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Basic immunology Basic immunology Presentation Transcript

  • BASIC IMMUNOLOGY BY MOHAMMAD AKHEEL II YEAR PG OMFS
  • BASIC IMMUNOLOGYIMMUNITYANTIGENSANTIBODIES - IMMUNOGLOBULINSANTIGEN – ANTIBODY REACTIONSCOMPLEMENT SYSTEMSTRUCTURE AND FUNCTION OF IMMUNE SYSTEMIMMUNE RESPONSEHYPERSENSITIVITYAUTOIMMUNITYORAL IMMUNOLOGY
  • IMMUNITYThe term Immunity is derived from the Latin word Immunitae, whichreferred to the protection from the legal prosecution offered to RomanSenators during their tenure in office.Refers to the resistance exhibited by the host towards injurycaused by microorganisms and their products.Protection against infectious diseasesDistinguishes self from non-selfEliminate potentially destructive foreign substances from body
  • IMMUNITY INNATE ACQUIRED Non specific Specific Active PassiveSpecies Racial ArtificialIndividual Natural
  • INNATE IMMUNITY ACQUIRED IMMUNITYResistance to infection which individual The resistance that an individualpossesses by virtue of his genetic and acquires during lifeconstitutional make upEarly defense response against Later defense responsemicrobesImmune response Non specific Immune response is highly specificInnate response do not alter on repeated Adaptive response improves with eachexposure successive encounter with same pathogenMemory effect absent Memory effect presentNot affected by immunisation or prior Is improved by immunisationcontact
  • INNATE IMMUNITYIt consists of cellular and biochemical defense mechanisms that are in placeeven before infections and poised to respond rapidly to infections. Thesemechanisms react only to microbes and not to non-infectious substances Innate Immunity Species Racial Individual
  • Species immunity Refers to the total or relative refractoriness to a pathogen, shown by all members of species. Person obtains by virtue of being a part of the human species. Determines whether or not a pathogen can multiply in them.For e.g. All human beings are totally unsusceptible to plant pathogens and to, many animal pathogens, such as render pest or distemper.Pasteur’s experiments on anthrax in frogs, which are naturally resistant to the disease but become susceptible when their body temperature is raised from 25° to 35°C.
  • Racial immunity Racial differences are known to be genetic in originFor e.g. People of Negroid origin in USA are more susceptible than the Caucasians to tuberculosis. Genetic resistance to Plasmodium falciparum Malaria seen in some parts of Africa and Mediterranean coast. A hereditary abnormality of red cells (sickling) prevalent in the area, confer immunity to infections by malarial parasite.
  • Individual immunity The difference in innate immunity exhibited by different individualsin a race The genetic basis of individual immunity is seen in twins.For e.g.Homozygous twins exhibit similar degrees of resistance orsusceptibility to Lepromatous leprosy and Tuberculosis.
  • Innate immunity does not recognize every possible antigen instead itrecognizes pathogen-associated molecular patterns. Receptors enable thephagocyte to attach to these patterns so it can be engulfed and destroyed bylysosomes.Pathogen-Associated Molecular Patterns Binding to Endocytic Pattern-Recognition Receptors on Phagocytes
  • Determinants of innate immunityI. Species and strainsII. AgeIII. Hormonal InfluencesIV. Nutrition
  • MECHANISMS OF INNATE IMMUNITYI. Epithelial surfaces Skin Mucosa of the respiratory tract Human eye. Flushing action of urineII. Antibacterial substances in Blood and tissuesIII. InflammationIV. FeverV. Cellular factors
  • ACQUIRED IMMUNITY A person is said to be immune when he possesses specific protective antibodies or cellular immunity as a result of previous infection or immunization or is so conditioned by such previous experience as to respond adequately to prevent infection Because this form of immunity develops as a response to infection and is adaptive to the infection, it is called adaptive immunity.The characteristics of adaptive immunity are Specificity for distinct molecules. An ability to remember and respond more vigorously to repeated exposure to the same microbe.Hence it is also called as specific immunity.
  • ACTIVE IMMUNITY PASSIVE IMMUNITY1. Produced actively by host’s immune Received passively by the host system2. Induced by infection or by contact No participation by the host’s immune with immunogens (vaccines, system allergens etc).3. Affords desirable and effective Conferred by introduction of protection readymade antibodies4. Immunity effective only after a lag Protection transient and less effective period (time required for generation Immunity effective immediately of antibodies).5. Immunological memory present; No immunological memory subsequent challenge more subsequent administration of effective (booster effect) antibodies less effective due to immune elimination6. Negative phase may occur No negative phase7. Not applicable in immunodeficient Applicable in immunodeficient hosts hosts
  • Natural Active immunity This results from either a clinical or inapparent infection. Immunity following chicken pox and measles infection is usually life longArtificial Active ImmunityThis is the resistance induced by vaccines.Vaccines are preparations of live or killed microorganisms or their products used for immunization.
  • Types of Vaccine: Immunizing agents that are used for immunoprophylaxis Bacterial vaccines: Live (BCG vaccine for T.B.). Killed (Cholera vaccine). Subunit (Typhoid Vi antigen). Bacterial products (Tetanus Toxoid). Viral Vaccine: Live (Oral polio vaccine – Sabin). Killed (Injectable polio vaccine – Salk). Subunit (Hepatitis B-vaccine). Combinations If more than one kind of immunizing agent is included in the vaccine, it is called a mixed or combined vaccine.DPT (Diphtheria – pertussis - tetanus)MMR (Measles, mumps and rubella).DPTP (DPT plus inactivated polio).
  • Natural Passive immunity This is the resistance passively transferred from the mother to the baby. Inhuman infants, maternal antibodies are transmitted predominantly through theplacenta. Human colustrum, which is also rich in IgA antibodies and resistant to intestinaldigestion.Synthesis of antibodies (IgM) occurs at 20th week of IUL but its immunogeniccapacity is still inadequate at birth. It is only by about the age of three month thatthe infants acquire a satisfactory level of immunological independence.
  • Artificial passive immunityThis is the resistance passively transferred to a recipient by administrationof antibodies.Passive immunization is indicated for immediate and temporary protectionin a non-immune hostEmployed for the suppression of active immunity, when the latter may beinjurious.Used as treatment of some infections.Hyper immune sera of animal or human origin, convalescent sera andpooled human gamma globulins are used for prophylaxis and therapy.Rh immune globulin is used during delivery to prevent immune response tothe Rhesus factor in Rh-negative women with Rh-positive babies.
  • Cells of the Innate Immune System:PhagocytesMacrophages play several roles in the immune responses: Phagocytosis. Required to process and present antigen to immunocompetent T cells for induction of CMI. Production of cytokines, such as IL-1 and TNFα, which are proinflammatory Lyses tumor cells by secreting toxic metabolites and proteolytic enzymes Examples of tissue macrophages are kuppfer cell of the liver, microglial cells of brain, mesangial phagocyte of the kidney, alveolar macrophages of lungs and osteoclasts of bone.
  • NEUTROPHILS:Mediate the earliest phase of inflammatory response and aids in phagocytosis.The cytoplasm contains enzymes such as lysozyme, collagenase, elastaselactoferrin, acid hydrolase, and myeloperoxidaseand other microbicidal substances. Enzymes stimulates Kallikrein catalyzes Bradykinin promotes InflammationThey also possess receptors for IgG antibody. These receptors enableneutrophils to participate in the inflammatory response and phagocytosis.
  • EOSINOPHILSThey are phagocytic cells.contains receptors for immunoglobulins, growth factors and complementcomponents on the cell surfaceTheir primary function may be secretion and extracellular killing ratherthan intracellular.perform specialized function namely immediate hypersensitivity inresponse to parasites and protozoa.secrete destructive enzymes such as acid phosphatase, peroxidases andproteinases and promotes inflammation
  • Mast cellHas inflammatory mediators such as histamine, eosinophils chemotacticfactor, neutrophil chemotactic factor and heparin and zinc ions.It also synthesizes SRS-A, TNFα and leukotriene C4. These cells possessreceptors for complement components (C3a and C5a) as well as receptors forthe Fc portions of the antibody molecules, IgE and IgGThe stimulation of these receptors can result in activation and secretion ofvasoactive substances that increase vascular permeability and dilation.
  • BASOPHILSBasophils contain several enzymes, histidine carboxylase.release histamine, leukotrienes, and prostaglandins, chemicals thatpromotes inflammationMONOCYTESphagocytes.Monocytes differentiate into macrophages serve as antigen-presenting cells inthe adaptive immune responsesLYMPHOCYTESB-lymphocytes (B-cells) mediate humoral immunityT-lymphocytes (T-cells) mediate cellular immunity
  • ANTIGENS An antigen has been defined as any substance which when introducedparenterally into the body stimulates the production of an antibody with which itreacts specifically and in an observable mannerThe two attributes of antigenicity are: Induction of an immune response (immunogenicity). Specific reaction with antibody or sensitized cells (immunological reactivity).Based on the ability of antigens to carry out these two functions, they may be classified into different types: Complete antigen is able to induce antibody formation and produce a specific and observable reaction with the antibody so produced. Haptens are substances, which are incapable of inducing antibody formation by themselves, but can react specifically with antibody.
