Adaptive Immune System Overview PDF

Immunolgy BIO 358 PROF. WALAA G. HOZAYEN  Definitions Immune system = cells, tissues, and molecules that mediate resistance to infections Immunology = study of structure and function of the immune system Immunity = re...

Immunolgy BIO 358 PROF. WALAA G. HOZAYEN  Definitions Immune system = cells, tissues, and molecules that mediate resistance to infections Immunology = study of structure and function of the immune system Immunity = resistance of a host to pathogens and their toxic effects Immune response = collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system Laboratory Training for Field Epidemiologists  The Immune System A complex system that is responsible for distinguishing us from everything foreign to us, and for protecting us against infections and foreign substances. The immune system works to seek and kill invaders.  Role of the immune system Defense against microbes. Defense against the growth of tumor cells. Homeostasis destruction of abnormal or dead cells (e.g. dead red or white blood cells, antigen-antibody complex) Laboratory Training for Field Epidemiologists  Immune System 1. Organs 2. Cells 3. Molecules Laboratory Training for Field Epidemiologists  Immune System: (1) organs Tonsils and adenoids Thymus Lymph nodes Spleen Payer’s patches Appendix Lymphatic vessels Bone marrow Laboratory Training for Field Epidemiologists  Immune system: (2) cells Lymphocytes T-lymphocytes B-Lymphocytes, plasma cells Natural killer lymphocytes Monocytes, Macrophage Granulocytes neutrophils eosinophils basophils Laboratory Training for Field Epidemiologists  Immune system: (3) molecules Antibodies Complement Cytokines Interleukines Interferons Laboratory Training for Field Epidemiologists  Two types of immunity 1. Innate (Non-adaptive, Non specific, Natural) first & second line of immune response. relies on mechanisms that exist before infection. 2. Acquired (Adaptive, Specific) Third line of response (if innate fails) relies on mechanisms that adapt after infection. handled by T- and B- lymphocytes. Laboratory Training for Field Epidemiologists  The innate and adaptive immune response Characteristics Cells Molecules Innate immunity (1st and 2nd level of defense) Responds Physical barriers Complement rapidly Phagocytes Acute phase Found since (macrophages) Proteins birth Natural killer Cytokines No memory cells No specificity Adaptive immunity (3rd line of defense) Responds T cells Antibodies Slowly B cells Cytokines Memory Granzymes Highly specific Highly effective Laboratory Training for Field Epidemiologists  Cells of Immune System Laboratory Training for Field Epidemiologists  Cells of immune system Laboratory Training for Field Epidemiologists  Role of Cells of the Immune System Innate Immunity Acquired Immunity Granulocytes: Lymphocytes: Neutrophils T cells Eosinophils B cells Basophils Monocytes / macrophages NK cells Laboratory Training for Field Epidemiologists  Mechanisms Innate immunity I- Mechanical barriers and surface secretions:( skin, cilia, sweat, sneezing, saliva, tears, gastric acidity) II- Normal bacterial flora: III- Humoral defense mechanisms in tissues and body fluids)  1- Lysosome 2- complement (plasma proteins inactive form activated by certain pathogen 3- Acute phase proteins (normally very low in serum, but by infection increased due to endotoxins secreted by microbes that activate macrophage to release IL-1 &IL-6 that stimulate liver to secret acute protein ex. CRP and fibrinogen that help in complement activation  4- Interferons: Type I (α &ß)…….Part of innate secreted by virus infected cells to prevent viral replication Type II (γ) secreted by T cell. IV: Cellular defense mechanism Ex. Phagocytes, NK, eosinophils Immune cells and other blood cells made in bone marrow -- all are descendents of self-renewing stem cells Make variable antibodies Membrane-bound variable T cell receptors Kill cells that are missing self proteins Phagocyte Phagocyte Note these are adult stem cells, NOT embryonic stem cells. p. 4 “How the Immune System Works” by Lauren Sompayrac Cells of the myeloid lineages  Innate immunity Depends on granulocytes ( neutrophils, eosinophils , basophils ) and monocytes 1- Neutrophils Phagocytic Most numerous (60-70%) Most important cells of innate immune response Short-lived Absent from normal tissue Attracted by chemotactic factors to site of infection Dead neutrophils form pus  2- Eosinophils Important in protection against helminthes by release of toxic chemicals from granules Important in allergy  3- Basophils Found in low concentrations in blood Action similar to mast cells (allergy and inflammation)  Mast cells -4 Found in tissues (not blood) Around blood vessels or in submucosa