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Alveolar (Lung) Macrophage Attacking E. coli (SEM x10,000) Dr Dennis Kunkel (used with permission)
I. Chain of Infection
Lecture nr. 6 Antigens. Antibodies. Immune response. Cell cooperation and mediators in immune response.
15.03.2011
evolved broad recognition mechanisms (innate immunity), and by highly specific lymphocyte antibodies and T cell receptors (adaptive immunity)
Different types of microbes are eliminated by different effectors mechanisms, which are designed to best combat each type of microbe
Classification of immunity
Acquired Immunity
Genetically determined
No Immunologic memory
Development of memory
Acquired Immunity:
Antigens or pathogens enter body naturally. Body generates an immune response to antigens. Immunity may be lifelong (chickenpox or mumps) or temporary (influenza or intestinal infections).
Antibodies pass from mother to fetus via placenta or breast feeding (colostrum). No immune response to antigens. Immunity is usually short-lived (weeks to months). Protection until childs immune system develops.
1. Artificially Acquired Active Immunity: Antigens are introduced in vaccines (immunization). Body generates an immune response to antigens. Immunity can be lifelong (oral polio vaccine) or temporary (tetanus toxoid).
2. Artificially Acquired Passive Immunity: Preformed antibodies (antiserum) are introduced into bod by injection.
Immunity is short lived (half life three weeks). Host immune system does not respond to antigens.
Beneficial:
Detrimental:
Lymphocytes
Originate : in liver, spleen and bone marrow of fetus in bone marrow after birth From stem cells hemocytoblasts that produce all blood cells.
Lymphocytes
To become mature, immunocompetent cells, they must pass through lymphoid tissues in other parts of the body. As they do so, they become committed to becoming either T cells or B cells 1. Cells that migrate through the bone marrow (bursal equivalent) become B cells , and will produce antigens and participate in humoral immunity. 2. Cells that migrate through the thymus glands become T cells and participate in Cell-mediated
LYMPHOCYTE DEVELOPMENT
Congenital immunodeficiency diseases are often caused by blocks at different stages of lymphocyte maturation
CD Nomenclature
Structurally defined leukocyte surface molecule that is expressed on cells of a particular lineage (differentiation) and recognized by a group (cluster) of monoclonal antibodies is called a member of a cluster of differentiation (CD) CD molecules (CD antigens, CD markers) are:
Identified by numbers Used to classify leukocytes into functionally distinct subpopulations, e.g. helper T cells are CD4+CD8-, CTLs are CD8+CD4Often involved in leukocyte functions Identify and isolate leukocyte subpopulations Study functions of leukocytes Eliminate particular cell populations
ANTIGENS
Antigens
An antigen is a molecule that stimulates an immune response. The word originated from the notion that they can stimulate antibody generation. The modern definition includes all substances that can be recognized by the adaptive immune system.
Antigens
Antigens - substances recognized as non-self. These can be:
Infectious agents - bacteria, viruses, fungi or parasites Noninfectious substances
Environmental - pollen, foods, bee, venoms Drugs, vaccines, transfusions and transplanted tissues
Some glycolipids and phospholipids can be immunogenic for T cells and illicit a cellmediated immune response
Antigens
Most are proteins or large polysaccharides from a foreign organism.
Microbes: Capsules, cell walls, toxins, viral capsids, flagella, etc. Nonmicrobes: Pollen, egg white , red blood cell surface molecules, serum proteins, and surface molecules from transplanted tissue. Lipids and nucleic acids are only antigenic when combined
Antigens
Antibody Generator
The best antigens are: large recognized as foreign complex
By endocytosis or phagocytosis, these antigens are taken into the antigen-presenting cells (APCs) and processed into fragments.
Types of Antigens
Allogenic antigen The specific antigen exists in different individuals. Blood type antigens. Autoantigens
usually a normal protein (sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease.
Self Antigens
Antigens of our own cells Do not cause an immune response in our body
MHC proteins
Tumor antigens
are presented by the MHC I molecules on the surface of tumor cells. can sometimes be presented only by tumor cells and never by the normal ones. they are called tumor-specific antigens (TSAs) and typically result from a tumor specific mutation.
Characteristics of Antigen
Immunogenicity The capacity to stimulate the production of antibodies or cell-mediated immune responses.
Characteristics of Antigen
Antigenicity
The ability to bind antibody.
Complete antigen Incomplete antigen, also known as hapten. Hapten: Small foreign molecule that is not antigenic. Must be coupled to a
carrier molecule to be antigenic. Once antibodies are formed they will recognize hapten.
Antigens
Epitope or, Antigenic determinants: Small part of an antigen that interacts with an antibody. Any given antigen may have several epitopes. Each epitope is recognized by a different antibody and may interact with them by paratopes of Antibody
F e
Types of Epitopes
1. Linear epitopes continuous and found in polysaccharides as well as in both native (nondenatured) and denatured proteins, especially fibrillar proteins. specificity depends upon primary sequence. typical size is 5-6 subunits in length.