  • Determinants of Antigenicity:Size: Large molecular size (6.75 million) : highly antigenic Low molecular size (<5000) : less or non-antigenicChemical nature: Proteins and polysaccharides : highly antigenic. Lipids and nucleic acids : less antigenic.Susceptibility to tissue enzymes: only substances, which are metabolized and are susceptible to the action of tissue enzymes, behave as antigens.Foreignness: Only antigens that are foreign to the individual (non self) induce an immune response.Antigen Specificity: It is the position of the antigenic determinant group in the antigenic molecule at ortho, meta and para positions which determines antigen specificity. It is not absolute. Cross reaction can occur between antigen which bear stereo-chemical similarities
  • Antigen reacting only with particular ImmunocytesB-lymphocytes have sIg molecules on their surface that recognize epitopesdirectly on antigens. Different B-lymphocytes are programmed to producedifferent molecules of sIg, each specific for a unique epitope.
  • Iso specificity: Isoantigens are antigens found in some but not all member of aspecies. A species may be grouped depending on the presence of differentantigens in its members e.g. human erythrocyte antigen based on whichindividuals can be classified into different blood groups.Autospecificity: Autologous or self-antigens are ordinarily non-antigenic butthere are exceptions. Sequestered antigens that are not normally found free in circulation ortissue fluids (such as lens protein normally, confined within its capsule) are notrecognized as self-antigens. Similarly antigens that are absent during embryoniclife and develop later (such as spleens) are also not recognize as self-antigens.
  • ANTIBODIES (IMMUNOGLOBULINS)They are specific glycoprotein configurations produced by B-lymphocytes andplasma cells in response to a specific antigen and capable of reacting withthat antigen.Antibody StructureA monomer has four glycoprotein chains: two identical heavy chains have a high molecular weight that varies withthe class of antibody. two identical light chains. The light chains come in two varieties: kappa orlamda and have a lower molecular weight. The four glycoprotein chains areconnected to one another by disulfide (S-S) bonds and noncovalent bondsAdditional S-S bonds fold the individual glycoprotein chains into a number ofdistinct globular domains. The area where the top of the "Y" joins the bottom iscalled the hinge. This area is flexible to enable the antibody to bind to pairs ofepitopes at various distances apart on an antigen.The two tips of the "Y" monomer are referred to as the Fab portions of theantibody.
  • The Fab portion of the antibody has specificity for binding an epitope of anantigen. The Fc portion directs the biological activity of the antibody.
  • Folding Domains of an AntibodyThe Fab portion of the antibody has the complementarity-determining regions(red) providing specificity for binding an epitope of an antigen. The Fc portion(purple) directs the biological activity of the antibody. (S-S = disulfide bond; N =amino terminal of glycoprotein; C = carboxy terminal of glycoprotein; CHO =carbohydrate.)
  • Epitope of an Antigen Binding to Fab of an Antibody
  • Ways That Antibodies Help to Defend the Body1. Opsonization: Using antibodies to attach microbes to phagocytes orphagocytes to cells recognized as nonself.2. MAC Cytolysis: Using antibodies to activate the classical complementpathway resulting in the lysis of gram-negative bacteria and cells recognizedas nonself by way of the membrane attack complex (MAC).3. Antibody-dependent Cellular Cytotoxicity (ADCC) by NK Cells: Usingantibodies to attach NK cells to infected cells and tumor cells.4. Neutralization of Exotoxins: Using antibodies to prevent exotoxins frombinding to receptors on host cells.
  • 5. Neutralization of Viruses: Using antibodies to prevent viruses frombinding to receptors on host.6. Preventing Bacterial Adherence to Host Cells: Using antibodies toprevent bacteria from binding to receptors on host.7. Agglutination of Microorganisms: Using antibodies to clump microbestogether for more effective phagocytosis.8. Immobilization of Bacteria and Protozoans: Using antibodies toagainst cilia and flagella to block motility.
  • The 5 Classes (Isotypes) of Human Antibodiesa. IgG (Immunoglobulin G; 4 subclasses)IgG makes up approximately 80% of the serum antibodies.The Fc portion of IgG can activate the classical complement pathway. bind to macrophage and neutrophils for enhanced phagocytosis. bind to NK cells for antibody-dependent cytotoxicity (ADCC). enables it to cross the placenta. (IgG is the only class of antibody that can cross the placenta and enter the fetal circulation.)
  • IgG
  • A Bacterial Capsule Preventing C3b Receptors on Phagocytes fromBinding to C3b Attached to a Bacterial Cell WallIn some bacteria, the capsule covers the opsonin C3b bound to the bacterial cellwall so that it cant bind to C3b receptors (called CR1) on the surface ofphagocytes.
  • Opsonization of an Encapsulated BacteriumThe Fab portion of IgG binds to epitopes of a capsule. The Fc portion can nowattach the capsule to Fc receptors on phagocytes for enhanced attachment.Once attached to the phagocyte by way of IgG, the encapsulated bacteriumcan be engulfed more efficiently and placed in a phagosome.
  • b. IgM (Immunoglobulin M)IgM makes up approximately 13% of the serum antibodies and is the firstantibody produced during an immune response.The Fc portions of IgM are able to activate the classical complementpathway. (IgM is the most efficient class of antibody for activating the classicalcomplement pathway.)Monomeric forms of IgM are found on the surface of B-lymphocytes as B-cell receptors or sIg.
  • IgMIgM is a pentamer and, therefore, has 10 Fab sites.
  • c. IgA (Immunoglobulin A; 2 subclasses) IgA makes up approximately 6% of the serum antibodies IgA is found mainly in body secretions (saliva, mucous, tears, colostrumand milk) as secretory IgA (sIgA) where it protects internal body surfacesexposed to the environment by blocking the attachment of bacteria andviruses to mucous membranes. While only 6% of the antibodies in the serumare IgA The Fc portion of secretory IgA binds to components of mucous andcontributes to the ability of mucous to trap microbes. IgA can activate the alternative complement pathway.
  • Secretory IgASecretory IgA is a dimer and has 4 Fab sites. A secretory component helpsprotect it from digestion in body secretions.
  • d. IgD: (Immunoglobulin D; 2 subclasses)IgD makes up approximately 0.2% of the serum antibodies.IgD is found on the surface of B-lymphocytes (along with monomericIgM) as a B-cell receptor or sIg where it may control of B-lymphocyteactivation and suppression.IgD may play a role in eliminating B-lymphocytes generating self-reactive autoantibodies.
  • e. IgE (Immunoglobulin E)IgE makes up about 0.002% of the serum antibodiesMost IgE is tightly bound to basophils and mast cells via its Fc region.The Fc portion of IgE made against parasitic worms and arthropodscan bind to eosinophils enabling opsonization.The Fc portion of IgE can bind to mast cells and basophils where itmediates many allergic reactions. Cross linking of cell-bound IgE by antigentriggers the release of vasodilators for an inflammatory response.
  • ANTIGEN-ANTIBODY REACTIONSAntigens and antibodies, by definition, combine with each other specifically andin an observable manner.In vivo, they form the basis of antibody mediated immunity in infectiousdiseases, or of tissue injury in some types of hypersensitivity and autoimmunediseases.In vitroIn the laboratory, they help in the diagnosis of infections,in epidemiologicalsurveys, in the identification of infectious agents and of noninfectious antigenssuch as enzymes.In general, these reactions can be used for the detection and quantitation ofeither antigens or antibodies. Antigen-antibody reactions in vitro are known asserological reactions.
  • General features of antigen-antibody reactionsI. The reaction is specific, an antigen combining only with its homologous antibodyand vice versa.2. Entire molecules react and not fragments. When an antigenic determinantpresent in a large molecule or on a carrier particle reacts with its antibody, wholemolecules or particles are agglutinated.3. There is no denaturation of the antigen or the antibody during the reaction.4. The combination occurs at the surface. Therefore, it is the surface antigensthat are immunologically relevant.
  • 5. The combination is firm but reversible. The firmness of the union isinfluenced by the affinity and avidity of the reaction. Affinity refers to the intensity of attraction between the antigen and antibody molecules. It is a function of the closeness of fit between an epitope and the antigen combining region of its antibody. Avidity is the strength of the bond after the formation of the antigen- antibody complexes.6. Both antigens and antibodies participate in the formation of agglutinatesor precipitates.7. Antigens and antibodies can combine in varyring proportions, unlikechemicals with fixed valencies. Both antigens and antibodies aremultivalent.
  • SEROLOGICAL REACTIONSPrecipitation reactionWhen a soluble antigen combines with its antibody in the presence ofelectrolytes (NACI) at a suitable temperature and pH, the antigen-antibodycomplex forms an insoluble precipitate.When, instead of sedimenting, the precipitate remains suspended asfloccules, the reaction is known as flocculation.Mechanism of precipitationMarrack (1934) proposed the lattice hypothesis. Multivalent antigens combinewith bivalent antibodies in varying proportions. Precipitation results when alarge lattice is formed consisting of altemating antigen and antibodymolecules.The lattice hypothesis holds good for agglutination also.
  • Antigens : Dark spheresAntibodies : SpindlesMechanism of Precipitation by lattice formationA: Antigen excess C: Antibody excess (Lattice formation does not occur)B: (Zone of equivalence) Lattice formation and precipitation occur optimally
  • Applications of precipitation reactionIt is very sensitive in the detection of antigens as little as 1 pg of protein can bedetected by precipitation tests.Finds forensic application in the identification of blood and seminal stains, andin testing for food adulterants.The following types of precipitation and flocculation tests are in common use:Ring test: Grouping of streptococci by the Lancefield technique.Slide test: The VDRL test for syphilis is an example of slide flocculation.Tube test: The Kahn test for syphilis is an example of a tube flocculation test.
