Immune response ppt

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  • 33.0.1. The Immune System Adapts, Using the Principles of EvolutionThe immune system comprises two parallel but interrelated systems. In the humoral immune response, soluble proteinscalled antibodies (immunoglobulins) function as recognition elements that bind to foreign molecules and serve asmarkers signaling foreign invasion (Figure 33.1). Antibodies are secreted by plasma cells, which are derived from Blymphocytes (B cells). A foreign macromolecule that binds selectively to an antibody is called an antigen. In aphysiological context, if the binding of the foreign molecule stimulates an immune response, that molecule is called animmunogen. The specific affinity of an antibody is not for the entire macromolecular antigen but for a particular site onthe antigen called the epitope or antigenic determinant.In the cellular immune response, cells called cytotoxic T lymphocytes (also commonly called killer T cells) kill cells thatdisplay foreign motifs on their surfaces. Another class of T cells called helper T lymphocytes contributes to both thehumoral and the cellular immune responses by stimulating the differentiation and proliferation of appropriate B cells andcytotoxic T cells. The celluar immune response is mediated by specific receptors that are expressed on the surfaces of theT cells.The remarkable ability of the immune system to adapt to an essentially limitless set of potential pathogens requires apowerful system for transforming the immune cells and molecules present in our systems in response to the presence ofpathogens. This adaptive system operates through the principles of evolution, including reproduction with variationfollowed by selection of the most well suited members of a population.If the human genome contains, by the latest estimates, only 40,000 genes, how can the immune system generate morethan 108 different antibody proteins and 1012 T-cell receptors? The answer is found in a novel mechanism for generatinga highly diverse set of genes from a limited set of genetic building blocks. Linking different sets of DNA regions in acombinatorial manner produces many distinct protein-encoding genes that are not present in the genome. A rigorousselection process then leaves for proliferation only cells that synthesize proteins determined to be useful in the immuneresponse. The subsequent reproduction of these cells without additional recombination serves to enrich the cellpopulation with members expressing a particular protein species.
  • LymphocytesLymphocytes are the only cells in the body capable ofspecifically recognizing and distinguishing differentantigenic determinants and are responsible for the twodefining characteristics of the adaptive immuneresponse, specificity and memory.
  • Antigen-Presenting CellsAPCs are cell populations that are specialized to capturemicrobial and other antigens, display them to lympllOcytes,and provide signals that stimulate the proliferationand differentiation of the lymphocytes. Byconvention, APC usually refers to a cell that displaysantigens to T lymphocytes. The major type of APC thatis involved in initiating T cell responses is the dendriticcell. Macrophages present antigens to T cells duringcell-mediated immune responses, and B lymphocytesfunction as APCs for helper T cells during humoralimmune responses. A specialized cell type called the folliculardendritic cell (FDC) displays antigens to B lymphocytesduring particular phases of humoral immuneresponses. APCs link responses of the innate immunesystem to responses of the adaptive immune system,and therefore they may be considered as components ofboth systems. In addition to the introduction presentedhere, APC function will be described in more detail inChapter 6.
  • Antigen-Presenting CellsAPCs are cell populations that are specialized to capturemicrobial and other antigens, display them to lympllOcytes,and provide signals that stimulate the proliferationand differentiation of the lymphocytes. Byconvention, APC usually refers to a cell that displaysantigens to T lymphocytes. The major type of APC thatis involved in initiating T cell responses is the dendriticcell. Macrophages present antigens to T cells duringcell-mediated immune responses, and B lymphocytesfunction as APCs for helper T cells during humoralimmune responses. A specialized cell type called the folliculardendritic cell (FDC) displays antigens to B lymphocytesduring particular phases of humoral immuneresponses. APCs link responses of the innate immunesystem to responses of the adaptive immune system,and therefore they may be considered as components ofboth systems. In addition to the introduction presentedhere, APC function will be described in more detail inChapter 6.
