphocytes originate from the cells of bone marrow, migrate to bursa equivalent and get differentiated in to B-lymphocytes ( Bursal-lymphocytes ). •	Their role is in the production of antibodies ( immunoglobins ), which are proteins designed to bind to and cause the destruction of an antigen. •	Each B-lymphocyte targets one specific antigen. •	B-lymphocytes do not circulate in body, but are fixed in lymphoid tissue ex: spleen and lymph nodules. •	B-lymphocytes recognize and bind antigen particles without having to be presented with them by an antigen presenting cell. •	Once its antigen has been detected and bound ( with the help of helper T cells ), the B-lymphocytes begin to divide ( clonal expansion ) to produce two functionally distinct types of cells viz: plasma cells and memory B-cells. 1.	Plasma cells: Plasma cells secrete antibodies in blood. Antibodies are carried throughout the tissues through humors ( fluids ) i.e. blood and lymph; hence called humoral immunity. Plasma cells live no longer than a day and produce only one type of antibody, which targets the specific antigen ( that originally bound to the B-lymphocyte ). Functions of Antibodies: •	Antibodies bind to antigens, labeling them as targets for other defence cells such as cytotoxic T-lymphocytes and macrophages. •	Antibodies combine with antigens and immobilize or destroy them. •	Antibodies bind to bacterial toxins and neutralize them. •	Antibodies activate the compliment system.

2.	Memory B cells: Memory B cells remain in the body long after the initial                  episode has been delt-with and rapidly respond to another encounter of the same antigen by stimulating the production of antibody secreting plasma cells.

From the above two systems it is clear that for every one of the millions of possible antigens that might be encountered in life, there is one corresponding T and B lymphocyte. Therefore there are a vast number of different T and B lymphocytes in body each capable of responding to their respective antigen. Antigen: •	Antigen is the abbreviation of ‘antibody generating’. •	Antigen is defined as a foreign substance when introduced in to a living body is capable of generating an immune response by stimulating the production of antibodies. •	Every cell possesses antigens on their cell membranes ( own antigens ). •	Human body produces antibodies against foreign antigens ( non self ) and not against own antigens ( self ). •	An antigen has antigenicity and immunogenicity. Antigenicity is the ability to generate a specific immune response to produce antibodies. Immunogenicity is the ability to react specifically with the antibody produced.

Types of antigen: They may be classified as  A.	Complete antigen and B.	Haptens or Incomplete antigen.

A. Complete antigen: These are substances which can induce antibody formation by themselves and can react specifically with these antibodies. B.  Haptens or Incomplete antigen: Haptens are substances unable to induce antibody formation on its own but can become immunogenic ( capable of inducing antibodies ) when covalently linked to proteins called carrier proteins.

Antigenicity: •	Foreignness: An antigen must be foreign to the individual ( Non self ) to induce an immune response. The immune system doesnot normally mount an immune response against its own antigens ( self ). •	Size: Larger molecules are highly antigenic whereas low molecular weight are either non-antigenic or weakly antigenic. •	Chemical nature: Antigens are either proteins or polysaccharides. Proteins are more effective antigens. •	Susceptibility to tissue enzymes: Substances which can be metabolized and susceptible to the action of tissue enzymes behave as antigens. •	Species specificity: Tissues of all individuals in a species possess species specific antigens. •	Isospecificity: Isospecificity depends on isoantigens which may be found in some but not all members of a species. A species may be grouped according to the presence of different isoantigens in its members. These are genetically determined. Blood grouping is one example depending on human erythrocyte antigens ( isoantigens ). Histocompatibility antigens are associated with the plasma membrane of tissue cells.These are important when some tissue is transplanted from one individual to another. •	Organ specificity: Organ specificity antigens are confined to a particular organ. Some organs like brain, kidney and lens protein of one species share specificity with that of another species. Ex: Brain specific antigens are shared by man and sheep. •	Heterophile specificity: The same or closely related antigens present in different tissues of more than one species are known as heterophilie antigens. Antibodies to these antigens produced by one species cross react with antigens of other species.

Immunoglobulins or Antibodies: Antibodies are substances which are formed in the serum and tissue fluids in response to an antigen and react with that antigen specifically and in some observable manner. Chemically antibodies are globulins and hence named as immunoglobulins.