  • AGGLUTINATION REACTIONWhen a particulate antigen is mixed with its antibody in the presence ofelectrolytes at a suitable temperature and pH, the particles are clumped oragglutinated.Agglutination is more sensitive than precipitation for the detection ofantibodies. The same principles govern agglutination and precipitation.Agglutination occurs optimally when antigens and antibodies react inequivalent proportions.
  • Applications of agglutination reactionSlide agglutination: When a drop of the appropriate antiserum is added toa smooth, uniform suspension of a particulate antigen in a drop of salineon a slide or tile, agglutination takes place. A positive result is indicated bythe clumping together of the particles an the clearing of the drop. It is themethod used for blood grouping and cross matching.Tube agglutination: This is a standard quantitative method for themeasurement of antibodies. When a fixed volume of a particulate antigensuspension is added to an equal volume of serial dilutions of an antiserumin test tubes, the agglutination titre of the serum can be estimated.Tube agglutination is routinely employed for the serological diagnosis of typhoid, brucellosis and typhus fever.
  • COMPLEMENT SYSTEM: The term complement refers to a system of factors, which occur in normalserum and are activated characteristically by Antigen antibody interaction andsubsequently mediate a number of biologically significant consequences.It is a non-specific serologic reagent in that complement from one species canreact with antibody from other species.Complement ordinarily does not bind to free antigen or antibody but only toantibody, which has combined with its antigen.All classes of Immunoglobulins do not fix to complement, only IgM. IgG3, 1 and 2in that order fix complement on the Fc portion of the Immunoglobulin molecule.But not IgG4, A, D & EComplement is a complex of different fractions called C1 to C9. The fraction of C1occurs in serum as a calcium ion dependent complex, which on chelation withEDTA yields three proteins subunits called C1q, r, and s. This complex is made upof a total of 11 different proteins.
  • Assembly of C1 during the Classical Complement PathwayThe Fab of IgG or IgM bind to epitopes on an antigen. C1q, C1r, and C1s thenassembles on the Fc portion of the antibodies to form C1, the first enzyme ofthe classical complement pathway. The enzyme C1 is able to cleave C4 intoC4a and C4b, as well as C2 into C2a and C2b.
  • Formation of C3 Convertase during the Classical Complement PathwayThe enzyme C1 is able to cleave C4 into C4a and C4b. The C4b binds toadjacent proteins and carbohydrates on the surface of the antigen. C2 then bindsto the C4b and C1 cleaves C2 into C2a and C2b. The C4b2a functions as a C3convertase that can subsequently cleave hundreds of molecules of C3 into C3aand C3b.
  • Formation of C5 Convertase during the Classical Complement PathwayThe C4a2b functions as a C3 convertase that can subsequently cleavehundreds of molecules of C3 into C3a and C3b. Much of the C3b binds toadjacent proteins and carbohydrates on the antigen to participate inopsonization while C3a can stimulate inflammatory responses. Some of the C3bbinds to C4b2a to form C4b2a3b, a C5 convertase that can cleave C5 into C5aand C5b.
  • The Membrane Attack Complex (MAC) Causing Cell LysisThis C5b6789n, or membrane attack complex (MAC), puts pores into lipidbilayer membranes of human cells to which antibodies have bound. Thisresults in cell lysis. MAC can also damage the envelope of enveloped virusesand put pores in the outer membrane and cytoplasmic membrane of gram-negative bacteria causing their lysis.
  • Benefits of C5a and C3bMost C3b binds to antigens on the microbial surface. Some C3b combineswith C2a and C4b to form the third enzyme of the complement pathway that isable to split C5 into C5a and C5b. C5a stimulates mast cells to releasehistamine for inflammation and diapedesis. It also functions as achemoattractant for phagocytes. The phagocytes are then able to bind to theC3b attached to the surface of the microorganism allowing for opsonization(enhanced attachment).
  • COMPLEMENT FIXATION TEST (CFT)Ability of antigen antibody complexes to fix complement is made use of inthe complement fixation test (CFT).This is a very versatile and sensitive test, applicable with various types ofantigens and antibodies and capable of detecting as little as 0.04 mg ofantibody nitrogen and 0.1 mg of antigen.CFT is a complex procedure consisting of two steps and five reagents-Antigen,Antibody,Complement,Sheep erythrocytes andAmboceptor (rabbit antibody to sheep red cells).
  • Inactivated serum incubated at Wassermann Guineapigof patient 37deg.C for 1hr. with AntigenComplement ( 2 units ) If complement is Fixed (utilised) not fixed (not utilised) Patient serum has Patient serum has no Syphilitic antibody Syphilitic antibody (Complement is left intact) Sheep RBC coated with Haemolysin Incubated at 37deg.C for 30 min. If no lysis of RBC If lysis of RBC Complement was utilised in I step Complement was not utilised SERUM HAS ANTIBODIES SERUM – NO ANTIBODIES
  • LECTIN PATHWAYMediated by mannan-binding lectin (also known as mannan-bindingprotein or MBP).MBP is a protein that binds to the mannose groups found in many microbialcarbohydrates but not usually found in the carbohydrates of humans. The MBPis equivalent to C1q in the classical complement pathway.Activation of the lectin pathway begins when mannan-binding protein (MBP)binds to the mannose groups of microbial carbohydrates.
  • Activation of the Lectin PathwayActivation of the lectin pathway begins when mannan-binding protein (MBP)binds to the mannose groups of the microbial carbohydrates. Two more lectinpathway proteins called MASP1 and MASP2 (equivalent to C1r and C1s ofthe classical pathway) now bind to the MBP. This forms an enzyme similar toC1 of the classical complement pathway that is able to cleave C4 and C2 toform C4bC2a, the C3 convertase capable of enzymatically splitting hundredsof molecules of C3 into C3a and C3b.
  • ALTERNATIVE COMPLEMENT PATHWAYThe alternative complement pathway is mediated by C3b, producedeither by the classical or lectin pathways or from C3 hydrolysis by water.(Water can hydrolize C3 and form C3i, a molecule that functions in amanner similar to C3b.)
  • Activation of the Alternative Complement Pathwayand Formation of C3 ConvertaseActivation of the alternative complement pathway begins when C3b (orC3i) binds to the cell wall and other surface components of microbes.Alternative pathway protein Factor B then combines with the cell-boundC3b to form C3bB. Factor D then splits the bound Factor B into Bb and Ba,forming C3bBb. A serum protein called properdin then binds to the Bb toform C3bBbP that functions as a C3 convertase capable of enzymaticallysplitting hundreds of molecules of C3 into C3a and C3b.
  • Formation of C5 Convertase duringthe Alternative Complement PathwaySome of the C3b subsequently binds to some of the C3bBb to form C3bBb3b,a C5 convertase capable of enzymatically splitting hundreds of molecules ofC5 into C5a and C5b.
  • Functions of Complement system include: Control of inflammatory reactions and chemotaxis. Clearance of immune complexes. Cellular activation and antimicrobial defense. Development of antibody responses Contributes to pathogenesis of Hereditary angioneurotic edema Nephrotoxic nephritis Paroxysmal nocturnal hemoglobinuria Infectious mononucleosis Autoimmune hemolytic anaemia Complement mediates immunological membrane damage (cytolysis bacteriolysis). Participates in pathogenesis of Type II & Type III hypersensitivity reaction. Antiviral activity. Promotes phagocytosis and immune adherence. It also interacts with the coagulation, fibrinolytic and kininogenic systems of blood.
  • Cytokines Cytokines are mediators that function as up and down regulation of immunogenic, inflammatory and reparative host responses to injury. Soluble mediators called cytokines control many critical interactions among cells of the immune system.They generally act over very short distances, being“autocrine” (acting on the cells that produce them) or“paracrine” (acting on cells close by)Cytokines can be of two types:Lymphokines : produced by lymphocyte.Monokines :produced by monocytes or macrophages.Interleukins, Interferons, Tumour necrosis factor and Growth factors are grouped under Cytokines
  • Interleukin 1 (IL-1):mediates host inflammatory response to infectionspromote neutrophil margination and migration into an inflamed site.In low conc., as a mediator of local inflammation. in larger conc., exerts endocrine effects.are endogenous pyrogens (i.e. they induce fever)early hematopoietic progenitor in the bone marrow.
  • Interleukin 2 (IL-2): This is a growth factor for antigen stimulated T lymphocytes and is responsible for T cell clonal expansion after antigen recognition and stimulus for antibody synthesis. Potentiates apoptotic death of antigen activated T cells.Interleukin 3 (IL-3): Induces growth of all types of hematopoetic cells known as multi colony stimulating factor
  • Interleukin 4 (IL-4):It is secreted by activated CD4+ T cells of the TH2 subset and by mast cells.IL-4 suppresses the induction and function of TH1 cellsEnhances IL-3 mediated mast cell growthIncrease macrophage expression of class II MHC proteinsInterleukin 5 (IL-5):stimulate the production of eosinophilsenhances the activities of basophil
  • Interleukin 6 (IL-6):Promotes B-cell differentiation and IgG productionInterleukin 7 (I- 7):A growth factor for both B and T cell progenitor and mature T cells as well asmacrophages and monocytesIncreases macrophage cytotoxic activity and induces cytokine secretion bymonocytes.Interleukin 8 (IL-8):Acts as a neutrophil chemotactic factor
  • Interferons: In 1957, it was discovered that cells exposed to inactivated viruses produces soluble factor that can “interfere” with viral replication when applied to newly infected cells. The factor was named interferon (IFN).Interferons do not exert their antiviral effects by acting on viral particle but rather by inducing an antiviral state within the host cell that makes it inhospitable to viral replication. This as well as the antiproliferative and immunomodulatory effects of interferon reflects their ability to regulate specific gene expression in their target cells.They can be classified into three distinct types: INF-α (leukocyte interferon) – type I INF-β (fibroblast interferon) – type I IFN-γ (immune interferon) – Type II.