  • LymphocytesLymphocytes are the only cells in the body capable ofspecifically recognizing and distinguishing differentantigenic determinants and are responsible for the twodefining characteristics of the adaptive immuneresponse, specificity and memory. Several lines of evidencehave established the role of lymphocytes as thecells that mediate adaptive immunity.o Protective immunity to microbes can be adoptivelytransferred from immunized to naive individuals onlyby lymphocytes or their secreted products.o Some congenital and acquired immunodeficienciesare associated with reduction of lymphocytes in theperipheral circulation and in lymphoid tissues. Furthermore,depletion of lymphocytes with drugs, irradiation,and cell type-specific antibodies, and bytargeted gene disruptions in mice, leads to impairedadaptive immune responses.o Stimulation of lymphocytes by antigens in cultureleads to responses in vitro that show many of thecharacteristics of immune responses induced undermore physiologic conditions in vivo.o Most important, specific receptors for antigens areproduced by lymphocytes but not by any other typesof cells.
  • Structure of the a.~ TCRThe antigen receptor of MHC-restricted CD4" helper Tcells and CD£1>cytotoxic T lymphocytes (CTLs) is a heterodimerconsisting of two transmembrane polypeptidechains, designated exand 13,covalently linked to eachother by a disulfide bridge (Fig. 7-3). (Another lesscommon type ofTCR, found on a small subset ofT cells,is composed of y and 8 chains and is discussed later.)Each ex chain and 13chain consists of one Ig-like Nterminalvariable (V) domain, one Ig-like constant (C)domain, a hydrophobic transmembrane region, and ashort cytoplasmic region. Thus, the extracellular portionof the exl3 heterodimer is structurally similarto the antigen-binding fragment (Fab) of an Ig molecule,which is made up of the V and C regions of a light chainand the V region and one C region of a heavy chain (seeChapter 4).The V regions of the TCR exand 13chains contain shortstretches of amino acids where the variability betweendifferent TCRs is concentrated, and these form thehypervariable or complementarity-determining regions(CDRs). Three CDRs in the exchain are juxtaposed tothree similar regions in the 13 chain to form the part ofthe TCR that specifically recognizes peptide-MHC complexes(described in the following section). The 13chainVdomain contains a fourth hypervariable region, whichdoes not appear to participate in antigen recognition butis the binding site for microbial products called superantigens(see Chapter 15, Box 15-2). Each TCR chain, likeIg heavy and light chains, is encoded by multiple genesegments that undergo somatic rearrangements duringthe maturation of the T lymphocytes (see Chapter 8). Inthe exand 13chains of the TCR, the third hypervariableregions are composed of sequences encoded by V and J(joining) gene segments (in the exchain) or V. 0 (diversity),and J segments (in the 13chain). These CDR3regions also contain junctional sequences that areencoded by added nucleotides, so-called N regions andP nucleotides (see Chapter 8). Therefore, most of thesequence variability in TCRs is concentrated in theCDR3 regions.The C regions of both exand 13 chains continue intoshort hinge regions, which contain cysteine residues
  • FIGURE 12-2 Properties ofcytokines. Selected examples areshown to illustrate the following propertiesof cytokines: pleiotropism, onecytokine having multiple effects ondiverse cell types; redundancy, multiplecytokines having the same or overlappingactions; synergy, two or morecytokines having greater than additiveeffects; and antagonism, one cytokineinhibiting the action of another. GENERAL PROPERTIES OF CYTOKINESCytokines are polypeptides produced in response tomicrobes and other antigens that mediate and regulateimmune and inflammatory reactions (Fig. 12-1).Although cytokines are structurally diverse, they