Release mediators from granules (Histamine & Heparine → allergy and inflammation  Monocytes/Macrophage s Monocytes in blood → leave blood → Macrophages in tissue. Examples of special macrophages: Kupffer cells Alveolar macrophages Microglial cells (CNS)  Macrophages can engulf and digest bacteria Macrophage about to eat a bacterium http://www.biochemweb.org/neutrophil.shtml p. 4 “How the Immune System Works” by Lauren Sompayrac Phagocytosis  Monocytes/Macrophages Functions.Dennis Kunkel Microscopy, Inc©  Phagocytosis and killing of bacteria  Antigen presenting cells (APC) Macrophage with ingested  Secretory cells asbestos fiber (encarta.msn.com)  Cytotoxic cells Macrophage functions: a- Phagocytosis b- APCs: to show or present foreign agents that have eaten to T cells c- Secretion: Secret chemical mediators (cytokines) e.g: interleukins such as IL-2: Stimulate cytotoxicity of NK cells IFN γ: That promote differentiation of T helper cell d- Direct cytotoxicity: They may kill targets without engulfing them as helminthic parasites are too large to be engulfed so can be killed by releasing their toxic contents onto them the same as tumor cells. Functions of Macrophages   Lymphocytes 1. Lymphocytes (except NK cells) are wholly responsible for the specific immune recognition of pathogens, so they initiate adaptive immune responses. 2. Lymphocytes are derived from bone-marrow stem cells. 3. B lymphocytes matured in the bone marrow. T lymphocytes matured in the thymus.  Lymphocytes: Include T and B cells as well as Nk cells 1- T cells: produced by bone marrow and complete maturation in thymus , comprise around 75% of peripheral blood lymphocytes. There are 2 kinds: a- T helper that secret cytokines to help other cells of immune system B- T cytotoxic: to kill infected cells and other abnormal cells such as tumor cells The ratio between Th : Tc 2:1  Lymphocyte subsets CLP T CELLS B CELLS Common T lymphoid precursor B Th CTL PC Secretory Kill virus- Produce antibodies Activate B cells infected cells PLASMA CELLS and macrophages CYTOTOXIC T T HELPER CELLS LYMPHOCYTES  T cells or T lymphocytes are a type of lymphocyte (comprises around 75% of peripheral blood lymphocytes) that play a central role in cell- mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T-cell receptor (TCR) on the cell surface. They are called T cells because they mature in the thymus.There are several subsets of T cells, each with a distinct function.  – T.helper cells: is to secrete cytokines that help other cells of immune system – There are two main kinds: – A) T helper 1 cells: secrete cytokines which help activation of macrophages to be more capable of killing pathogen inside them ex. M.Tuberculosis after being ingested by macrophages, resist digestion and can survive for long time – B) T Helper 2 cells: play an important role in destruction of extracellular pathogens by secreting cytokines help in activation of B cells to become plasma cell and produce Abs B lymphocytes: they are produced in bone marrow where they complete their maturation. They comprises 10% of peripheral blood lymphocytes. When B Cell becomes active it changes into plasma cell that secret protein molecule (antibodies or immunoglobulins) - NK cells: They are large granullar cells constitute 10-15% of peripheral blood lymphlocytes. They are capable killing abnormal or infected cells similar to T cytotoxic by differ in the way they recognize their targets.  LYMPHOID ORGANS The lymphatic system is part of the circulatory system, comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph  Lymphatic organs play an important part in the immune system, having a considerable overlap with the lymphoid system. Lymphoid tissue is found in many organs, particularly the lymph nodes,  Lymphoid tissue is divided into primary, secondary Primary lymphoid organs: (sites where lymphocytes complete their maturation) The thymus and the bone marrow constitute the primary lymphoid tissues involved in the production of lymphocyte tissues. Bone marrow is responsible for the creation of both T-cells, and the production and maturation of B- cells , thymus where T cells complete maturation.  Secondary lymphoid tissue ( they are the places where lymphocytes can meet antigens) It is exemplified by the lymph nodes, and the lymphoid follicles in tonsils, spleen, adenoids, skin, appendix etc.  