5-IMMUNE RESPONSE

IMMUNE RESPONSE • Def: Specific reactivity induced in a host following an antigen stimulus STARTING AN IMMUNE RESPONSE Foreign invaders - viruses, bacteria, allergens, toxins and parasites - constantly bombard our body. – these are antigens    • The response to this assault is carefully orchestrated. • It is a controlled interaction between immune cells to eliminate the invader by pathogen-specific mechanisms. Types of Immune Response: Humoral or Antibody mediated Immune response (HMI/AMI). Cellular or Cell – mediated Immune response (CMI). Antibody mediated immunity (AMI) • Defense against most extracellular bacteria and viruses those infect through respiratory or intestinal tracts. • Takes part in the pathogenesis of immediate hypersensitivity (type I,II &III) • Takes part in certain autoimmune diseases. Cell Mediated Immunity (CMI) • Protects against fungi, viruses & intracellular bacteria & parasites. • It plays an important role in allograft rejection, graft – versus – host reaction. • Mediates the pathogenesis of delayed hypersensitivity and certain autoimmune diseases. • Provides immunity against cancer. The Immune System is the Third Line of Defense Against Infection • Components of Human Immune System • First Line of Defence: Skin and Mucus Membranes -- NonSpecific A. Skin Surface B. Mucus • Second Line of Defence: Non-Specific Internal Defences A. Cells 1. Phagocytic Cells a. White Blood Cells b. Macrophages - engulfing behaviour 2. Natural Killer Cells a. recognize body cells infected with foreign bodies (i.e. viruses) b. transfer membrane containing "hole-forming" proteins c. secrete enzymes Antimicrobial Proteins: Complement System • a. group of at least 20 proteins, circulate in blood b. activated in a progressive (cascade) fashion; • "classical pathway": initiated with antibodies (specific targets). "alternative pathway": initiated by microbial substances (non-spec.) • b. lyses invading microbes. c. some proteins are chemo attractants for phagocytes (smell). Interferons: Viral infection of cells directly stimulates the production of interferons e.g. the "type 1" interferons are produced non-specifically by many cell types in response to viral infection. These are quite distinct from the T cell cytokine gamma interferon which is produced by CD4+ and CD8+ T cells in response to antigenic stimulation. Type I interferons lead to the induction of an "antiviral state" in the cells, which is characterized by inhibition of both viral replication and cell proliferation, and also enhancement of the ability of natural killer cells to lyse virally infected cells • Types: Alpha Beta Gamma Inflammatory Response: Damaged cells release HISTAMINE • a. histamine makes capillary walls leaky b. relaxes smooth muscle results in increased blood flows into wounded areainflammation • - increased delivery of WBCs, etc. Clotting response - chemically stimulated by wounded cells (platelets, etc.) Attraction of Phagocytic WBCs (i.e. Macrophage) / pus Fever a. Hypothalamus controls body thermostat (set point: 37oC). b. Invasion > specific WBCs release hormones: "endogenous pyrogens" c. Pyrogens travel blood > hypothalamus, inducing thermostat change d. Elevated temperature... - inhibits bacteria metabolism - stimulates phagocytic WBCs - increases production of interferon in viral attacks - aspirin reduces fever; prolongs viral (flu) infections Third Line of Defense: Immune Response – Specific Complex system of interacting cells: WBCs B-Cells: Humoral Immunity a. Born and differentiate in bone marrow T-cells: Cell-Mediated Immunity a. Born in bone marrow, migrate to and differentiate in thymus Macrophages: trigger T-Cell response Primary Response: • Has a long lag phase • Low titer of Antibodies that do not persists longer. • Predominantly IgM antibody is formed Primary response The primary antibody response has four phases: Inductive, latent, or lag phase – • Antigen is recognized as foreign and the cells begin to proliferate and differentiate in response to the antigen. • The duration of this phase will vary depending on the antigen but it is usually 5-7 days. • The plasma cells begin to secrete antibody. Log or Exponential Phase – • As more B cells proliferate and differentiate into antibody secreting cells, the antibody concentration increases exponentially. • The plasma cells initially secrete IgM antibody. • Eventually some B