Immunity by dr anita teli

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IMMUNITY:

IMMUNITY Speaker : Dr Anita.Teli Date & Time : 18 th August 2010 BLDEU Shri B M Patil Medical College

Introduction:

Introduction Our environment is rich in varieties of infectious microbes, such as bacteria, viruses, fungi, protozoa & multicellular parasites. These organism when enter our body they multiply, & if their growth & multiplication is unchecked ,they produce disease in the host & eventually they may even kill the host. Therefore ,the living beings require quick & continous mechanisms to kill & remove pathogens from their body.

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So we mammalians are endowed with various defence mechanisms that can broadly be divided into specific & non-specific defenses. The specific defense mechanisms of the body are collectively known as immunity.

Definition:

Definition “Free from burden”. Ability of an organism to recognize and defend itself against specific pathogens or antigens. Immune responses broadly involve two steps : 1. recognition of pathogen or foreign material. 2. the reaction to eliminate it. Largely immune responses are of two types: A. Innate or non-adaptive immunity B. Acquired or adaptive immunity

Types of immunity:

Types of immunity A.Innate immunity 1. Nonspecific defenses 2. Relatively specific defenses by NK cells B.Acquired immunity 1. Naturally acquired a) Active (usually through infections) i. Cellular immunity ii. Humoral immunity b) Passive (transfer of antibody from mother) i. IgG via placenta ii.IgA via breast feeding 2. Artificially acquired a). Active immunity i). Vaccination b). Passive immunity i). i.v. injection of antibodies such as anti-D immunization of Rh –ve mother.

Innate Immunity( Non-specific defence mechanism):

Innate Immunity( Non-specific defence mechanism) Immunity an organism is born with. Genetically determined. May be due to lack of receptors or other molecules required for infection.

Component of Innate Immunity:

Component of Innate Immunity Innate Immune system First line Second line 1) Mechanical barriers A- cells 2) Chemical & biochemical inhibitors 1- Natural killer 3) Normal flora 2- Phagocytes B- Soluble factors C- Inflammatory barrier

First line:

First line 1) Mechanical barriers - Intact skin - Mucous coat - Mucous secretion - Cilia - Saliva - Urine & Defecation - Blinking reflex and tears - Hairs - Coughing and sneezing reflex

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2) Chemical & biochemical inhibitors - Sweat and bacterial substances of sebaceous secretion - Acidic pH of skin - Hydrolytic enzymes in saliva - HCl of the stomach - Proteolytic enzyme in small intestine - Lysozyme in tears - Acidic pH in the adult vagina - Complement proteins - Interferons.

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3) Normal bacterial flora - Competition for essential nutrients - Production of inhibitory substances

Second line:

Second line A) cells B) Soluble factors C) Inflammatory Barriers

1- Natural killer (NK) Cells:

1- Natural killer (NK) Cells Definition: Also called natural killer cells are third category of lymphocytes that are neither B or T cells ,Large granular lymphocytes, Innate cytotoxic lymphocytes Source : Bone marrow precursors, they constitute about 15% of total lymphocytes in the body. Location : spleen, lymph nodes, bone marrow & peripheral blood

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Functions: a). Cytotoxic for Viral infected cells, tumor cells, bacterial, fungal, parasitic infection b). Responsible for antibody–dependent cell mediated cytotoxicity (ADCC). They kill microbes by following mechanism. 1). Osmotic lysis by incorporating perforins into the surface of the microbes 2). They release interferons that activate phagocytosis & immunity 3). They posses Fc receptors that allow them to kill antibody coated viruses.

