Immunology Lecture Notes PDF

Cell migration to the site of inflammation The Results of Ag-Ab Binding Figure 17.7  Neutralization ANIMATION Humoral Immunity: Antibody Function Figure 17.7  B-cells: Mature in the bone marrow...

Cell migration to the site of inflammation The Results of Ag-Ab Binding Figure 17.7  Neutralization ANIMATION Humoral Immunity: Antibody Function Figure 17.7  B-cells: Mature in the bone marrow (or bursa in birds) B-cell receptor binds foreign material (proteins, carbohydrates, etc.) B-cells activated to secrete antibody after binding antigen to antigen specific immunoglobulin (Ig). Each B-cell express 105 of B cell receptor (BCR) - Stimulated B-cells differentiate into plasma cells that secrete copious quantities of antibody. - Stimulated B-cells also form memory B-cells that do not secrete antibody. - Stimulation of B-cells is enhanced by T-cells.  The Life Of The B Cell B lymphocytes are formed within the bone marrow and undergo their development there They have the following functions: To interact with antigenic epitopes, using their immunoglobulin receptors To subsequently develop into plasma cells, secreting large amounts of specific antibody, or To circulate as memory cells To present antigenic peptides to T cells, consequent upon interiorization and processing of the original antigen  * B cells become plasma cells, which produce antibodies when a foreign antigen triggers the immune response  B-lymphocytes in bon marrow * The lymphoid stem cells differentiate into B cells * B-cells precursors mature, differentiate into immunocomptent B- cells with a single antigen specificity * Immature B-cells that express high affinity receptors for self antigens, die or fail to mature i.e negative selection or clonal deletion * This process induces central self tolerance and reduces autoimmune diseases  B-lympocytes * Immature B cells express IgM receptors on the surface * Mature B cells express IgM, IgD molecules on surfaces * IgM and IgD molecules serve as receptors for antigens * Memory B-cells express IgG or IgA or IgE on the surface * B-cells bear receptors for Fc portion of IgG and a receptor for C3 component of the complement * They express an array of molecules on their surfaces that are important in B-cells interactions with other cells such as MHC II, B7 and CD40  Mechanism of Humoral immunity * Antibodies induce resistance through: 1) Antitoxin neutralize bacterial toxins (diphtheria,tetanus) Antitoxin are developed actively as a result of: a- Previous infection b- Artificial immunization c- Transferred passively as antiserum * Neutralization of toxin with antitoxin prevents a combination with tissue cells  T-cells: - Produced in bone marrow, but mature in the thymus. - Recognize foreign peptides bound to major histocompatibility proteins (MHC) via the T-cell receptor. T-cell mediasted immunity response are often referred to as cell mediated immunity or cellular immunity. T-Cell unable to bind directly to Ag T-cell bind to Antigen presenting cell (APC) such as macrophages and Dendritic cell.  Two signalls required to activate T-Cell 1- T-Cell expression of peptide (epitope) specific TCRs. 2- Ligation of costimulatory molecules expressed by T-Cell with complementary molecule expressed by APC. T-Cell begins to express and release new gene products (e.g. cytokine) they undergo clonal expansion to increase number of TCR-expressing cells within the T-cell repertoire and they differentiate to create a pool of memory cells. This events occur in secondary lymphoid organ. T-Cell facilitate the acivation of B-Cell respondig to Ag, by binding of T-cell derived cytokines to specific cytokine receptors expressed by B-cell Interrelationship Between Innate and Acquired Immunity  Antigen: is any agent capable of binding specifically to components of the immune system such as the BCR (B cell receptor) on B lymphocyte and soluble molecule. Immunogen; any agent capable of inducing immune response and is therefore immunogenic. All immunogens are antigen but not all antigens are immunogens.  Requirments for immunogenicity: 1. Foreignness 2. High molecular weight 3. Chemical complexity 4. Degradability and interaction with the host`s MHC.  Requirments for immunogenicity 1-Foreigness : Foreign substances are immunogenic 2- Molecular size: High molecular weight increase immunogenicty 3- Chemical structure complexity: High complexity increase immunogenicty 4- Degradability and interaction with the host`s MHC.  Foreignness: Eg. Inject rabbit with own serum no immune response, while if rabbit serum injected into guinea pig, the guinea pig recognize the rabbit serum as foreign and produce immune response. The more foreign the substance the more immunogenic its. in autoimmunity the individual mount an immune response against his own tissues. 5- genetic make up of the individual. 6- Doses of antigen: insufficent doses of antigenmay not stimulate immune response due to: A. The amount administrated fails to activate enough lymphocytes B. Such a dose renders the responding cells unresponsive (induce state of tolerance to that Ag).  Factors influencing Immunogenicty a- Antigen dose: Appropriate dose optimum antigenicty Low dose low- zone tolerance High dose high-zone tolerance b- Adjuvant: Substance when injected with an antigen enhance immunogenicty 7- Route of administration: Subcutaneously generally elicit the strongest immune response because langerhans cells in the skin responsible for antigen uptake, processing, and presentation to T cell are among the most patent antigen presenting cell (APC). Parenteral routes are more immunogenic to oral route  Hapten Hapten are unable to induce immune reponse because of their low molecular weight and teir chemcial simplicity. Carrier is the high molecular weight compound to which the hapten is conjugated in able to activate immune system.  