  • STRUCTURES AND FUNCTIONS OF IMMUNE SYSTEMTHE LYMPHOID SYSTEMThe body uses the lymphoid system to enable lymphocytes to encounterantigens and it is here that adaptive immune responses are initiated.a. Primary lymphoid organsThe bone marrow and the thymus constitute the primary lymphoid organs.B-lymphocytes mature in the bone marrow while T-lymphocytesmigrate to the thymus and mature there.b. Lymphatic vesselsLymphatic vessels are responsible for flow of lymph within the lymphoidsystem and are a part of the bodys fluid recirculation system.c. Secondary lymphoid organsAdaptive immune responses require antigen-presenting cells, such asmacrophages and dendritic cells,lymph nodes and the spleen
  • Number of surface antigens or markers have been identified on Lymphocytes.These markers reflect the stage of differentiation and functional properties of cells.When a cluster of monoclonal antibodies was found to react with a particular antigen,it was defined as a separate marker and given a CD (cluster of differentiation)number. CD Cell type association number CD 1 Thymocytes, Langerhans cells CD 2 T cell SRBC receptors CD 3 T cell antigen receptor complex CD 4 Helper T cell (receptor for HIV) CD 8 Suppressor/cytotoxic T cells CD 19 B cells
  • Antigen-Presenting Cells (APCs)APCs include dendritic cells, macrophages, and B-lymphocytes.1. Dendritic CellsCaptures and present protein antigens to naive T-lymphocytes . (Naivelymphocytes are those that have not yet encountered an antigen.)2. MacrophagesCaptures and present protein antigens to effector T-lymphocytes. (Effectorlymphocytes are lymphocytes that have encountered an antigen, proliferated,and matured into a form capable of actively carrying out immune defenses.)3. B-lymphocytesCaptures and present protein antigens to effector T4-lymphocytes.triggers the T4-cell to produce and secrete various cytokines that enable thatB-lymphocyte to proliferate and differentiate into antibody-secreting plasmacells.
  • T4-Lymphocytes (T4-Helper Cells, CD4+ Cells)T-lymphocytes displaying CD4 molecules on their surface that regulate theimmune responses through their production of cytokines. T4-lymphocytesrecognize epitopes bound to MHC-II molecules by way of the T-cell receptors(TCR) and CD4 molecules on their surface.Have a shape, capable of recognizing peptides from exogenous antigensbound to MHC-II molecules on the surface of APCs and B-lymphocytes. TheTCR recognizes the peptide while the CD4 molecule recognizes the MHC-IImolecule.overall role of these effector T4-lymphocytes is to:1. activate macrophages and NK cells.2. produce cytokines that enable activated B-lymphocytes to produce antibodies and T-lymphocytes into effector cells.
  • Different types of effector T4-lymphocytes based on the cytokines theyproduce are Th1 cells and Th2 cells.a. Th1 lymphocytesTh1-lymphocytes recognize antigens presented by macrophages and functionprimarily to activate and heighten cell-mediated immunity by producingcytokines such as interleukin-2 (Il-2), interferon-gamma (IFN-gamma),lymphotoxin, and tumor necrosis factor-beta (TNF-beta).b. Th2 lymphocytesTh2-lymphocytes recognize antigens presented by B-lymphocytes. Theyproduce cytokines such as interleukins 2, 4, 5, 10, and 13 that promoteantibody production.
  • Activation of a Macrophage by a Th1 Lymphocyte1. Bacteria are engulfed by a macrophage and placed in a phagosome. A lysosome fuses with thephagosome forming a phagolysosome.2.An activated Th1 lymphocyte binds to a peptide/MHC-II complex on a macrophage by way of its TCRand CD4 molecule.3.Co-stimulatory molecules such as CD40L on the Th1 cell then bind to CD40 on a macrophage.4. The Th1 lymphocyte secretes the cytokine interferon-gamma (IFN-gamma) that binds to IFN-gammareceptors on the macrophage.5. The IFN-gamma activates the macrophage enabling it to produce more hydrolytic lysosomal enzymes,nitric oxide, and toxic oxygen radicals that destroy the microorganisms within the phagosomes andphagolysosomes.
  • T8 -LYMPHOCYTEST-lymphocytes displaying CD8 molecules on their surface and carrying out cell-mediated immunity. T8-lymphocytes recognize epitopes bound to MHC-Imolecules by way of the T-cell receptors (TCR) and CD8 molecules on theirsurface.During its development, each T8-lymphocyte becomes geneticallyprogrammed, by gene-splicing reactions, to produce a TCR with a uniqueshape capable of binding epitope/MHC-I complex with a corresponding shapeOne of the bodys major defenses against viruses, intracellular bacteria, andcancers is the destruction of infected cells and tumor cells by cytotoxic T-lymphocytes or CTLs.
  • B-lymphocytes (B-cells)B-lymphocytes refer to lymphocytes that are produced in the bone marrow andrequire bone marrow stromal cells and their cytokines for maturation. During itsdevelopment, each B-lymphocyte becomes genetically programmed through aseries of gene-splicing reactions to produce an antibody molecule with a uniquespecificity - a specific 3-dimensional shape capable of binding a specific epitopeof an antigenAntibodies on the surface of B-lymphocytes that function as B-cell receptors arealso known as surface immunoglobulin (sIg)
  • a. Activation of naive B-lymphocytes by T-dependent antigensMost proteins are T-dependent antigens. In order for naive B-lymphocytes toproliferate, differentiate and mount an antibody response against T-dependentantigens, these B-lymphocytes must interact with effector T4-lymphocytes.b. Activation of B-lymphocytes by T-independent antigensT-independent (TI) antigens are usually large carbohydrate and lipid moleculeswith multiple, repeating subunits. B-lymphocytes mount an antibody responseto T-independent antigens without the requirement of interaction with T4-lymphocytes.
  • CLONAL SELECTION:The selection and activation of specific B-lymphocytes and T-lymphocytes bythe binding of epitopes to B-cell receptors or T-cell receptors with acorresponding fit.CLONAL EXPANSION:The proliferation of B-lymphocytes and T-lymphocytes activated by clonalselection in order to produce a clone of identical cells. This enables the bodyto have sufficient numbers of antigen-specific lymphocytes to mount aneffective immune response.
  • Clonal Selection, Step-1During its development, each B-lymphocyte becomes genetically programmed,through a process called gene translocation, to make a unique B-cell receptor.Molecules of that B-cell receptor are placed on its surface where it can reactwith epitopes of an antigen.
  • Clonal Selection, Step-2B-lymphocyte with an appropriately fitting B-cell receptor can now react withepitopes of an antigen having a corresponding shape. This activates the B-lymphocyte.
  • An Effector T4-Lymphocyte Recognizing Epitope/MHC-II on an Activated B- LymphocyteAn effector T4-lymphocyte uses its TCR and CD4 molecule to bind to acomplementary shaped MHC-II molecule with attached peptide epitope on anactivated B-lymphocyte. This interaction, along with the binding of co-stimulatorymolecules such as CD40 and B7 on the B-lymphocyte with their complementaryligands on the effector T4-lymphocyte triggers the T4-lymphocyte to producecytokines that enable the activated B-lymphocyte to proliferate, differentiate intoantibody-secreting B-lymphocytes and plasma cells, and switch classes of theantibodies being made.
  • Proliferation and Differentiation of a B-Lymphocyte after Interaction withan Effector T4-Helper LymphocyteAn effector T4-helper lymphocyte, by way of its TCR and CD4, binds to the MHC-II/epitopeon the activated B-lymphocyte. This, along with co-stimulatory signals that result from thebinding of costimulatory molecules such as CD40 and B7 on the B-lymphocyte with theircorresponding ligands on the activated T4-lymphocyte enable the T4-helper cell to releasecytokines such as IL-4, IL-5, IL-6, and IL-10. These cytokines then bind to cytokine receptorson the activated B-lymphocyte triggering its proliferation into a large clone of identical B-lymphocytes. The clone of B-lymphocytes eventually differentiates into antibody-secreting B-lymphocytes and plasma cells. Some of the B-lymphocytes also differentiate into B-memorycells for heightened secondary response against that T-dependent antigen.
  • Differentiation of B-lymphocytes into Plasma Cells and B-Memory Cells The B-lymphocytes now differentiate into plasma cells that secrete large quantities of antibodies that "fit" the original epitope. Some B- lymphocytes differentiate into B-memory cells capable of anamnestic response.
  • Natural Killer Cells (NK Cells)Participate in both innate immunity and adaptive immunity.NK cells are lymphocytes that lack B-cell receptors and T-cell receptors. Theyare designed to kill certain mutant cells and virus-infected cells in one oftwo ways:1. They kill cells to which antibody molecules have attached through a processcalled antibody-dependent cellular cytotoxicity (ADCC); and2. They also are able to kill cells lacking MHC-I molecules on their surface.