2- Phagocytes:

2- Phagocytes Specialized cells for capture, Ingestion and destruction of invading microorganisms * Polymorphonuclear leucocytes, mainly neutrophils: granulocytes circulate in blood * Mononuclear cells (macrophages) - Monocytes in blood - Histocytes in connective tissues - Fixed reticuloendothelial cells in liver, spleen, lymph nodes, bone marrow

Phagocytosis:

Phagocytosis The engulfment, digestion, and subsequent processing of microorganisms by macrophages and neutrophils 1) Chemotaxis & attachment : a- Attraction by chemotactic substances (microbes, damaged tissues) b- Attachment by receptors on surfaces of phagocytes 2) Ingestion: * Phagocyte pseudopodia surround organism forming phagosome * Opsonins and co-factors enhance phagocytosis * Fusion with phagocytic granules and release of digestive, toxic contents

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3- Killing (two microbicidal routes) a)- Oxygen dependent system (powerful microbicidal agents) Oxygen converted to superoxide anion, hydrogen peroxide, activated oxygen and hydroxyl radicals. b)- Oxygen-independent system (anaerobic conditions) Digestion and killing by lysozyme, Lactoferrin, low pH, cationic proteins and hydrolytic and proteolytic enzymes

3-Interferon:

3-Interferon Proteins usually produced by virally infected cell Types of interferons : 1- Alpha interferon : Secreted by Macrophages Induced by Viruses. 2- Beta interferon : Secreted by Fibroblasts,virus 3- Gamma interferon : T- lymphocytes, Specific antigens Protective action of interferons: 1) Activate T-cells 2) Activate macrophages 3) Activate NK

Soluble factors:

Soluble factors 1- Acute phase protein (Plasma protein, CRP=C reactive protein, Fibrin.) 2- Complement (proteins in serum, body fluids) 2- Interferons (Proteins against viral infections) 3- Properdin (Complement activation) 4- Beta lysine (Antibacterial protein from Platelets) 5- Lactoferrrin, Transferrin (Iron binding protein) 6- Lactoperoxidase (Saliva & Milk) 7- Lysozyme (Hydrolyze cell wall)

Inflammatory Barriers :

Inflammatory Barriers * Tissue damage by a wound or by invading pathogen * Inflammatory response: -Tissue damage Release of chemical mediators from -Leukocytes (Histamine, fibrin, kinins, cytokines) -Invading microbe Redness of tissue Tissue temperature Vasodilatation of capillaries Capillary permeability Influx of fluids Influx of phagocytes into tissues

Acquired Immunity (Specific Defence mechanism) :

Acquired Immunity (Specific Defence mechanism) Immunity that an organism develops during lifetime. Not genetically determined. May be acquired naturally or artificially. Acquired immunity is broadly divided into two categories: a. Cellular (cell mediated immunity) b. Humoral (antibody mediated immunity)

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Cell Mediated Immunity - Involves specialized set of lymphocytes called T cells that recognize foreign antigens on the surface of cells, organisms, or tissues: Helper T cells Cytotoxic T cells T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc.

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Defense against: Bacteria and viruses that are inside host cells and are inaccessible to antibodies. Fungi, protozoa, and helminths Cancer cells Transplanted tissue

Cell Mediated Immunity is Carried Out by T Lymphocytes:

Cell Mediated Immunity is Carried Out by T Lymphocytes

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II. Humoral (Antibody-Mediated) Immunity Involves production of antibodies against foreign antigens. Antibodies are produced by a subset of lymphocytes called B cells. B cells that are stimulated will actively secrete antibodies and are called plasma cells . Antibodies are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells. Defense against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells. Also cause certain reactions against transplanted tissue.

Development of immunity:

Development of immunity The major sites of lymphocyte development are the primary lymphoid organs . These organs constitute thymus, bone marrow, fetal liver. In these organs, lymphocytes differentiate from their precursors that originate from bone marrow, & proliferate & mature into functionally potent cells. In mammals, T cells mature from thymus & B cells mature from bursa equivalents. After their maturity, they circulate in blood & migrate to secondary lymphoid organs where they reside.

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Primary lymphoid organs are : Thymus bone marrow fetal liver Secondary lymphoid organs are : Lymph node Spleen Gut associated lymphoid organs: tonsils, payer patches, vermiform appendix.