Structure of Immunoglobulin: Typically, an immunoglobulin molecule is a Y shaped heteromere. It consists of two identical heavy and two identical light chains. The heavy ( H ) chains are longer and light ( L ) chains are shorter. Both types of chains are polypeptide in nature. The two heavy chains are held together by disulphide ( S-S ) bonds. Each light chain is also attached to heavy chain by disulphide bond. The H chains are structurally and antigenically distinct in different classes of immunoglobulins.

Class of Immunoglobulin Heavy Chain. IgG	gamma (G) IgM	mu (M) IgA	alpha (A) IgD	delta (D) IgE	epsilon (E)

The L chains are present in two forms viz kappa (K) and lambda (L). Each immunoglobulin has either two kappa or two lambda light chains but both (K&L) are never found together in a molecule. Both L & H chains consist of two portions each, a variable (V) region and a constant (C) region. In the L chain the two regions are of equal length while in the H chains the variable region constitutes approximately only a fifth of the chain. Variable (V) regions are present at aminoterminus (NH2) and constant (C) region at carboxyterminus (COOH). Antigen combining site is at its aminoterminus which consists of both H and L chains. The aminoacid sequence in the aminoterminal half of the chain is highly variable, variability determines the immunological specificity of the antibody molecule. There are many hypervariable regions in variable portions of both H and L chains and are involved with the formation of the antigen binding site.

Structure of Immuniglobulin G ( IgG ) IgG represents the most abundant form of body’s antibodies (75%) and is one of the most extensively studied immunoglobulins. IgG has a molecular weight of 1,50,000 and is composed of four polypeptide chains in its Y shaped quarternary molecule- two identical H chains and two identical L chains. The L chains have the molecular weight of 20,000 to 25,000 and consists of about 450 aminoacids. Each L chain is covalently linked to H chain by a disulphide bridges (near the hinge). There are also 12 intra-chain disulphide bridges, four in each H chain and two in each L chain. Lastly, an aspargine residue in H chain is bounded to carbohydrate, since an immuniglibulin is also a glycoprotein. IgG is produced in large quantities during secondary responses and is involved in antibody dependent cell-mediated killing. IgG molecules are the only antibodies that can pass from mother to foetus via the placenta and provide natural passive immunity to the newborn. •	Half life of IgG is longest of all the immunoglobulins and is 23 days. It is distributed equally between the intra-vascular and extra-vascular compartments. IgG appears late but persists for longer period. It appears after the initial immune response which is IgM in nature. IgG participates in precipitation, complement fixation and neutralization of toxin and viruses. IgG is protective against those micro-organisms which are active in the blood and tissues.

Distinction between antigen and antibody:

Antigen	Antibody Generally it is a protein, but it may be polysaccharide, lipid or nucleic acid. It is only protein type of Immunoglobulin. They are foreign substances and capable of stimulating antibody production. They are protective chemicals produced in the body against antigens. They ate present on the surface of micro-organisms or as a free molecule. They are present on plasma cells and in body fluids. They bind to macrophage to reach helper T cell to initiate a immune response. They react with antigen to destroy them.

Immunization – Vaccination

•	Vaccination is the process in which a small amount of antigen called vaccines are injected in to the body to produce immunity against certain disease. •	The idea of vaccination was first conceived by Dr E.Jenner of England. Later Louis Pasteur of France and Robert Koch extended the idea to other infectious diseases. •	Vaccines are prepared consisting of either live or killed micro-organisms or their products. They are prepared by subjecting microbes to heat and antiseptics. •	Vaccination involves first vaccination shot and second booster shot. •	First vaccination shot: It brings a strong immune response to the antigens on the surface of the killed micro-organisms. •	Second booster shot: It is given after some days or months in which memory cells immediately differentiate and form more plasma cells which produce antibodies and memory T cells. •	Thus if a vaccinated person comes in contact with microbes, his/her body is ready to combat the infection with the antibodies present in their blood and also T cells. •	The immunity thus developed lasts for a longer period.