  • Anamnestic (Memory) ResponseA subsequent exposure to that same antigen results in a more rapidproduction of antibodies, in greater amounts, and for a longer period oftime.The primary response to a new antigen generally peaks at 5 - 10 days,however, because of the numerous circulating B-memory cells, the secondaryanamnestic response peaks in only 1 - 3 daysBecause of clonal expansion and affinity maturation, there is now apool of B-memory cells and pool of T4-memory cells enable an acceleratedhelper function.
  • MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)The primary function of the immune system is the recognition andelimination of foreign cells and antigens that enter the body. Tissues andorgans grafted from one individual to another of same species arerecognized as foreign and rejected.MHC Molecules are originally characterized as the antigens responsiblefor the rejection of organs hence the name (histo or tissue compatibility).also known as human leukocyte antigens or HLA, are the products of acluster of genes in the human DNA known as the major histocompatibilitycomplex (MHC). These antigens are present on various human cells andenable T-lymphocytes to recognize epitopes and discriminate self fromnonself.
  • A. MHC-I Molecules (Class I HLA Molecules)These molecules are made by all nucleated cells in the body. They bindpeptide epitopes from endogenous antigens to enable immune recognitionby T8-lymphocytes.Endogenous antigens are proteins found within the cytosol of humancellsa. The TCRs and CD8 molecules on the surface of naive T8-lymphocytesare designed to recognize peptide epitopes bound to MHC-I molecules onantigen-presenting cells (APCs).b. The TCRs and CD8 molecules on the surface of cytotoxic T-lymphocytes(CTLs) are designed to recognize peptide epitopes bound to MHC-Imolecules on infected cells and tumor cells.
  • Binding of Epitopes from Endogenous Antigens to MHC- I Moleculesby an Antigen Presenting Cell (APC)1. Exogenous antigens, such as viruses, are engulfed and placed in a phagosome.2. Lysosomes fuse with the phagosome forming an phagolysosome.3. During phagocytosis, some proteins escape from the phagosome or thephagolysosome and enter the cytosol of the APC and become endogenousantigens.4. These endogenous antigens pass through proteasomes where they aredegraded into a series of peptides.
  • 5. The peptides are transported into the rough endoplasmic reticulum (ER)by a transporter protein called TAP.6. The peptides then bind to the grooves of newly synthesized MHC-Imolecules.7. The endoplasmic reticulum transports the MHC-I molecules with boundpeptides to the Golgi complex.8. The Golgi complex, in turn, transports the MHC-I/peptide complexes byway of an exocytic vesicle to the cytoplasmic membrane where theybecome anchored. Here, the peptide and MHC-I/peptide complexes can berecognized by naive T8-lymphocytes by way of TCRs and CD8 moleculeshaving a complementary shape.
  • B. MHC-II Molecules (Class II HLA Molecules)Class II HLA molecules are made primarily by antigen-presenting cells (APCs,eg, macrophages and dendritic cells) and B-lymphocytes. They bind peptideepitopes from exogenous antigens to enable immune recognition by T4-lymphocytes.MHC-II molecules have a deep groove that can bind peptide epitopes, from10-30 but optimally from 12-16 amino acids long, from exogenous antigens.Exogenous antigens are antigens that enter from outside the body such asbacteria, fungi, protozoa, and free viruses.Binding of Epitopes from Exogenous Antigens to MHC-II Molecules in aMacrophage takes place in same manner as binding in MHC-I molecules butHere, the peptide and MHC-II complexes can be recognized by T4-lymphocytes by way of TCRs and CD4 molecules having a complementaryshape.
  • An MHC- II Molecule on an Antigen-Presenting Cell Presenting a BoundViral Epitope to a Naive T4-Lymphocyte with a Matching TCR/CD4 on itsSurfaceNaive T4-lymphocytes via the unique T-cell receptors and CD4 molecules ontheir surface recognize peptide epitopes from exogenous antigens bound toMHC-II molecules on antigen presenting cells (APCs). Different T-cell receptorsrecognize different epitopes.
  • HLA and Disease association:Inflammatory disease including ankylosing spondylitis and several post infectious arthropathies are all associated with HLA B27 (Rheumatoid arthritis and HLA DR4).Inherited errors of metabolism such as 21 hydroxylase deficiency (HLA Bw47).Autoimmune disease including autoimmune endocrinopathy associated with certain DR alleles, HLA DRS.
  • IMMUNE RESPONSE The specific reactivity induced in a host by an antigenic stimulus is known as the immune response. In infectious disease it is generally equated with protection against invading microorganisms. Immune response includes reactions against any antigen, living or non- living. It may lead to consequences that are beneficial, indifferent or injurious to the host. It also includes the state of specific non reactivity (tolerance) induced by certain types of antigenic stimuli.The immune response can be of two types:1. Humoral (Antibody mediated) response.2. Cellular (cell mediated) response.
  • Two major branches of the adaptive immune responses are1. Humoral immunity :Involves the production of antibody molecules in response to an antigenand is mediated by B-lymphocytes.2. Cell-mediated immunityInvolves the production of cytotoxic T-lymphocytes, activated macrophages,activated NK cells, and cytokines in response to an antigen and is mediated byT-lymphocytes.
  • Humoral immune response:The production of antibodies consists of three steps: The entry of the antigen, its distribution and fate in the tissues and its contact with appropriate immunocompetent cells (afferent limb). The processing of antigens by cells and the control of the antibody forming process (central functions). The secretion of antibody, its distribution in tissues and body fluids and the manifestations of its effects (efferent limb).
  • Antibody production follows a characteristic pattern consisting of: 3 2 4 1Primary Immune response. An antigen stimulus1. Latent period or lag phase2. Rise in titre of serum antibody3. Steady state of antibody titre4. Decline of antibody titre
  • The primary response is slow, sluggish and short lived with a long lag phase andlow titre of antibodies that does not persist for long. The antibody formed - IgMIn contrast the secondary response is prompt, and a much higher level ofantibodies that lasts for long periods. The antibody formed - IgG. 4 2 3 1 A B CEffect of repeated antigenic stimulus. A, B, C antigenic stimulus1. Primary immune response 2. Secondary immune response3. Negative phase 4. High level of Ab following Booster Inj.
  • Cellular immune response: CMI refers to the specific immune response that does not involve antibodies. They include delayed hypersensitivity (DH), which results in injury rather than protection.CMI participates in the following immunological functions: Delayed hypersensitivity. Immunity in infectious diseases caused by obligate and facultative intracellular parasites. bacteria (for example, tuberculosis, leprosy, listeriosis, brucellosis) fungi (for ex. Histoplasmoses, coccidioidomycosis, bastomycosis), protozoa (ex. Leishmaniasis, trypanosomiasis) and viruses (for ex: measles, mumps). Transplantation immunity and graft versus host reactions. Immunological surveillance and immunity against cancer. Pathogenesis of certain autoimmune diseases (thyroiditis encephalomyelitis).
  • THEORIES OF IMMUNE RESPONSE:Theories of immunity fall into two categories, instructive and selective.Instructive theories postulate that an immunocompetent cell is capable ofsynthesizing antibodies of any specificity. The antigen encounters animmunocompetent cell and instructs it to produce the complementaryantibody.Selective theories, on the contrary, shift the emphasis from the antigen tothe immunocompetent cell. They postulate that immunocompetent cells haveonly a restricted immunological range. The antigen exerts only a selectiveinfluence by stimulating the appropriate immunocompetent cell to synthesizean antibody.
  • Side chain theory:by Ehrlich (1900).Cells were considered to have surface receptors capable of reacting withsubstances having complementary ‘side chains.When foreign antigens are introduced into the body, they combine with thosecell receptors, which have at complementary fit.This inactivates the receptors and interferes with the absorption of nutrients.As a compensatory mechanism, there is an overproduction of the same type ofreceptors, which spill over into the blood and circulate as antibodies.This theory explained elegantly the specificity of the antibody response.However, when Landsteiner demonstrated that antibodies could be formed notonly against natural antigens but also against various synthetic chemicals, thistheory was abandoned because a large number of receptors would be needed tofor antibody specificity.
  • Direct template theories: by Breinl and Haurowitz (1930), Alexander (1931) and Mudd (1932). Antigen (or the antigenic determinant) enters antibody-forming cells andserves as a template against which antibody molecules are synthesized so thatthey have combining sites complementary to the antigenic determinant. These are therefore known as ‘direct template’ theories.Indirect template theory: by Burnet and Fenner (1949) proposed this instructive theory to explain thesynthesis of antibody as an adaptive protein. entry of the antigenic determinant into the antibody-producing cell induces init a heritable change. A genocopy of the antigenic determinant was thus incorporated in itsgenome and transmitted to the progeny cells (indirect template).This theory explained specificity and the secondary response but becameuntenable with advances in the molecular biology of protein synthesis.