Immunogens or Antigens Haptens: - Low molecular weight substances - These substances not immunogenic by itself - If couple to a larger carrier molecule (albumin, globulins), they become immunogenic - Examples : simple chemicals and drugs: penicillin, sulphonamid, aspirin, cosmetic, tranquillizers, neomycin skin ointment  Antigen Binding And Recognition Molecules Antigens are recognized by and bind to: 1) B-cell receptors (BCR) : - These are membrane-bound immunoglobulins (IgM and IgD) on B-cells - BCRs can be secreted in plasma as antibodies CDR complementary binding region (paratope) is the portion of Ig that bind to the epitope (antigen determinant) 2) T-cell receptors (TCR) - α and β chains anchored to T-cells - There is a groove which binds small peptides presented by MHC on surface of APCs 3) MHC molecules They are essential for presentation of peptides so that they can be recognized and bind to TCRs  Major Classes of Antigen The following major chemical families may be antigenic: a) Carbohydrate (polysaccharide): it can induce Ab response in the absence of T cell help. Ab can be induced against many kind of polysaccharide molecules such as components of microorganism (e.g. teichoic acid of Gram-negative bacteria). Polysaccharide on the surface of red blood cells are good examples of carbohydrate that are immunogenic. b) Lipid: rarely immunogenic, but become immunogenic when bind to protein carriers. Lipid regards as hapten. c) Nucleic acid: poor immunogenic Become more immunogenic when they are conjugated to protein carrier One important clinical example is the appearance of anti-DNA antibodies in patient with systemic lupus erythematosus. d) protein; virtually all protein are immunogenic Binding of Ag to Ag-specific antibodies or T cell receptors  Cross-Reactivity Some macromolecular Ag contain several distinct epitopes. Some of this Ag can be altered without changing immunogenic or the antigenic structure of the entire molecule. Example it is possible to destroy biological activity of toxin without affecting their immunogenicity such toxin called toxoid which is used for vaccination. In this case toxoid cross react with toxin as they share enough epitopes to allow immune response. Multi-epitope antigens  Adjuvants Is asubstance that when mixed with immunogen, enhance the immune response against the immunogen. Hapten become immunogenic when attached to carrier but will not be immunogenic if attached to adjuvants.  Adjuvanet mechanism 1. Increase biological or immunological half life of vaccine antigens. 2. Increase production of local inflammatory cytokines. 3. Improve antigen delivery and Ag processing and presentation by APC especially the dendritic cell.  Topics Covered to Date 1. Medical Importance of Immune System (vaccines) 2. How the Immune System Works (innate & adaptive immune mech., B/T cells, Abs, Cytokines) 3. Cells and Organs of Immune System  Chapter 4 Antibody structure and function  Antibodies: belong to class of proteins called globulins because of their structure, today know as immunoglobulin (Ig). Ig can be membrane bound or secreted. Membrane bound on the B cell surface, serve as Ag receptors. Membrane bound Ab associated with heterodimer call Igα /Igβ to form BCR. Secreted Ab produce by plasma cells the terminally defrentiated B cells.  The most important featuers of Ab are; 1. Specificity: due to the complimentary determining region (CDR). All B-cell receptors are identical on a single B- cell, but diversity is on the order of 108 different B-cells. 2. Biological activity: variation in biological activity attributed to structural properties.  Isolation and characterization of Immunoglobulin's Separation of serum protein in electrophoresis at pH 8.2 show five major components. The slowest in migration is γ- globulin  Structure of light and heavy chain Fab (fragment antigen-binding): retain the Ab ability to bind Ag specifically. Fc (fragment crystallizable: can not bind to Ag, responsible for biological activity after Ag binding to Fab. γ-globulin composed of 4 chain: 1. Heavy chain (H chain): 2 identical heavy chain molecular weight 53kD each.(λchain, κchain) 2. Light chain (L chain):2 identical light chain 22KD each. These data lead to proposal of a Y-shaped structure by Porter in 1962, many years before the first crystal structure was known.  Proteolytic digestion of Ig using papain and pepsin. Porter and Nisonoff used enzymes to cleave Ig, studied function of isolated fragments Edelman treated Ig with reducing agents to cleave S S bonds, studied the resulting polypeptide chains Schematic representation of the Ig molecule showing Ig-fold domain by interchain disulfid bond  5 classes of H chains in humans Similarities in aa sequence, but each class has aunique sequence. H chains named with Greek letters corresponding with the class name, IgG, IgA, IgM, IgE, IgD (γ, α, μ, ε, δ) These calsses differ in their differ in their protein sequence, carbohydrate content and size. IgG has 4 subclasses, IgA has 2 subclasses  Ig Light Chains Two types of Light chains are found in Ig of all animals, aa sequence differs Kappa chains: Human 60%, mice 95% Lambda chains: Human 40%, mice 5%  Immunoglobulin Domain Early studies showed regularity of structure of all the Ig classes Each 100-110 aa has a 60 aa S-S Loop V domains code the paratope, binds Ag C domains code regions important for mediating secondary biological functions, ie binding complement, crossing the placenta, transfer to mucosal surfaces. Each light chain has 2 domain. Each heavy chain has four or five domains separated by a short unfolded stretch.  Ig Hinge Regions Hinge regions on IgG, IgA and IgD are coded by distinct exons Short span of aa between 1st and 2nd C Domains Rich in Cys and Pro Provides for flexibility of the molecule Is readily accessible to solvent and enzymes