shareseveral properties.. Cytokine secretion is a brief, self-limited event.Cytokines are not usually stored as preformed molecules,and their synthesis is initiated by new genetranscription as a result of cellular activation. Suchtranscriptional activation is transient, and the mes-IInnate immunity@ I Naturalkiller cell Microbes ~. *** ~/MaCrOPhage~ ...0I InflammationINeutroPhilSO\@senger RNAs encoding most cytokines are unstable,so cytokine synthesis is also transient. The productionof some cytokines may additionally be controlledby RNA processing and by posttranslational mechanisms,such as proteolytic release of an active productfrom an inactive precursor. Proteolytic processing isimportant, for example, in production of active tumornecrosis factor (TNF), IL-l, and transforming growthfactor-~ (TGF-~). Once synthesized, cytokines arerapidly secreted, resulting in a burst of release whenneeded. . The actions of cytokines are often pleiotropic andredundant (Fig. 12-2). Pleiotropism refers to theability of one cytokine to act on different cell types.This property allows a cytokine to mediate diversebiologic effects, but it greatly limits the therapeuticuse of cytokines because administration of a cytokinefor a desired clinical effect may result in numerousunwanted side effects. Redundancy refers to theproperty of multiple cytokines having the same functionaleffects. Because of this redundancy, antagonistsagainst a single cytokine or mutation of onecytokine gene may not have functional consequences,as other cytokines may compensate.CD4+T lymphocytesMacrophage Antibody secretion;activation isotype switchingCTLdifferentiationFIGURE 12-1 Functions of selected cytokines in host defense. In innate immunity, cytokines produced by macrophages and NK cellsmediate the early inflammatory reactions to microbes and promote the elimination of microbes. In adaptive immunity, cytokines stimulateproliferation and differentiation of antigen-stimulated lymphocytes and activate specialized effector cells, such as macrophages. The propertiesof the cytokines shown in this figure are discussed later in this chapter. APC, antigen-presenting cell.B~ell.~ IlgE productionICo Activated CD4+ . .,g helper T cell / CD4+~ .-.IIL-41,. :> ~ITH2differentiatlonl>- i...~,-6 IIL-41 ' Q)a:FIGURE 12-2 Properties ofcytokines. Selected examples areshown to illustrate the following propertiesof cytokines: pleiotropism, onecytokine having multiple effects ondiverse cell types; redundancy, multiplecytokines having the same or overlappingactions; synergy, two or morecytokines having greater than additiveeffects; and antagonism, one cytokineinhibiting the action of another.. Cytokines often influence the synthesis and actions ofother cytokines. The ability of one cytokine to stimulateproduction of others leads to cascades in whicha second or third cytokine may mediate the biologiceffects of the first. Two cytokines may antagonizeeach other's action, produce additive effects, or, insome cases, produce greater than anticipated, or synergistic,effects (see Fig. 12-2).. Cytokine actions may be local and systemic. Mostcytokines act close to where they are produced, eitheron the same cell that secretes the cytokine (autocrineaction) or on a nearby cell (paracrine action). T cellsoften secrete cytokines at the site of contact withantigen-presenting cells (APCs), the so-calledimmune synapse (see Chapter 9). This may be onereason why cytokines often act on cells that are incontact with the cytokine producers. When producedin large amounts, cytokines may enter the circulationand act at a distance from the site of production(endocrine action). TNF is an example of a cytokinethat has important local and systemic effects.. Cytokinesinitiate their actions by binding to specificmembrane receptors on target cells. Receptors forcytokines often bind their ligands with high affinities,with dissociation constants (K.Jvalues) in