  • Natural selection theory: By Jerne (1955) This postulated that about a million globulin (antibody) molecules wereformed in embryonic life, which covered the full range of antigenic specificitiescalled by ‘natural antibodies’. When an antigen was introduced, it combined selectively with the globulinthat had the nearest complementary ‘fit’ and stimulates to synthesize the samekind of antibody.Selection was postulated at the level of the antibody molecule. It did not explain the fact that immunological memory resides in the cells, andnot in serum
  • Clonal selection theory: By Burnet (1957) He shifted immunological specificity to the cellular level. During immunological development, cells capable of reacting with differentantigens were formed by a process of somatic mutation. Elimination of ‘forbidden clones’ during embryonic life. Their persistence or development in later life by somatic mutation could leadto autoimmune processes. Each immunocompetent cell was capable ofreacting with one antigen introduced into the body. Result of the contact - is cellular proliferation to form clones synthesizing theantibody.The clonal selection theory is more widely accepted than the other theories,though it is unable to account for all the features of the immune response.
  • CLASSIFICATION Immediate hypersensitivity (B cell or antibody mediated) Anaphylaxis Type I Atopy Antibody mediated cell damage Type II Arthus phenomenon Serum sickness Type III Delayed hypersensitivity (T cell mediated) Infection (tuberculin) type Type IV Contact dermatitis type
  • Type I Hypersensitivity (Anaphylactic, IgE or reagin dependent) Antibodies (‘cytotropic’ lgE antibodies) are fixed on the surface of tissue cells (mast cells and basophils) in sensitized individuals. These cells carry large numbers of receptors called Fc ER receptors, IgE molecules attach to these receptors by their Fc end. The antigen combines with the cell fixed antibody, this increases the permeability of the cells to calcium ions and leads to degranulation, with release of vasoactive amines which produce the clinical reaction. Anaphylaxis: the acute, potentially fatal, systemic form Atopy: the chronic or recurrent, nonfatal, typically localized form
  • Type- I Hypersensitivity: Production of IgE in Response to an Allergen The allergen enters the body and is recognized by sIg on a B- lymphocyte. The B-lymphocyte proliferates and differentiates into plasma cells that produce and secrete IgE against epitopes of the allergen.
  • Type- I Hypersensitivity: Allergen Interaction with IgE on the Surface of Mast Cells Triggers the Release of Inflammatory MediatorsThe next time the allergen enters the body, it cross-links the Fabportions of the IgE bound to the mast cell. This triggers the mast cell todegranulate, that is, release its histamine and other inflammatorymediators.
  • Anaphylaxis(ana = without, phylaxis = protection) classical immediate hypersensitivity reactionThe inflammatory agents released, causes: dilatation of blood vessels. increased capillary permeability. constriction of bronchial airways. stimulation of mucous secretion. stimulation of nerve endings.
  • PRIMARY MEDIATORS OF ANAPHYLAXISHistamine: formed by the decarboxylation of histidine found in the granules of mast cells, basophils and in platelets. stimulates sensory nerves, producing burning and itching. Flare effect : vasodilatation and hyperemia by an axon reflexand Wheal effect : edema by increasing capillary permeability. Histamine induces smooth muscle contraction in intestines, uterus and bronchioles. secretogogue effect.
  • Serotonin (5-hydroxy tryptamine) Derived by decarboxylation of tryptophan. Found in the intestinal mucosa, brain tissue and platelets. Smooth muscle contraction, increases capillary permeability and vasoconstriction.Eosinophil Chemotactic factors: (ECF-A) Acidic tetrapeptides released from mast cell granules. Contributes to the eosinophilia accompanying many hypersensitivity.HeparinAcidic mucopolysaccharide.Contributes to anaphylaxis in dogs, but apparently not in human
  • SECONDARY MEDIATORS OF ANAPHYLAXISProstaglandins and leukotrienesDerived by pathways from arachidonic acid, which is formed from disrupted cell membranes of mast cells and other leucocytes.The Lipoxygenase pathway leukotrienes, cyclo-oxygenase pathway prostaglandins and thromboxane.Slow Reacting Substance Of Anaphylaxis (SRS-A) produces low, sustained contraction of smooth muscles, identified as a family of leukotrienes (LTB4, C4, D4, E4).Prostaglandin F2a and thromboxane A2 are powerful, but transient, bronchoconstrictors.Prostaglandins also affect secretion by mucous glands, platelet adhesion, permeability and dilatation of capillaries and the pain threshold.
  • Treatment of Type I hypersensitivityepinephrine. 0.3 – 0.5ml of 1:1000 Epinephrine s.c. or i.m. withrepeated doses, if required at 20 mts. intervalsIf not corrected, Hypoxia due to airway obstruction or related tocardiac arrhythmias is considered then O2 is givenEpinephrine relaxes smooth muscle, constricts blood vessels, andstimulates the heart. It is used for severe systemic reactions.antihistamines diphenhydramine 50-100mg i.m. / i.v.Block the binding of histamine to histamine receptors on targetcells.Nasally administered steroids. Corticosteroids are potent anti-inflammatory agents.sodium cromolyn. Sodium cromolyn prevents mast cells fromreleasing histamines.Aminophylline 0.25-0.5 gm i.v. for bronchospasm
  • Blocking Type-1 Hypersensitivity Using Monoclonal AntibodiesAgainst IgEA new experimental approach to treating and preventing Type-Ihypersensitivity involves, giving the person with allergies, theinjections of monoclonal antibodies that have been made againstthe Fc portion of human IgE. This, in turn, blocks the attachment ofthe IgE to the Fc receptors on mast cells and basophils and thesubsequent release of histamine by those cells upon exposure toallergen.
  • ATOPY: (out of place or strangeness)Refer to naturally occurring familial hypersensitivities of human beings, typified by hay fever and asthma.Inhalants (for example, pollen, house dust)Ingestants (for example, eggs, milk).Generally not good antigens when injected parenterally but induce IgE antibodies.It is difficult to induce atopy artificially.Often associated with a deficiency of IgA. This association has led to the suggestion that IgA deficiency may predispose to atopy.Clinical features includesconjunctivitis,rhinitis,gastrointestinal symptoms and dermatitis following exposure through theeyes, respiratory tract, intestine or skin, respectively.
  • Type II (cytotoxic and cytolytic) These reactions involve a combination of IgG (or rarely IgM)antibodies with the antigenic determinants on the surface of cellsleading to cytotoxic or cytolytic effects.Cell or tissue damage occurs in the presence of complement ormononuclear cells.Mechanism:Either IgG or IgM is made against normal self antigens as a resultof a failure in immune tolerance ora foreign antigen resembling some molecule on the surface of hostcells enters the body and IgG or IgM made against that antigen thencross reacts with the host cell surface.
  • Opsonization During Type-II HypersensitivityIgG reacts with epitopes on the host cell membrane. Phagocytes then bind tothe Fc portion of the IgG and discharge their lysosomes.
  • MAC Lysis During Type-II HypersensitivityIgG or IgM reacts with epitopes on the host cell membrane and activates theclassical complement pathway. Membrane attack complex (MAC) then causeslysis of the cell.
  • Examples include: AB and Rh blood group reactions; Autoimmune diseases such as: Rheumatic fever where antibodies result in joint and heart valve damage; Idiopathic thrombocytopenia purpura where antibodies result in the destruction of platelets; Myasthenia gravis where antibodies bind to the acetylcholine receptors on muscle cells causing faulty enervation of muscles; Goodpastures syndrome where antibodies lead to destruction of cells in the kidney; Graves disease where antibodies are made against thyroid- stimulating hormone receptors of thyroid cells leading to faulty thyroid function; Multiple sclerosis where antibodies are made against the oligodendroglial cells Some drug reactionsType II hypersensitivity also participates in early transplant rejections.
  • TYPE III (IMMUNE COMPLEX - MEDIATED)A hypersensitivity resulting from large quantities of soluble antigen-antibody complexes passing between endothelial cells of the bloodvessels and becoming trapped on the surrounding basement membrane.The antigen/antibody complexes then activate the classical complementpathway.This may cause:a. massive inflammationb. influx of neutrophilsc. MAC lysis of surrounding tissue cellsd. aggregation of platelets
  • Type-III Hypersensitivity: Immune ComplexLarge quantities of soluble antigen-antibody complexes form in the blood andare not completely removed by macrophages. These antigen-antibodycomplexes lodge in the capillaries between the endothelial cells and thebasement membrane. The antigen-antibody complexes activate the classicalcomplement pathway and complement proteins and antigen-antibodycomplexes attract leukocytes to the area. The leukocytes then discharge theirkilling agents and promote massive inflammation. This leads to tissue deathand hemorrhage
  • Examples include: Serum sickness, a combination type I and type III Hypersensitivity; Autoimmune acute glomerulonephritis; Rheumatoid arthritis; Systemic lupus erythematosus; Some cases of chronic viral hepatitis; and Skin lesions of syphilis and leprosy.
  • ARTHUS REACTIONArthus (1903) observed that when; rabbits were repeatedlyinjected subcutaneously with normal horse serum, the initial injectionshad no local effect but with later injections, there occurred intenselocal reaction consisting of edema, induration and hemorrhagicnecrosis. This is known as the Arthus reactionThe tissue damage is due to formation of antigen-antibody precipitatescausing complement activation and release of inflammatorymolecules. This leads to increased vascular permeability andinfiltration of the site with neutrophils.Leucocyte-platelet thrombi are formed that reduces the blood supplyand lead to tissue necrosis.For example, intrapulmonary Arthus-like reaction to inhaled antigens,such as thermophilic actinomycetes from mouldy hay or graincauses Farmers lung and other types of hypersensitivity pneumonitis.