cells switch from making IgM to IgG, IgA or IgE. Plateau or steady-state phase – • As antigen is depleted, T and B cells are no longer activated. • In addition, mechanisms which down-regulate the immune response come into play. • Furthermore, plasma cells begin to die. • When the rate of antibody synthesis equals the rate of antibody decay, the stationary phase is reached. Decline or decay phase – • The rate of antibody degradation exceeds that of antibody synthesis and the level of antibody falls. • Eventually the level of antibody may reach base line levels. Secondary Humoral Response: • Has a shorter lag phase. • High level of antibody that persist for a long time. • IgG antibody formed. The secondary, memory, or anamnestic* antibody response also has four phases: Inductive, latent, or lag phase – • This is normally shorter than that observed in a primary response. Log or Exponential Phase – • The log phase in a secondary response is more rapid and higher antibody levels are achieved. Plateau or steady-state phase – No difference. Decline or decay phase – • The decline phase is not as rapid and antibody may persist for months, years or even a lifetime. Mechanism of Humoral Immune Response: • Two types of antigens seen – T cell– Independent Ag. T cell- Dependent Ag. T cell-Independent Antigens: – Antigens are mainly polysaccharides or lipopolysaccharides (bacterial capsules). – Antibody production does not require assistance from T cells. – Weaker immune response got, than the T celldependent antigens. Clonal Selection: • When a B cell encounters an antigen. • It is stimulated and undergoes clonal proliferation and differentiate into clone of plasma cells, which actively secrete Abs. • And clone of memory B cells • Clonal Selection of B Cells is Caused by Antigenic Stimulation T cell-Dependent Antigens: – Antigens are – proteins on viruses, bacteria, hapten-carrier molecules etc. Antigen presentation •An APC after ingestion of Ag “presents” pieces of the Ag on MHC Class II molecules to CD4 T cell. •T cells have special Ag– recognizing molecules on their surfaces called T cell receptors (TCR). T helper cell Antigen-presenting cells (APCs) may be macrophages or B cells •This, and a 2nd signal produced by IL-1 produced by APC, activates the T cell. B cell activation and differentiation •Activated T cells interact with B cells through the action of cytokines (IL-4, Activated T helper cell IL-5 &IL-6). •The B cells undergo clonal proliferation and differentiate into plasma cells & memory B cell. Antibodies •Plasma cells secrete Ab, which help to inactivate the Ag. • Factors Influencing Antibody Production: 1. Age 2. Genetic response 3. Nutritional status 4. Dose of Antigen 5. Adjuvants Adjuvants: • Substance that enhance the immunogenicity of an antigen is called adjuvant. Types: a. Depot: Aluminium hydroxide or phosphate, alum & Freund’s incomplete adjuvant (water in oil). b. Bacterial: Freund’s complete adjuvant – incomplete adjuvant with a suspension of killed tubercle bacilli. Cannot be used in humans- delayed hypersensitivity c. Chemical: Bentonite, calcium alginate & silica particles. • Action: a) Sustained release of antigen from depot. b) Stimulate lymphocytes non-specifically. c) Activate macrophages d) Stimulate CMI. • Antibodies: exist free in body fluids, e.g. serum, and are also membrane bound to B lymphocytes. • Their function when membrane bound is to capture antigen for which they have specificity, after which the B lymphocytes will take the antigen into its cytoplasm for further processing. • Free antibodies have the following functions: o Agglutination of particulate matter, including bacteria and viruses. IgM is particularly suitable for this, as it is able to change its shape from a star form to a form resembling a crab. o Opsonization: coating of bacteria for which the antibody's Fab region has specificity (especially IgG). o This facilitates subsequent phagocytosis by cells possessing an Fc receptor. e.g. neutrophil polymorphonuclear leucocytes ("polymorphs"). o It can be seen that in opsonization and phagocytosis both the Fab and the Fc portions of the immunoglobulin molecule are involved. o Neutralization: of toxins released by bacteria e.g. tetanus toxin is neutralized when specific IgG antibody binds, thus preventing the toxin binding to motor end plates and causing persistent stimulation, manifest as sustained