•	Types of Vaccins: 1.	Live vaccine (Attenuated): It consists of inactive micro-organisms but can stimulate antibody synthesis Ex: Polio, Mumps & TB vaccoines. 2.	Inactivated vaccine: It consists of killed micro-organisms which can stimulate antibody synthesis. Ex: Typhoid and Influenza vaccines. 3.	Toxoids: They consist of detoxified toxins of microbes, that can stimulate antibody synthesis. Ex: Tetanus & Dipteria vaccines. •	Biotechnologically prepared vaccines contain only antigen part. Ex Hepatitis B-virus, Typhoid, Pneumonia vaccines. •	Vaccination is the best means of controlling the infections. World wide eradication of small pox is achieved through vaccination.

AIDS: Acquired Immuno- Deficiency Syndrome.

The causative factors: It is caused by a virus named Human Immunodeficiency virus (HIV). It belongs to family lentiviruses. There are two closely related HIV types viz HIV-1 and HIV-2. They differ in their genomic structure and antigenicity. HIV-1 is more common. The HIV virion is spherical. It has a cone-shaped capsid of proteins. It encloses two copies of viral genome RNA. Each is made up of 9.2 kb. Each copy of RNA is associated with synthesis of enzymes viz reverse transcriptase (RT), protease and integrase. Outer to capsid is matrix of proteins. Surrounding all these is a phospholipids membrane or envelope. The envelope has projections called spikes. They are made up of glycoprotein (gp). They are named gp120 and gp40. They are meant for binding to receptors of the infecting cell. HIV infection begins with its gp120 binding to the surface receptors of CD4 cells (T4 lymphocytes). The viral RNA is injected in to the cell. It is then copied as DNA with RT. The DNA then enters the nucleus of the cell and becomes incorporated randomly in to the DNA of chromosomes. The integrated HIV DNA is called provirus. The provirus after a period of latency, starts transcribing viral RNA and synthesizing viral proteins. These assemble in to new HIV particles. They escape from CD4 cells, incorporating the host cell membrane as their cover and infect fresh cells. The life cycle is lytic and the infected cell breaks down when the new viral particles are released. This leads to immunodeficiency, produced by a decline of CD4 lymphocytes from 1200/mm3 to about  200/mm3. Since HIV can survive only in body fluids, its transmission occurs either by blood or by semen. In 90% of the cases, it acts as a STD, spreading by sexual contact. Persons can acquire HIV infection in three major ways. •	By sexual contact with HIV infected persons. •	By infected blood. •	By mother to child during pregnancy and breast feeding.

Effects and symptoms of AIDS: Four phases are distinguished in the disease: (i)	The first or primary phase starts 2 to 4 weeks after infection, when the body starts producing anti HIV antibodies, and an influenza like fever occurs. Skin rashes, swollen lymph glands, fatigue, head ache and ulcers of the mouth are sometimes produced. There is a fall in CD4 cell count to 300 to 400/mm3. (ii)	The second phase is a period between infection and the appearance of clinical symptoms, lasting from a few weeks to fifteen or more years. It is called the antibody positive period or HIV positive phase. (iii)	The third phase is named AIDS related complex (ARC), in which HIV positive patient contacts opportunistic infections by bacteria, other viruses and fungi. Throat infections, diarrhea, oral herpes etc are examples. In a person with ARC these persist longer. There is a significant reduction in CD4 cells in the blood. (iv)	The fourth phase is marked by opportunistic infections and diseases of all organ systems. Most of them are life threatening, and most individuals with full-blown AIDS die within 3 years from infections or cancers.

Test for AIDS: The specific test for HIV is named ELISA ( Enzyme Linked Immuno- Sorbent Assay ). The test detects antibodies in the blood against the AIDS virus. In the test, about 5 ml of blood is drawn and checked to see whether any antibodies are present that interact with HIV proteins chemically attached to the surface of a plastic dish. If antibodies are present they bind to the viral proteins and the test will be positive.

Preventive measures: The important measures include a.	Safer sex methods; including use of condoms. b.	Screening blood and blood products before transfusion. c.	Screening donors for semen, cornea, kidney, bone marrow etc. d.	Weaning away drug addicts. e.	Use of sterilized instruments and safer disposal of used instruments such as needles, blades etc. f.	Advising infected women against pregnancy.