Cells, tissues and organs of the immune system Immune cells are bone marrow-derived, & distributed through out the body Primary lymphoid organs: – Thymus: T cell maturation – Bone marrow : B cell maturation Secondary lymphoid organs: – Lymph nodes – Spleen – Mucosal lymphoid tissues (lung, gut)  Circulation of lymphocytes between blood and lymph 1- B and T lymphocytes have matured, but not meet antigen are called (naïve lymphocytes), then they leave bone marrow and thymus and circulate from blood into 2ry lymphoid organs (lymph nodes) 2- Antigen are drained from site of infection through lymphatic vessels into lymph nodes. Lymphocytes will recognize a certain Ag and undergo series of changes  The changes which occur are A- Activation: They become lymphoblasts B- Proliferation: rapid multiplication C- Differentiation: they change into effector cells that capable of being effective against the invading agent and memory cells. T into ( T h and T c) B into plasma cells  Clonal selection theory T and B lymphocytes are very specific. They recognize Ag by receptors present on their surface. Only those lymphocytes which meet Ag which their receptor recognize, will undergo activation, proliferation and differentiation to produced clone of identical daughter cells (clonal selection theory)  Difference between Tand B receptors 1- Bcell receptor has two Ag recognition sites while Tcells receptor has only one recognition site 2- B cell receptor recognize an Ag directly and T cell receptor recognize via APC 3- B cells recognize Ag outside cells ( in plasma and extracellular fluids)………humoral immunity But T cells detect Ag inside the cells……cell mediated immunity  Failure of host defence mechanism: Immune system may be unable to free our body of infections………..immunodeficiency Ex.: AIDS in which virus infects T helper cells and destroys them.  Harmful Immune responses 1- Allergy: inappropriate immune response against certain Ag 2- Autoimmune diseases: immune response against person,s own Ag 3- Graft rejection: immune response against foreign tissues or organs transplanted  Antigens (an immunogen) It is a substance that can stimulate the immune system to produce an immune response. Antigenic determinants (Epitopes) It is a structurally limited parts of Ag help Ag recognition. (4-5 A.A OR monosacch residues)  Epitopes determine the specificity of the Ag Ag may posses more than one Epitopes that may be different or similar If Ag share one or more similar epitopes are known as cross-reactive (heterophil) antigens.  Hapten: It is a low Mwt substance which incapable of inducing immune response alone but when coupled with a carrier molecule (protein) it can act as an antigen. Ex: pencillin Factor affecting Immunogenicity 1- Foreignness: To be antigenic, it must be foreign to the host in which it is introduced (self or non self) 2- Molecular size: larger molecule------- stronger antigenicity except: insulin it is a small molecule but is immunogenic  3- Chemical Nature: The more complex the molecule, the more immunogenic ex: protein 4- Route of administration: Subcutaneous and intramuscular routes are more best in stimulation immune response. 5- Dosage: There is an optimum dose at which Ag is most immunogenic. Very low or very high may cause unresponsiveness. 6- Adjuvants: It is a non-specific potentiators of the immune response  Ex: Aluminium hydroxide which added to diphtheria and tetanus toxoids to delay the absorption of toxoids and prolongs the period of their exposure to the immune system 7- Host factors: Some Ag stimulate an immune response in human but not in animals  Also, immune system may be not respond to an Ag at certain age due to aging or immaturity of the immune system.  T cell mediated immunity - T T lymphocytes are a type of lymphocyte (itself a type of white blood cell) that play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells (NK cells), by the presence of a T-cell receptor (TCR) on the cell surface. They are called T cells because they mature in the thymus.  Adaptive Immune System: Cells Antigen Presenting Cells (APCs) APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells – T-cells: respond to antigen only if it is displayed on plasma membrane. APCs: Macrophages, Dentritic cells & B lymphocytes Interactions between APCs & lymphocytes are critical to immune response  Cell Mediated Immune Response T-cell activation: involves recognition of PM surface antigens only – Antigen is combined with MHC & displayed on PM – T-cell receptors: bind to the MHC & are stimulated by the associated antigen – The addition of a co-stimulator (cytokines, interleukins, etc) prompts the T-cell to form a clone  Cell Mediated: MHC MHC (Human leucocyte Ag [HLA antigens] : it is a cell surface glycoproteins. occurs as two classes – MHC I on virtually all tissue cells – MHC II only on PM some immune system cells  T Cell surface molecules: 1- TCR: consists of two polypeptide chains (α and ß). Each chain has constant part near the cell membrane and a peripheral variable region which detect specificity of the Tcell. All TCR on a single T cell are identical and recognize