muscular contraction which is the hallmark of tetanic spasms. o This applies particularly to IgG. o In the case of viruses, antibodies can hinder their ability to attach to receptors on host cells. Here, only Fab is involved. o Immobilization of bacteria: Antibodies against bacterial ciliae or flagellae will hinder their movement and ability to escape the attentions of phagocytic cells. Again, only Fab is involved. o Complement activation (classical pathway) especially by the Fc region of IgM and IgG. o Leads eventually to death of bacteria by the terminal complement components which punch holes in the cell wall, leading to an osmotic death. o Complement components also facilitate phagocytosis by cells possessing a receptor for C3b, e.g. polymorphs. o Thus complement kills micro-organisms in two ways: o Opsonisation followed by phagocytosis and intracellular killing (indirect). o Assembly of the cytolytic C5b-9 membrane attack complex (direct). o Mucosal protection. This is provided mainly by IgA, and to a lesser degree, IgG. o IgA acts chiefly by inhibiting pathogens from gaining attachment to mucosal surfaces. o This is a Fab function. o Expulsion as a consequence of Mast cell degranulation. As a consequence of antigen (e.g. parasitic worms) binding to specific IgE attached to mast cells by their receptor for IgE-Fc, there is release of mediators from the mast cell. o This leads to contraction of smooth muscle, which can result in diarrhoea, and expulsion of parasites. o Here we see involvement of both Fab v. Parasite antigen, and Fc anchoring the reacting participants. o Precipitation of soluble antigens by immune complex formation: These consist of antigen linked to antibody. Depending on ratio of antigen to antibody, these can be of varying size. o When fixed at one site, they can be removed by phagocytic cells. o They may also circulate prior to localization and removal, and can fix complement. o Here Fab and Fc are involved. o Antibody dependent cell mediated cytotoxicity (ADCC): Antibodies bind to organisms via their Fab region. o Large granular lymphocytes (Natural Killer cells abbreviated NK cells). o They attach via Fc receptors, and kill these organisms not by phagocytosis but by release of toxic substances called perforins. o Conferring immunity to the foetus by the transplantal passage of IgG: IgG is the only class (isotope) of immunoglobulin that can cross the placenta and enter the foetal circulation, where it confers immune protection. o This is of great importance to the foetus in the first 3 months. o The precise function of IgD is not known. o It may serve as a maturation marker of B lymphocytes. • Consequences of Antibody Binding T cells: 1. T helper (CD4) Cells: Central role in immune response. • Recognize antigen on the surface of antigen presenting cells along with class II MHC proteins. Induce formation of cytotoxic T cells • • Stimulate B cells to produce Abs. Delayed Hypersensitivity T (TD) Cells: • Mostly T helper and a few cytotoxic T cells that are involved in some allergic reactions and rejection of transplanted tissue. Cytotoxic T (Tc) Cells:  Destroys target cells.  Recognize antigens on the surface of all cells: - Kill host cells that are infected with viruses or bacteria. - Recognize and kill cancer cells. - Recognize and destroy transplanted tissue. T Suppressor (Ts) Cells: ▪ Certain T cells - suppresses Ab production.  Failure - leads to Ab production to self Ags autoimmune disease.  eg. In AIDS the normal ratio of CD4:CD8 cells (>1.5) is greatly  CD4 cells are lysed by HIV, CD8 cells  This imbalance infections. susceptibility to opportunistic • Cytokines: These are biologically active substances secreted by monocytes, lymphocytes and other cells. • lymphokines – by lymphocytes • Monokines - by monocytes & macrophages. • Interleukins are chemical substance that function as growth and differentiating factors. They exert a regulatory influence on other cells. Q- APCs that activate helper T cells must express which one of the following on their cell surface. 