  • SERUM SICKNESSby von Pirquet and Schick (1905), this appeared 7-12 days followingsingle injection of a high concentration of foreign serum such as thediphtheria antitoxin.The clinical syndrome consists of fever, lymphadenopathy,spleenomegaly, arthritis, glomerulonephritis, endocarditis, vasculitis,urticarial rashes, abdominal pain, nausea and vomiting.The plasma concentration of complement falls due to massivecomplement activation and fixation by the antibody complexes. Thedisease is self-limited.The latent period of 7-12 days is required only for serum sicknessfollowing a single injection. With subsequent injections, the diseasemanifests earlier. Serum sickness differs from other types ofhypersensitivity reaction in that a single injection can serve both asthe sensitizing dose and the shocking dose.
  • TYPE IV (DELAYED HYPERSENSITIVITY)It is cell-mediated rather than antibody-mediated.Mechanism:T8-lymphocytes become sensitized to an antigen and differentiateinto cytotoxic T-lymphocytes, while Th1 type T4-lymphocytesbecome sensitized to an antigen and produce cytokines.CTLs, cytokines, and/or macrophages then cause harm ratherthan benefit.
  • Examples include:tuberculosis, leprosy, smallpox, measles, herpes infections,candidiasis, and histoplasmosis;the skin test reactions seen for tuberculosis and other infections;contact dermatitis like poison ivy;type-1 insulin-dependent diabetesmultiple sclerosis, where T-lymphocytes and macrophages secretecytokines that destroy the myelin sheath that insulates the nerve fibersof neurons;chronic transplant rejection as seen in host versus graft rejection orgraft versus host rejection.
  • Tuberculin (infection) typeWhen a small dose of tuberculin is injected intradermally in an individual sensitized to tuberculoprotein by prior infection or immunisation, an indurated inflammatory reaction develops at the site within 48-72 hours. In unsensitized individuals, the tuberculin injection provokes no response.The tuberculin test therefore provides useful indication of the stateof delayed hypersensitivity (cell mediated immunity) to the bacilli.Tuberculin type hypersensitivity develops in many infections with bacteria, fungi, viruses and parasites, especially when the infectionis subacute or chronic and the pathogen intracellular.
  • Contact dermatitis typeDelayed hypersensitivity usually occurs due to skin contact with a varietyof substances– Sensitization is particularly liable when contact is with an inflamed area of skin and when the chemical is applied in an oilybase. The substances involved are in themselves not antigenic but may acquire antigenicity on combination with skin proteins. Sensitization requires percutaneous absorption. Langerhans cells of the skin capture locally applied hapten and migrate to the draining lymph nodes, present hapten along with MHC molecules, to T cells. The sensitized T cells travel to the skin site, where on contacting the antigen they release various lymphokines
  •  Contact with the allergen in a sensitized individual leads to ‘contact dermatitis’, characterized by maculopapular lesions to vesicles that break down, leaving behind raw weeping areas typical of acute eczematous dermatitis. Hypersensitivity is detected by the ‘patch test’. The allergen is applied to the skin under an adherent dressing. Sensitivity is indicated by itching appearing in 4-5 hours, and local reaction, which may vary from erythema to vesicle or blister formation, after 24-28 hours.Metals : nickel and chromium,Chemicals : dyes, picryl chloride, dinitrochlorobenzene,Drugs : penicillin
  • Shwartzman reactionShwartzman (1928) observed that if a culture filtrate of S. typhi isinjected intradermally in a rabbit, followed 24 hours later by the samefiltrate intravenously, a hemorrhagic necrotic lesion develops at thesite of the intradermal injection.The intradermal and intravenous injections need not be of the sameor even related endotoxins. This absence of specificity and the shortinterval between the two doses preclude any immunological basis forthe reaction.The four types of immunopathogenic mechanisms described are notmutually exclusive. Any given hypersensitive reaction may comprisethe components of more than one, or all of these mechanisms.
  • AUTOIMMUNITY The immune reaction to self-antigens Autoimmunity is a condition in which structural or functionaldamage is produced by the action of immunologically competentcells or antibodies against the normal components of the body. Autoimmunity literally means ‘protection against self’ but itactually implies injury to self. It is also known as ‘Autoallergy’. Autoimmunity also implies loss of self-tolerance.
  • Features of diseases of autoimmune origin1. An elevated level of immunoglobulins2. Demonstrable autoantibodies3. Deposition of immunoglobulins at sites of election4. Accumulation of lymphocytes and plasma cells at site of lesion5. Benefit from immunosuppressive therapy like corticosteroid6. Occurrence of more than one type of autoimmune lesion7. A genetic predisposition towards autoimmunity8. Incidence higher among females9. Chronicity. Usually nonreversible
  • Immunologic tolerance: is a state in which an individual is incapable ofdeveloping an immune response against a specific antigen. Self-tolerance specifically refers to a lack of immune responsiveness to one’sown tissue antigens.Central tolerance: This refers to the deletion of self-reactive T and B-lymphocytes during their maturation in central lymphoid organs. Anydeveloping T cell or B cell that expresses a receptor for such self-antigen is deleted by apoptosis.Peripheral tolerance: Self-reactive T cells that escape negativeselection in the thymus can potentially dangerous outside in peripherallymphoid organs.Anergy: This refers to prolonged or irreversible inactivation (rather thanapoptosis) of lymphocytes induced by encounter with antigens undercertain conditions.
  • Mechanisms of Autoimmune DiseaseBreakdown of one or more of the mechanisms of self-tolerance canunleash an immunologic attack on tissues that leads to the developmentof autoimmune diseases.Failure of toleranceFailure of Activation induced Cell Death: Defects in this pathwaymay allow persistence and proliferation of autoreactive T cells inperipheral tissues, which may lead to autoimmune disease.Breakdown of T-Cell Anergy: Autoreactive T cells that escape centraldeletion are rendered anergic when they encounter self-antigens in theabsence of costimulation.
  • Molecular Mimicry: Some infectious agents share epitopes with self-antigens, and an immune response against such microbes will elicitsimilar responses to the cross-reacting self-antigen.Polyclonal B cell activation: While an antigen generally activates onlyits corresponding B cell, certain stimuli nonspecifically turn on multipleB cell clones. These polyclonal antibodies are IgM in nature.Release of Sequestered antigens: Any self-antigen that is completelysequestered during development is likely to be viewed as foreign ifsubsequently introduced to the immune system. Spermatozoa andocular antigens fall into this category.
  • AUTOIMMUNE DISEASES Localized Hemolytic (organ specific) Systemic Transitory(non organ specific)
  • HEMOLYTIC AUTOIMMUNE DISEASES1. Autoimmune hemolytic anemias: Autoantibodies against RBC aredemonstrable. Two group of anemias are: Cold autoantibodies: Complete agglutinating antibodies belongingto IgM class Warm autoantibodies: Incomplete nonagglutinating antibodiesbelonging to IgG class2. Autoimmune thrombocytopenia: Autoantibodies directed againstplatelets eg. In Idiopathic thrombocytopenia purpura3. Autoimmune leucopenia: nonagglutinating antileucocyte antibodiesin serum of SLE and RA patients
  • LOCALIZED (ORGAN SPECIFIC) AUTOIMMUNE DISEASES1. Autoimmune diseases of thyroid gland: Hashimoto’s disease and Thyrotoxicosis (Graves’ disease)2. Addison’s disease: Antibodies directed against cells of Zona glomerulosa3. Autoimmune Orchitis: Antibodies against sperms and germinal cells4. Myasthenia Gravis: Antibody against acetyl choline receptors on myoneural junctions of striated muscles
  • 5. Autoimmune diseases of Eye: In cataract surgery autoimmune response to lens protein leads to intraocular inflammation (phacoanaphylaxis)6. Pernicious anemia: Antibodies directed against parietal cell of gastric mucosa and intrinsic factor7. Autoimmune disease of Skin: Pemphigus vulgaris, Bullous pemphigoid and dermatitis herpetiformis
  • SYSTEMIC (NONORGAN SPECFIC) AUTOIMMUNE DISORDERS1. Systemic lupus erythematosus: Autoantibodies directed against: Cell nuclei, intracytoplasmic cell constituents, immunoglobulins and thyroid gland2. Rheumatoid arthritis: Presence autoantibody called as Rheumatoid factor against the Fc fragment of immunoglobulin3. Polyarteritis nodosa4. Sjogren’s syndromeTRANSITORY AUTOIMMUNE PROCESSESIncludes conditions like Anemias, thrombocytopenias or nephritis thatfollow infection or drug therapy. They induces antigenic alteration inself antigens. Disease is transient.
  • ORAL IMMUNOLOGYThe health of the mouth is dependent on the integrity of mucosa,saliva, gingival crevicular fluid and their immune components, whichdoes not normally allow microorganisms to penetrate.The oral tissues are drained by an anatomically well defined collectionof extraoral lymph nodes and intraoral lymphoid tissue aggregations.I The tonsils (palatine and lingual)2 Salivary gland, plasma cells and lymphocytes3 Gingival aggregation of plasma cells, lymphocytes, macro-phages4 The scattered submucosal lymphoid cells
  • The functional significance of the intraoral lymphoid tissue has notbeen clearly defined. It appears that The tonsils guards the entry into the digestive and respiratorytracts The gingival lymphoid aggregation responding to the dentalbacterial plaque accumulation. The salivary lymphoid tissue for secretary IgA synthesis andprotection against infection within the salivary gland.The secretary IgA in saliva may combine with microorganisms andprevent their adherence to the mucosal surface.