the same Ag. (1st signal)  2- CD3 molecule: close to TCR on all T cells to transmit signals from TCR to inside the cell 3- CD4 and CD8: T cells carry either CD4 or CD8 molecules (co-receptors) If CD4………..T Helper is to help other cell of immune system by secreting cytokines. If CD8……….T cytotoxic……..to kill infected cells or tumor cells  4- CD28 Molecule: during Ag Recognition, it binds to B7 molecule on APC (2nd signal for activation) 5- CD40 Ligand(CD40L): It is present on activated Thelper and involved in activation of B cells by T cells as it binds with CD40 on B cell  T cells: Helper T cells (Th cells): Cytotoxic T cells (Tc or – T cell Receptor (TCR) CTL): – CD4+ – TCR+ – Produce cytokines & – CD8+ direct immune responses. – Cytotoxic 65  Mechanism of activation of macrophages by Th1 cells An infected macrophage posses pep-MHCII complex to an effector Th1 cell. If it is specific induce cytokines secretion (IF-γ) causes macrophage activation to more capable of killing bacteria. 1-As it causes more efficient fusion between phagosomes and lyzosomes, 2- Increased production of oxygen radicals, nitric oxide and antibacterial enzymes  Cell Mediated: MHC display properties Figure 21.16b  This macrophage activation can sometimes cause tissue damage but its absence can lead to serious infection. As seen in case of AIDS patients with mycobacterial infection , number of Th cells very low.  Cell Mediated: T-cell roles Activated TH cells interact with B- cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody by secret IL 4,5,6 &10 Figure 21.18  II Function of effector CD8 Tcells (cyto Tcells) The main function of effector CD8 T cells is to eliminate abnormal cells such as virus- infected cells or tumor cells. The virus-infected cell, displays on its surface viral peptide in conjunction with an MHC I molecule. Peptide –MHC I complex recognized by effector Tc leading to death of the target cell Mechanism of killing by Tc cells 1- Induction of apoptosis (process of suicide) 2- Osmotic lysis  1- Induction of apoptosis A- Release of cytoplasmic granules: Tc releases two kinds of granules (perforins and granzymes. Perforins: causes perforations in the cytoplasmic membrane of the target cell, through which granzymes enter the target cells and cause enzymes activations leading to cell,s DNA degradation Cell Mediated: T-cell roles Figure 21.19a  B – Interaction of cell surface molecules: A receptor called FAS, present normally on cytotoxic cells, giving a signal for apoptosis for the target cell. Apoptosis is a clean death in which cell destroys itself, shrinking and degrading it self via fragmentation of cell DNA.  2- Osmotic lysis The pores produced in the target cell membrane by perforins allow enterance of fluid into the cell, leading to cell death by osmotic lysis. But apoptosis is more faster and efficient than osmotic lysis.  The humoral immune response The main function is the destruction of extracellular pathogens or prevention of spread of internal ones through production of antibodies or immunoglobulins. A- activation B- proliferation C- differentiation into effector cells  B cell surface molecules A- B cell receptor (BCR): Immature B cells express only IgM B- CD 40: essential for interaction with T Cells C- MHC II: These molecules are essential for Ag presentation to Th cell  Sequence of events in activation of naïve B cells In the presence of target Ag, B cell binds to Ag via BCR, activation take place by receive two signals: 1- 1st signal: by binding of Ag to BCR, B cell engulf the Ag, degrades it into peptides and presents them on cell surface with MHC II 2- 2nd signal (co-stimulatory): the peptide- MHC II recognized by T helper cell.  A- CD 40L binds to CD40 on B cell surface molecule. B- T helper secretes cytokines IL-4,5,6 &10 to activate B cell to become lymphoblast and then divided rapidly (clonal expansion), differentiated into effector cells, IgM is first secreted. (Thymus-dependent (TD) antigens)  - Some Ag such as bacterial polysaccharides can activate B cells directly in absence of T cells but only IgM produced and no memory cells are produced.  