1. IgE 2. Gamma Interferons 3. Class I MHC antigens 4. Class II MHC antigens* Cell Mediated Immune Response T cell activation •Presentation of antigen to T cell by APCs along with MHC molecule triggers its activation into a helper T (TH) cell. •Activated TH cells undergo blast transformation, clonal proliferation and differentiate into memory cells and effector cells (Tc & Ts). Activated T helper cells induce effector and memory TH cells Activation requirements for antibody production: • Interaction between cell receptors and co-receptors • A membrane protein on activated helper T cells –CD40 ligand (CD40L) must interact with a protein called CD40 on the surface of the resting B cells to stimulate the differentiation of B cells into antibody-producing plasma cells. • Other proteins on the surface of these cells serve to strengthen the interaction between the helper T cell & APC. e.g. CD 28 on T cell interacts with B7 on the B cell & LFA-1 on the T cell interacts with ICAM-1 on the B cell. Intercellular adhesion molecu1e-ICAM leukocyte-function-associated antigen-LFA • TCR on T cell with MHC I/II antigen complex – stimulation • Both signals required for activation and proliferation • Followed by intracellular pathways of activation in T cells • Complex enzymatic steps • CD8+ cells recognize combination of foreign antigen and Class I MHC molecule and differentiate into Tc & Ts lymphocytes. • These are involved in killing of virally infected cells and the destruction of tissue grafts from MHC – incompatible donors. • CD4+ cells recognize combination of foreign antigen with Class II MHC molecule and differentiate into Th & Td cells. • They produce lymphokines that stimulate & support production of immune system cells. Production of cytotoxic T cells •Activated lymphocytes release lymphokines - which are responsible for various manifestation of CMI. Activated T helper cell Cytotoxic T cell (Tc) Memory Tc Effector Tc •Tc lymphocytes gets attached to the target cell – releases cytolysins leading to lysis of target cell. • Cytotoxic response: Destroys the virus infected cells –  By inserting perforins and degradative enzymes – granzymes  Target cell is lysed by Fas – Fas Ligand (FasL) interaction.  By Antibody – dependent cellular cytotoxicity (ADCC) • Perforins form a channel through the membrane, the cell contents are lost, and the cell dies. • Granzymes are proteases that degrade proteins in the cell membrane leading to loss of cell contents. Cytotoxic T Cells Lyse Infected Cells • Fas is a protein displayed on the surface of many cells. • When T cell receptor recognizes an antigen on the surface of a target cell, FasL is induced in the cytotoxic T cell. • When Fas and FasL interact apoptosis (death) of the target cell occurs. • ADDC – ab bound to the surface of the infected cell is recognised by IgG receptors on the surface of phagocytic cells, and the infected cell is killed. • ADDC can bring about killing of the worms (helminths) PUTTING IT ALL TOGETHER… APC T helper cell Activated T helper cell Cytotoxic T cell (Tc) Antibodies Memory Tc Effector Tc Lysis 1. Which of the following functions are macrophages unable to carry out: A. Pinocytosis. B. Phagocytosis. C. Antigen processing. D. T-cell priming. E. Antigen presentation to activated cells. 2. CD8 is a marker of: A. B-cells B. Helper T-cells C. Cytotoxic T-cells D. An activated macrophage E. A neutrophil precursor 3. B-cells as distinct from T-cells: A. Are polyclonally activated by phytohemagglutinin. B. Bear surface Ig receptors for antigen. C. Bear surface CD3 molecules. D. Are lymphocytes. E. Can be activated by stimulation through the antigen receptor alone. 4. A major factor regulating the adaptive immune response is: A. The neutrophil. B. Complement membrane attack complex. C. C-reactive protein. D. Antigen concentration. E. Haptoglobin. 5. Extracellular bacteria are killed by: A. Secreting exotoxins. B. Impeding inflammatory reactions. C. Phagocytosis and complement. D. Toxin neutralization. E. C-reactive protein. 6. In antibody-dependent cell-mediated cytotoxicity (ADCC)the specificity of killing of target cells by the effectors is a function of A. Large granular lymphocytes B. Natural killer cells C. Macrophages D. Cytotoxic T lymphocytes E. IgG 7. Protection against worm infestations is particularly associated with an increase in: A. IgD. B. IgE. C. IgG. D. IgA. E. IgM. 8. The macrophages are involved in many different immune activities. What is the role of the macrophage during the formation of antibody? A. Making antibody B. Delayed hypersensitivity reactions C. Lyse virus-infected cells D. Process antigen and present it to T-helper CD4 cells E. Activate cytotoxic CD8 T cells References: Levinson-7th edition- chapter58