Mechanism of development of T cells:

Mechanism of development of T cells The stem cells or precursor cells that migrate to thymus before they mature into competent lymphocytes in the thymic environment are called pre T-cells. The lymphocytes that develop pre-T cells are called T-cells. Experimental evidences suggest that migration of stem cells into thymus is not a random process but results from chemotactic signals that are periodically emitted from the thymus. Beta-microglobulin, a component of MHC-I molecule is putative chemoattractant for pre-T cells. Specialised epithelial cells called thymic nurse cells contain pockets of thymocytes that secrete IL-7, which supports differentiation & proliferation of pre-T cells.

Changes during development:

Changes during development The changes are formation of specific receptors & synthesis of chemokines Formation of specific receptors on T cells: 4 types- α , β , γ , δ . 2. Synthesis of chemokines to kill antigens : the cells acquire capacities to form various chemokines that are capable of killing invading organism. Imp once are lymphotoxin & interferons.

Types of T cells:

Types of T cells 1 . Helper T cells(T 4 cells): these cells are called T 4 cells as they contain CD4 protein on their cell surface. They are known as helper or inducer cells as they assist in induction both cellular & humoral immunity. 2. Cytotoxic T cells(T 8 cells) or killer cells 3. Memory T cells

Development of B cells:

Development of B cells During the development of B cells in bursa these cells acquire characteristics surface molecules i.e, receptors to recognize antigens & receptors for various cytokines, & most importantly the genes for immunoglobulin synthesis. First gene rearrangement occurs for heavy chain & then the gene rearrangement occurs for light chain of immunoglobulins. Each B cell lineage is committed for making only one specific antibody against a specific antigen. This is the central theme of clonal selection theory of antibody production .

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B lymphocytes once mature in bursa equivalents migrate to lymph nodes, bone marrow, blood & other tissues. On specific immunologic stimulation, B cells undergo transformation to form plasma cells that produce large quantities of antibodies, which will kill or neutralize antigens. A small subset of B cells form memory B cells that on subsequent exposure to an antigen get readily converted into effective B cells (plasma cells) to carry out immunological functions.

Antigens :

Antigens Antigens are living organisms or substances that on entry into the body induce specific immunological reactions. Antigens have two important properties; immunogenicity & reactivity. Immunogenicity is the ability to provoke an immune response i.e, to stimulate the production of specific antibody or proliferation of specific T cells or both. Reactivity is the ability of the antigen to react specifically with an antibody or a cell or both.

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An antigen that possesses both the properties is defined as a complete antigen , an antigen that has the reactivity but lack immunogenicity is called partial antigen or a hapten Types : micro organisms- bacteria, virus or part of organism like capsule of virus, flagella of bacteria or cell wall of organism. Or non microbial organism like pollen, egg white, transplanted tissue or incompatible blood cells.

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Chemical nature : antigens are large complex molecules, usually they are protein in nature. T cells respond to protein antigen & B cell respond to protein & non protein antigen. Epitope : Small part of an antigen that interacts with an antibody. Any given antigen may have several epitopes. Each epitope is recognized by a different antibody.

Epitopes: Antigen Regions that Interact with Antibodies:

Epitopes: Antigen Regions that Interact with Antibodies

MHC Antigens:

MHC Antigens Major histocompatibility complex or MHC antigens are self antigens that help in identifying & rejecting the foreign antigens. They also called as HLA antigens( human leucocyte associated antigens), as they were first identified on the membrane of leucocyte). They are found to be present on the surface of all the body cells expect in red cells & are chemically glycoprotein in nature.

T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces:

T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces

Mechanism of action of MHC antigens:

Mechanism of action of MHC antigens Types : a. MHC Type I- present on the cell membrane of all body cells expect red cells. b. MHC Type II- present on surface of antigen presenting cells, thymus cells & activated T cells MHC-I molecules pick up the peptide fragments containing 8-10 amino acids, where as MHC-II molecule pick up antigens containing 13-17 amino acids. When peptide fragment of a self protein is picked up by the MHC antigen & expressed on the surface of the APC along with MHC protein,T cells ignore it, if a foreign protein is presented then T cells get activated inducing cell-mediated immunological responses.