  • Sources of Immunoglobulin in whole saliva
  • Synthesis, assembly and secretion of IgA
  • Local and systemic immunity affecting the toothTooth surface is influenced by both local salivary and systemic immunemechanisms. The division between the two immune mechanismsoccurs near the gingival margin, the only site of the body where aninterphase can be found between the local secretory and systemicimmune mechanisms. The salivary domain depends on the function ofsecretary IgA and the gingival domain is controlled by immunecomponents found in blood.
  • Blood Crevicular Gingival fluidcrevicular IgG, IgM, IgA domain Protein Complement Enzymes Electrolytes Polymorphs Oral fluid B, T Lymphocytes Macrophages sIgA IgG, IgA Salivary Proteins domain Enzymes sIgA Electrolytes Proteins Polymorphs Enzymes ElectrolytesSalivary Salivary Salivarygland fluid domainHumoral and Cellular components in crevicular, salivary and oral fluids
  • IMMUNOLOGY OF DENTAL BACTERIAL PLAQUE DENTAL PLAQUE COMPONENTSCARIOGENIC IMMUNOPOTENTIATING AND PERIODONTOPATHICMICRO-ORGANISMS IMMUNOSUPPRESIVE AGENTS MICRO-ORGANISMSStreptococcus mutans Lipopolysaccharides, Dextrans, Actinomyces,Actinomyces viscosus Levan, Lipoteichoic acid Actinobacillus,Lactobacilli Veillonella, Eikenalla, Spirochaetes IMMUNE RESPONSEANTIBODY COMPLEMENT CHEMOTAXIS: PHAGOCYT- T- AND B - ACTIVATION PMNL, OSIS: PMNL LYMPHOCYTESIgA, IgM, Classical and MACROPHAGES Killing, Suppression,IgA, sIgA, Alternative Lysosomal Proliferation,IgE pathway enzymes Memory, Help CARIES GINGIVITIS, PERIODONTITIS
  • IMMUNOLOGY OF PERIODONTAL DISEASELocal immunopathological and systemic immune responses during fourstages of development of periodontal disease
  • TYPE I TYPE II TYPE III TYPE IV IgE Antibodies Immune complex LymphocytesMast cell Opsonic Cell lysis: ADCC Complement Platelet Lymphokines: adherence C5 – 9 activation aggregation Mitogenic factor MIF Lymphotoxin OAFVasoactive Phagocytes Histamine, Micro thrombiAmines Chemotaxis Vocative of polymorphs amines Killing The complex nature of immune responses in immunopathogenesis of periodontal disease
  • IMMUNOLOGY OF DENTAL CARIESSerum IgG, salivary IgA and IgM antibodies and cell mediated immunityto Streptococcus mutants can be correlated with the DMF index of caries.Principal immunological mechanisms of protection against cariesincludesDirect immunization of the minor salivary glands or of the gut associatedlymphoid tissue, so that salivary IgA antibodies thus secreted prevent S.mutans from adhering to the tooth surface and thereby prevent caries.Humoral and cellular components elicited by systemic immunization.Antibodies, complement, PMN, lymphocytes and macrophages pass fromthe gingival blood vessels to the gingival domain of the tooth andmediates IgG-induced opsonization, binding and phagocytosis.Local gingivo-salivary immunization with synthetic peptides induces adual gingival IgG and salivary IgA antibodies to S. mutans.
  • Time TOOTH CARIES Bacteria Sugar NO CARIES AntibodiesFive principles factors in the development of caries
  • Local passive immunization with monoclonal antibodies against S. mutansprevents colonization of this organism and is a local non-invasive method ofprevention of caries.
  • 4 – phase hypothesis of mechanism of prevention of colonization of S. mutans by Specific Monoclonal Antibodies
  • Four preventive immuno – microbiological measures from gestation to childhood
  • IMMUNOLOGY OF ORAL INFECTIONSImmunopathology of Herpes virus infectionHerpes simplex virus is a DNA virus2 types: Type 1 and Type 23 genes: Alpha, beta and gammaBeta gene codes for viral glycoproteins gB, gC, gD and gE. gB is involved in viral penetration of the cell membrane, gC constitutes the C3b receptor (binding the activated C3b), gF is the Fc receptor for IgG and Antibodies against gD neutralize HSV and block penetration of HSV.
  • Primary herpetic infectionThe incubation period is between 2 and 7 days.Within the first week of onset of clinical manifestations sensitizedlymphocytes to HSV can be detected in the peripheral blood but nosignificant antibodies or macrophage migration inhibition factor (MIF).After 2 weeks significant antibody titres and MIF appear. Recoveryfrom infection coincides therefore with the appearance of antibody andof MIF.Recurrent HSV infectionA deficiency of MIF production and decreased cytotoxicity by sensitizedCD8 cells may play a part in re-current infection.CD4-T cells produce interferon and decreased interferon productionhas been correlated with an increased fre-quency of recurrent HSVinfections.Due to selective deficiency in cell-mediated immunity
  • IMMUNOLOGICAL FEATURES OF CANDIDIASISCandidiasis is seen in patient with defective generation or differentiation oflymphoid stem cellsT-cell immune responses prevents muco-cutaneous candidiasis and serumIgG and IgM antibodies prevents systemic candidiasis.Immunodeficiencies of cellular, humoral or phagocytic components play animportant part in candidiasis.Oral candidiasis is found in patients with AIDS who have a deficiency of CD4cells.Patients with B-lympho-cyte defects alone are not susceptible to candidiasis,unless they also have a concurrent T-cell deficiency, as in the severecombined immunodeficiency syndrome.
  • IMMUNLOGICAL AND AUTOIMMUNE DISORDERS OF ORAL MUCOSARecurrent aphthous ulcersPatients with RAU show an association with HLA-B12 and it offersimmunogenic basis for development of the diseaseCell mediated immunity is involved in RAUThis induces type III and type IV hypersensitivity reactionsImmunohistological investigation reveals increase in no. of CD4 and CD8cells, Langerhans cells and macrophages.
  • Pemphigus vulgarisAssociation with DR4 or DRw6Autoantibodies to intercellular substance of epithelial cells (IgG type)circulating and bound to keratinocytes at site of diseaseEpithelial cells with autoantibodies release plasminogen activatorswhich activate plasmin and leads to acantholysisBenign mucous membrane pemphigoid (BMMP)Presence of circulating anti-basement membrane antibodies (IgG, IgAand IgM) with or without complementAutoantibodies react with the lamina lucida of basement membrane
  • Lichen planusHistology shows a increase in Langerhans cells and well defined T-cell(CD4 and CD8) infiltration of lamina propriaLichen planus usually develops in mouth and/or skin of patients inwhich Graft versus host reaction takes placeVariety of drugs can induce lichenoid reactions in the mouthSjogren’s syndromePresence of Antinuclear factor Organ specific antibodies Salivary duct antibodies
  • IMMUNE RESPONSES IN DENTAL PULP AND PERIAPICAL TISSUESPulp of normal tooth contains T-cells with the CD4 and CD8 cells in aratio of 1:2 reverse to that found in circulation (2:1)B-cell are not found in normal pulp, so they have to home to pulp duringinflammatory reactionPulp and periapical tissues possess the cellular components to mounthypersensitivity reactions namely Type III, II and IImmune responses to dental caries leads to development of Chronicpulpitis and periapical granulomasCysts shows plasma cell infiltration in cyst conc. Of IgG, IgM and IgA incyst fluid
  • IMMUNE FUNCTION TESTSA careful history and physical examination will usually indicate whetherthe major problem involves the Antibody – Complement phagocytesystem or Cell mediated immunity
  • HUMORAL IMMUNITYTEST COMMENTImmunoglobulin survey (serum protein General assessment of B cell functionelectrophoresis, Ig quantification) To assess levels of IgG, A, M, D and EIsohemagglutinin titer (anti-A, anti-B) General indication of IgM productionTiters before and after immunization Demonstrates the in vivo ability towith a specific vaccine (TT, respond to known antigenpneumovax, Typhoid – paratyphoid)B cell enumeration by surface sIg or Measures the no. of circulating B cellsflow cytometryBiopsy of bone marrow, lymph node, Assessment of presence and/oror gut location of lymphocytes (germinal centers, plasma cells)
  • CELL MEDIATED IMMUNITY TEST COMMENTPeripheral WBC count and General assessment of T cellmorphology presenceT cell enumeration by nonimmune Measures the total no. T cells inrosetting or flow cytometry (CD3) peripheral bloodEnumeration T cell subsets (CD4, The TH / TS ratio is usually 2:1CD8)Measurement of lymphokine Assessment of T cell ability to secreteproduction (MIF, IL-2) lymphokineResponse to phytohemagglutinin or Evaluation of T cell ability to undergomixed lymphocyte culture blastogenesis
  • Response to phytohemagglutinin or Evaluation of T cell ability to undergomixed lymphocyte culture blastogenesisDelayed hypersensitivity skin testing to Assessment of in vivo function of T cellrecall antigens (PPD, histoplasmin, to a previously encountered antigenCandida, mumps, streptokinase)Dinitrochlorobenzene skin (DNCB) Assessment of in vivo function of T cellsensitization to respond to a newly encountered antigenBiopsy of lymph node Assessment of the presence of T cell in thymus – dependent areasComplement CH50 assays (classic and alternative pathway)Phagocyte function Reduction of Nitroblue tetrazolium Chemotaxis assays, Bactericidal activity
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