the range ofChapter 12 - CYTOKINES 269>B~>~)IProliferationI) IIFN-YI~) ITNFI ~Increased expressionof class IMHCmoleculeson many cell types) IIFN-yI, Macrophageactivation (:)>0 Inhibition ofmacrophageactivation10-10 to 1O-12M. (For comparison, recall that antibodiestypically bind antigens with a K.Jof 10-7 to10-11M and that T cell antigen receptors bind MHCassociatedpep tides with a K.Jof 10-5to 10-7M.) Therefore,only small quantities of a cytokine are needed tooccupy receptors and elicit biologic effects. Most cellsexpress low levels of cytokine receptors (on the orderof 100 to 1000 receptors per cell), but this is adequatefor inducing responses.. External signals regulate the expression of cytokinereceptors and thus the responsiveness of cells tocytokines. For instance, stimulation of T or B lymphocytesby antigens leads to increased expressionof cytokine receptors. For this reason, during animmune response, the antigen-specific lymphocytesare the preferential responders to secreted cytokines.This is one mechanism for maintaining the specificityof immune responses, even though cytokines themselvesare not antigen specific. Receptor expression isalso regulated by cytokines themselves, including thesame cytokine that binds to the receptor, permittingpositive amplification or negative feedback.o The cellular responses to most cytokines consist ofchanges in gene expression in target cells, resulting inthe expression of new functions and sometimes in the270 SECTIONIV- EFFECTOR MECHANISMS OF IMMUNE RESPONSESproliferation of the target cells. Many of the changesin gene expression induced by cytokines result in differentiationofT and B lymphocytes and activation ofeffector cells such as macrophages. For instance,cytokines stimulate switching of antibody isotypesin B cells, differentiation of helper T cells into Tilland TII2 subsets, and activation of microbicidalmechanisms in phagocytes. Exceptions to the rulethat cytokines work by changing gene expressionpatterns are chemokines, which elicit rapid changesin integrin affinity and cytoskeletal reorganizationthat favor migration, and a cytokine called TNF,which can induce apoptosis by activating cellularenzymes, without new gene transcription or proteinsynthesis.. Cellular responses to cytokines are tightly regulated,and feedback inhibitory mechanisms exist to turndown these responses. These mechanisms includecytokine induction of genes encoding inhibitors ofthe cytokine receptors or the downstream signalingpathways activated by the receptors. The inhibitorsinclude decoy cytokine receptors expressed on thecell surface, molecules that block interactions ofsignaling kinases, phosphatases that counteract theeffects of activating kinases, and molecules that blockproductive interactions of cytokine-induced transcriptionfactors with DNA.
  • Immune response ppt

    1. 1. 8/23/2013 3:53:19 AM 1
    2. 2. The key is our ability to produce more than 108 distinct antibodies and more than 1012 T-cell receptors 8/23/2013 3:53:19 AM 2
    3. 3. Innate immunity Adaptive immunity 8/23/2013 3:53:19 AM 3
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    6. 6. 1. Humoral (AMI) 2. Cellular (CMI) 8/23/2013 3:53:19 AM 6
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    8. 8. Humoral Immune response(AMI) Entry Processing Secretion 8/23/2013 3:53:19 AM 8
    9. 9. Lag phase Log phase Plateau or steady state Phase of decline 8/23/2013 3:53:19 AM 9
    10. 10. 8/23/2013 3:53:19 AM 10
    11. 11. 8/23/2013 3:53:19 AM 11 Antigen Introduced I.V SPLEEN LIVER BM KIDNEY LUNGS Broken down by RE cells Introduced S.C Draining lymph nodes
    12. 12. Non- immune phase Phase of immune elimination 8/23/2013 3:53:19 AM 12
    13. 13. • Immune response to an antigen is brought about by 3 type of cells APC T-cells B-cells 8/23/2013 3:53:19 AM 13
    14. 14. Capture Display Signal 8/23/2013 3:53:19 AM 14
    15. 15. 8/23/2013 3:53:19 AM 15