Mechanism of cellular immunity:

Mechanism of cellular immunity Cellular immunity is activated mainly against viral infection, fungal infection, tumor cells, transplanted cells, parasitic infection & chronic bacterial infection like tuberculosis, brucellosis. Process of cellular immunity includes following steps: a). antigen recognition, processing & presentation b). activation & proliferation of T cells c). elimination of the invader

Antigen recognition, processing & presentation:

Antigen recognition, processing & presentation Each T or B cell has the ability to respond to a particular antigen On entry into the body, antigens bind with an appropriate receptors present on the B cell surface & activate the B cells. For activation of T cell to occur the antigen should be processed & presented by the APCs to the appropriate receptors on the T cell. The cell that process & present antigens to the T cells are called antigen presenting cells. These cells include macrophages, dendritic cells & B cells.

Steps of antigen presentation:

Steps of antigen presentation There are 5 major steps in antigen presentation: 1. Ingestion of the antigen : Ags are ingested by process of endocytosis by APCs 2. Digestion of the antigen & formation of vesicles : following phagocytosis, Ag is digested partially by the lysosomal enzymes & form phagosome within the cytoplasm of APCs. Simultaneously MHC II molecules are formed in the cell(MHC vesicle) 3. Fusion of vesicle ; the phagosomal vesicle containing peptide fragement of Ag combine with the vesicles containing MHC II molecule. These two merge to form single vesicle.

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4. Binding of peptide fragment with MHC II molecules : fused vesicles containing MHC-II & peptide fragments undergo exocytosis. 5. Incorporation of Ag-MHC complex into the cell membrane of APC : a. During the process of exocytosis, the peptide fragments-MHC-II complex get incorporated into the cell membrane of APC b. An APC containing the MHC- Ag complex migrate into the lymphatic tissue or circulate in the blood. c. The complex comes in contact with a particular T cell, attaches with the T-cell receptor, leading to activation of cell mediated immunity.

Activation & proliferation of T cells:

Activation & proliferation of T cells An activated T cell undergoes differentiation & proliferation into the effector T cells,which eliminates the Ag. Activation involves two steps : 1. Activation of T cells: T cell attaches to TCR & come in contact with MHC-Ag complex & gets activated. 2. proliferation & differentiation of T cells:

Elimination of the invader:

Elimination of the invader The cytotoxic T cells kill the invading organism by following three major mechanisms; 1. Cytolysis ; killer cells synthesize & secrete perforins & incorporate them into the membranes of the invading organisms. perforins are water channels that freely allow water to enter the microorganism along the osmotic gradient. The invading cell swells & finally undergoes osmotic lysis. 2. Lymphotoxin : activated T cells secret lymphotoxin that kills the microbes. Tumor necrosis factor(TNF)-beta is an imp once. 3. Interferons : cytotoxic T cells secrete gamma-interferons that are mainly antiviral, also they increase the phagocytic activity of neutrophils & macrophages by promoting opsonization.

Mechanism of humoral immunity:

Mechanism of humoral immunity Humoral immunity is mediated by antibodies produced by plasma cells found from B cells on specific antigenic stimulation Steps of activation of humoral immunity – 6 steps 1) presentation of antigen: antigen presentation through APCs is not must for induction of humoral immunity instead they are presented directly to B cells 2) activation of B cells: antigen binds to receptor on the surface of B cells leading to their activation. This process is accentuated by co-stimulation from type 2 helper cells through secretion of IL-2,4 & 5.

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3) differentiation of B cells into plasma cells: B cells enlarge in size and transform to plasma cells. Co-stimulation by T helper cells facilitate the process. 4). proliferation of plasma cells and antibody production: plasma cells proliferate in millions and secrete a large quantities of antibodies. 5).killing of the invaders by antibodies that include activation of complement system: antibodies attack antigens and kill organisms by following mech. A. neutralizing antigens B. immobilization of microbes C. activation of complement system D. precipitation of antigens- soluble antigen become insoluble & are phagocytized E. facilitation of phagocytosis by opsonization.