Antibodies Constant (C) region defines antibody class determines chemical & cellular interactions determines how class functions to eliminate antigens  Antibody Classes Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)  Antibody Classes Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)  “Memory” in adaptive immunity 1st infection  memory  2nd infection slow response fast response pathogen proliferate pathogen killed disease no disease symptoms no symptom Memory & specificity – key features of the adaptive immunity Classification of Acquired immunity I- active: Ag in contact with cells of immune system resulting in B and/or T cells stimulation. i.e: takes some times to develop and it lasts after Ag elimination. A- Natural active immunity:Following natural infections B- Artifical active immunity: By deliberate administration of Ag (vaccination) This pathogen may be introduced in killed or non- pathogenic form  II- Passive acquired immunity It involves transfer of ready made antibodies. So, the immune system has no role in initiating an immune response. This acquired immunity is immediate but is temporary. A- Natural passive immunity: The transfer of maternal antibodies (IgG) to foetus across the placenta, or passage of IgA to the newborn in the colostrum to protect newborn against diseases during the six months of life  B- Artificial passive immunity: 1- Administration of antitoxic serum for treatment against infection that has already made Ab that has repeated injection to this toxoid. 2- Administration of gamma globulin to immunodeficient people Types of Acquired Immunity Figure 21.11  Complement The complement system is a group of heat- labile proteins normally found in blood and tissue fluids (except urine and CSF). They are mainly produced by the liver.  The basic complement proteins are termed C1 to C9, in addition to factor B, D and properdin and some complement regulatory proteins. Most of them are normally found in an inactive form. Activation of complement occurs through interaction of complement factors in a sequential manner one step after the other. The product of one reaction forms the enzyme for the next, and so on. This mode of activation is called complement activation cascade.  When they become activated, some complement factors are split into a small fragment (a) which is considered a by- product, and a large fragment (b) which continues the activation process.  There are 3 pathways for complement activation: The classical pathway The lectin Alternative pathways  The early steps in all pathways involve a series of cleavage reactions which end with the production of an enzyme, C3 Convertase, that splits the third complement C3 into C3a and C3b. C3b becomes attached to microbial surface and initiates the late steps of the complement cascade  1- The classical pathway The reaction starts by binding of the first complement (C1) to the Fc portion of the antibody molecule attached to the antigen (e.g. a bacterial cell). This causes activation of C1 which acts as an enzyme that cleaves 2 other complement proteins, C4 and C2,  The resultant C4bC2b is the C3 convertase of the classical pathway, that splits C3 into C3a and C3b. C3b adheres to the microbial surface to start the late steps of complement activation. by cleavage of C5 into C5a and C5b. C5b binds to the terminal complement components C6, C7, C8 and C9 sequentially to form a complex, called membrane attack complex (MAC).  This complex (C5b,6,7,8,9) forms a hollow cylinder that becomes inserted into the target cell membrane, allowing free passage of water and solutes across the membrane which leads to cell death (osmotic lysis).  2- The lectin pathway: This pathway is activated when a plasma protein, mannose binding lectin (MBL), binds to mannose residues on microbial surface. MBL is structurally similar to C1 and activates C4, C2.  3- The alternative pathway The alternative pathway is triggered when C3b becomes deposited on the surface of microbe. Here, C3b forms stable bonds with microbial products, such as endotoxins and Zymosan of yeast cell wall, and is thus protected from degradation.  The microbe-bound C3b forms a complex with factor B: this complex is the C3 convertase of the alternative pathway. Factor D and properdin also help in the generation and stabilization of the C3 convertase. This convertase breaks down more C3 resulting in the attachment of more C3b to the microbial surface.  Functions of complement 1- Direct cytolysis: Insertion of the MAC into the cell surface leads to killing of many cells, e.g: Bacterial and tumor cells, through osmotic lysis.  2- Opsonization: During complement activation, C3b becomes deposited on the surface of the pathogen (antigen). Phagocytic cells recognize C3b bound to the pathogen via their C3b receptors. This facilitates the attachment , subsequent uptake and killing of the C3b-coated pathogen by the phagocytic cell..  3- Immune complex clearance: C3b receptors are also found on RBCs. These recognize C3b bound to soluble immune complexes. Erythrocytes bind the immune complexes via these receptors and transport them to organs rich in fixed phagocytes ( e.g. liver and spleen).  4- Inflammatory response: During complement activation, the byproduct C3a and C5a are produced. These molecules, known as anaphylatoxins Complement activation Thank You For Your Attention!