    16. 16. • The task of displaying cell-associated antigens for recognition by T cells is performed by specialized proteins that are encoded by genes in a locus called the MHC 2 TYPES Class I MHC Class II MHC8/23/2013 3:53:19 AM 16
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    21. 21. 8/23/2013 3:53:19 AM 21 Helper T cells Cytotoxic T cells NK cells
    22. 22. • Provides 2 defining characteristics of the adaptive immune response, 1.Specificity 2. Memory 8/23/2013 3:53:19 AM 22
    23. 23. 8/23/2013 3:53:19 AM 23
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    25. 25. © Ranjith’s 8/23/2013 3:53:19 AM 25
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    28. 28. Genetic Age Nutrition Route of administration Size & number of doses Multiple antigens Adjuvants Immunosuppressive drugs Effect of antibody 8/23/2013 3:53:19 AM 28
    29. 29. Specific immune response that do not involve antibodies. Delayed hypersensitivity Immunity in infections Transplantation immunity Immunological surveillance Autoimmune disease Scope of CMI 8/23/2013 3:53:19 AM 29
    30. 30. • Antigenic stimulus • Only T-cell dependant antigens lead to CMI • T-cell bears specific receptor on its surface • T cells recognize antigens only when presented with MHC molecules • Helper T-cells • Cytotoxic T-cells 8/23/2013 3:53:19 AM 30
    31. 31. • Biologically active substances released by activated T lymphocytes were called LYMPHOKINES 8/23/2013 3:53:19 AM 31 • Similar substance produced by Monocytes Macrophages
    32. 32. 8/23/2013 3:53:19 AM 32 • MIF • MAF • MCF Affecting macrophages • BF/MF • TGF • BGF Affecting lymphocytes • CF • CSF Affecting granulocytes • LT • IFN • TNF Affecting cultured cells • SRF • TF Others
    33. 33. • IL-1 • IL-2 • IL-3…13 Interleukins • GM-CSF • G-CSF • M-CSF Colony stimulating factors • TNF-α • TNF-β Tumour necrosis factors • IFN-α • IFN-β • IFN-γ Interferons • TGF-β • LIF Others 8/23/2013 3:53:19 AM 33
    34. 34. • Peptide mediators or intracellular messengers which regulate immunological, inflammatory and reparative host responses • They are potent hormone like substances • Produced by lymphocytes, macrophages, platelets & fibroblasts 8/23/2013 3:53:19 AM 34
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    37. 37. Macrophages & other cells • IL-1α and IL-1β Proliferation & differentiation of T, B and other cells Pyrogenic Induce acute phase proteins Bone marrow cell proliferation Interleukin-1 (LAF) 8/23/2013 3:53:19 AM 37
    38. 38. T-cells • Powerful modulator of the immune response Promote growth and differentiation of T and B cells Cytotoxicity of T and NK cells Secretions of other lymphokines Interleukin-2[TCGF] 8/23/2013 3:53:19 AM 38
    39. 39. Interleukin-2[TCGF] 8/23/2013 3:53:19 AM 39
    40. 40. Other interleukins Interleukin-3 (multi-CSF) Growth factor for bone marrow stem cells Stimulates hematopoiesis Interleukin-4 (BCGF-I) Differentiation and proliferation of B and T cells Enhances the activity of cytotoxic T cells Activates mast cells Interleukin-5 (BCGF-II) Proliferation of activated B cells Induces maturation of eosinophils Interleukin-6 Induces immunoglobulin synthesis by activated B cells Induces formation of IL2 receptors on T cells 8/23/2013 3:53:19 AM 40
    41. 41. • Stimulates the growth & differentiation of pleuripotent stem cells in the bone marrow • Responsible for adjusting the rate of production of blood cells • Treating hematopoietic dysfunctions in infections & malignancies Colony stimulating factors 8/23/2013 3:53:19 AM 41
    42. 42. • Induce hemorrhagic necrosis in certain tumours TNFα and TNFβ • Cachectin is TNFα Tumour necrosis factors 8/23/2013 3:53:19 AM 42
    43. 43. • Originally identified as antiviral agents  Interferons 8/23/2013 3:53:19 AM 43
    44. 44. 8/23/2013 3:53:19 AM 44
    45. 45. Kuby IMMUNOLOGY Fifth Edition 458/23/2013

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