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Types of humoral immune responses 1 primary response : an antigen entering for the first time in the body produces primary response. The response mainly due to IgM. 2 secondary response : same antigen when enters second time produces speedy and intense response, due to immunological memory. Mainly IgG type

Complement system:

Complement system Group of plasma proteins which complement the efffects of antibodies in destroying antigens. >30 in no, 11 are categorized C1-C9 C1- C1q,r,s Normally inactivated form, once activated they exert their immunological and inflammatory action and boost the humoral immune mechanism. Mechanism of activation of complement system by 1.Classical pathway. 2.Alternative pathway( properdin pathway). 3.Mannose binding lectin pathway

Antibodies :

Antibodies Proteins that recognize and bind to a particular antigen with very high specificity One virus or microbe may have several antigenic determinant sites , to which different antibodies may bind. Each antibody has at least two identical sites that bind antigen: Antigen binding sites . Valence of an antibody: Number of antigen binding sites. Most are bivalent. Belong to a group of serum proteins called immunoglobulins (Igs).

Antibody Structure:

Antibody Structure Monomer: A flexible Y-shaped molecule with four protein chains: 2 identical light chains 2 identical heavy chains Variable Regions: Two sections at the end of Y’s arms. Contain the antigen binding sites (Fab). Identical on the same antibody, but vary from one antibody to another. Constant Regions: Stem of monomer and lower parts of Y arms. Fc region: Stem of monomer only. Important because they can bind to complement or cells.

Immunoglobulin Classes:

Immunoglobulin Classes I. IgG- 4 types Structure: Monomer Percentage serum antibodies: 80% Location: Blood, lymph, intestine Half-life in serum: 23 days Has lower molecular weight Complement Fixation: Yes Placental Transfer: Yes Known Functions: Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn.

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II. IgM Structure: Pentamer Percentage serum antibodies: 5-10% Location: Blood, lymph, B cell surface (monomer) It has higher molecular weight Half-life in serum: 5 days Complement Fixation: Yes Placental Transfer: No Known Functions: First antibodies produced during an infection. Effective against microbes and agglutinating antigens.

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III. IgA Structure: Dimer Percentage serum antibodies: 10-15% Location: Secretions (tears, saliva, intestine, milk), blood and lymph. Half-life in serum: 6 days Complement Fixation: yes Placental Transfer: No, secreted through breast milk. Known Functions: Localized protection of mucosal surfaces. Provides immunity to infant digestive tract .

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IgD Structure: Monomer Percentage serum antibodies: 0.2% Location: B-cell surface, blood, and lymph Half-life in serum: 3 days Complement Fixation: No Placental Transfer: No Known Functions: In serum function is unknown. On B cell surface, initiate immune response.

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V. IgE Structure: Monomer Percentage serum antibodies: 0.002% Location: Bound to mast cells and basophils throughout body & Blood. Half-life in serum: 2 days Complement Fixation: No Placental Transfer: No Known Functions: Allergic reactions. Possibly lysis of worms.

Mechanism of self recognition (immunological tolerance):

Mechanism of self recognition (immunological tolerance) Self recognition is the process by which own MHC proteins do not recognize self antigens, due to immunological tolerance. Immunological tolerance is defiened as unresponsiveness of the individual to an antigen. Immunological tolerance depends on the process of negative & positive selection.

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a.) negative selection : during the process of development of T cells in thymus, cells with TCR that recognise peptide fragments of self proteins are eliminated while the with TCR that do not recognise of self proteins are retained. This is either due to either deletion & anergy. Clonal anergy : self reactive clone of T & B cells those remain alive during post-natal life loose the capacity to be activated in response to self antigens. Because they loose the activity of their receptors & lymphokine systems to react against self-antigens, which is due to immune suppresion of these cells by body’s self regulating systems. This state of idleness is called clonal anergy

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Positive selection : T cells that are capable of recognizing self-MHC molecules during their thymic development survive & those that do not recognize undergo apoptosis. T cells recognize MHC-self Ag complex as the self Ags & don’t react against them.

Fetal tolerance:

Fetal tolerance Fetus is immunologically a foreign tissue, but not rejected from the body due to fetal tolerance, due to following reasons: a. during formation of placenta , trophoblast cells seperating the mother & fetus don’t express MHCI &II Ags, instead placenta expresses HLA-G a nonpolymorphic Ag, because of which Abs against fetal tissue do not develop. b. placenta- fas ligand on its surface attaching T cells which causes apoptosis of T cells supposed to react against fetal tissue c. AFP formed suppresses the T & B cells that react against fetal graft. d. high level of progesterone also suppresses immunity against fetal tissue.

Applied physiology:

Applied physiology Organ transplantation ; replacement of diseased tissue with new tissue. Transplanted tissue is rejected as recipient develops an immune response against transplanted tissue which is foreign to him, due to activation of cellular immunity. The rapidity at which the tissue is rejected depends on degree of matching of MHC Ag (HLA Ag) of donor with HLA Ag of recipient.

Types of transplants:

Types of transplants Autograft ; tissue from one part of body to another. e,.g skin graft Isograft ; organ transplantation between identical twins. Never rejected. Allograft ; transplantation between individuals of the same species. Xenograft ; tranplant between different species.

Prevention of graft rejection:

Prevention of graft rejection Immunosupresive drugs : azathioprine Glucocorticoid therapy ; inhibit cytotoxic T cells by inhibiting IL-2 from helper cells. Antilymphocyte globulins ; Antiboitics ; cyclosporine, rapamycin & tacrolimus Monoclonal antibodies

Immunological disorders:

Immunological disorders Allergy : hyperreactive response of the body to an antigen types: 1. local: swelling of the lips, eczema. 2. systemic allergy( anaphylaxis) : anaphylactic reaction to penicillin

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Hypersensitivity reactions- 4 types 1. type-1 or anaphylaxis 2. type-2 or cytotoxic: caused by IgG or IgM antibodies directed against antigens present on red cells. Ex: hemolytic disease of newborn, incompatible blood transfusion 3. type-3 or immune complex diseases: Ag-Ab complex formed deposited on basement membrane of vessels activate complements and induce inflammation. Ex: SLE, glomerulonephritis 4. type-4 or cell mediated or delayed hypersensitivity reactions: these reactions are mediated by macrophages that are activated by T cells Ag taken up by APCs & presented to T cells proliferation of T cells which migrate to allergen entry site, secreting cytokines & inducing inflammatory reaction. Ex PTB

Autoimmune diseases:

Autoimmune diseases Immune system does not react against self protiens Autoimmune disease occurs when persistence of T cells or B cells that are active against self Ags( autoantibodies)i,e. immune system fails to neglect self Ags & triggers immune response. ex: SLE, RA, MG

Immunodeficiency states:

Immunodeficiency states Congenital: defect in development of either cellular or humoral immunity. Autosomal recessive SCID X-linked SCID X-linked agammaglobulinemia MHC class II deficiency

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Acquired immunodeficiency syndrome ( AIDS ) -HIV- Binds to CD4 protien on helper T cell and decreases T 4 cells. -helper cells induce both cellular & humoral immunities, so leads to severe immunodeficiency states - Predispose to all types of serious infections and malignancies.

Immunotherapy :

Immunotherapy Treatment aims at induction of immune system- called immunostimulation/immune enhancement. Helps in treating malignancy. Types of immunotherapy: 1. cellular immunothearpy : cells with antitumour activity are injected into the blood of the cancer patient. Patient own inactive cytotoxic T cells or NK cells used. These cells cultured with IL-2 & activated called as lymphokine activated killer cells( LAK cells). 2. cytokine therapy : interferons & IL-2 used for viral infections & malignancies.

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3). antibody therapy : monoclonal antibodies for malignancies or preventing transplant rejection. 4). adjuvant thearpy : compound that enhance immune responses non-specifically against the Ag( freund’s adjuvant). Stimulate lymphocytes and macrophages. Adjuvants can cause delayed hypersensitivity reactions. - complete adjuvants : TB bacilli & gram negative bacilli - incomplete adjuvants: aluminium hydroxide, aluminium phosphate, mineral oils etc

References :

References Text book of medical physiology- G K Pal Text book of medical physiology- guyton & hall Review of medical physiology- Ganong Internet sources.

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