Types of Epitopes
2. Conformational epitopes
Discontinuous (involve multiple subunits, often located far apart in the primary sequence of the antigen molecule) and are thus found only in native (globular) proteins.
Antigenic epitopes
Antigens: T-independent
Activate B cells without MHC class II T help Polysaccharides Properties
Examples
Polymeric structure Polyclonal B cell activation, but poor memory Resistance to degradation Pneumococcal polysaccharide, LPS Flagella
Antigens: T-dependent
Require T help to activate B cells Proteins Examples
Hapten-carrier conjugates
Definition
Structure
ANTIBODY
Antibodies
Proteins that recognize and bind to a particular antigen with very high specificity. Made in response to exposure to the antigen. One virus or microbe may have several antigenic determinant sites, to which different antibodies may bind. Each antibody has at least two identical sites that bind antigen: Antigen binding sites. Valence of an antibody: Number of antigen binding sites. Most are bivalent. Belong to a group of serum proteins called immunoglobulins (Igs).
Antibody Structure
Monomer: A flexible Y-shaped molecule with four protein chains: 2 identical light chains 2 identical heavy chains Variable Regions: Two sections at the end of Ys arms. Contain the antigen binding sites (Fab). Identical on the same antibody, but vary from one antibody to another. Constant Regions: Stem of monomer and lower parts of Y arms. Fc region: Stem of monomer only. Important because they can bind to complement or cells.
Immunoglobulins
IgG - monomer IgA dimer 2 units IgM pentamer 5 units IgD monomer IgE monomer
I. IgG
Structure: Monomer Percentage serum antibodies: 80% Location: Blood, lymph, intestine Half-life in serum: 23 days Complement Fixation: Yes Placental Transfer: Yes Known Functions: Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn.
II. IgM
Structure: Pentamer Percentage serum antibodies: 5-10% Location: Blood, lymph, B cell surface (monomer) Half-life in serum: 5 days Complement Fixation: Yes Placental Transfer: No Known Functions: First antibodies produced during an infection. Effective against microbes and agglutinating antigens.
III. IgA
Structure: Dimer Percentage serum antibodies: 10-15% Location: Secretions (tears, saliva, intestine, milk), blood and lymph. Half-life in serum: 6 days Complement Fixation: No Placental Transfer: No Known Functions: Localized protection of mucosal surfaces Provides immunity to infant digestive tract.
IV. IgD
Structure: Monomer Percentage serum antibodies: 0.2% Location: B-cell surface, blood, and lymph Half-life in serum: 3 days Complement Fixation: No Placental Transfer: No Known Functions: In serum function is unknown. On B cel surface, initiate immune response.
V. IgE
Structure: Monomer Percentage serum antibodies: 0.002% Location: Bound to mast cells and basophils throughout body. Blood. Half-life in serum: 2 days Complement Fixation: No Placental Transfer: No Known Functions: Allergic reactions. Possibly lysis of worms.
After maturation B cells migrate to lymphoid organs (lymph node or spleen). Clonal Selection: When a B cell encounters an antigen it recognizes, it is stimulated and divides into many clones called plasma cells, which actively secrete antibodies. Each B cell produces antibodies that will recognize only one antigenic determinant.
Apoptosis
Programmed cell death (Falling away).
Human body makes 100 million lymphocytes every day. If an equivalent number doesnt die, will develop leukemia. B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains. Many virus infected cells will undergo apoptosis, to help prevent spread of the infection.
Immune response
Involves production of antibodies against foreign antigens. Antibodies are produced by a subset of lymphocytes called B cells. B cells that are stimulated will actively secrete antibodies and are called plasma cells. Antibodies are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells. Defense against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells. Also cause certain reactions against transplanted tissue.
Humoral Immunity
Plasma cells secrete antibodies, which can circulate and interact with antigen. Antigens are processed by antigen-presenting cells (lots in lymphoid tissues) - macrophages - dendritic cells - B cells. MHC plays a critical role in antigen presentation
IgM (decavalent) is more effective that IgG (bivalent). Hemagglutination: Agglutination of red blood cells. Used to determine ABO blood types and to detect influenza and measles viruses.
Antibody-dependent cell-mediated cytotoxicity: Used to destroy large organisms (e.g.: worms). Target organism is coated with antibodies and bombarded with chemicals from nonspecific immune cells.
5. Complement Activation: Both IgG and IgM trigger the complement system which results in cell lysis and inflammation.
Immunological responce
Primary Response: After initial exposure to antigen, no antibodies are found in serum for several days. A gradual increase in titer, first of IgM and then of IgG is observed. Most B cells become plasma cells, but some B cells become long living memory cells. Gradual decline of antibodies follows.
Secondary Response:
Subsequent exposure to the same antigen displays a faster and more intense antibody response.
Increased antibody response is due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation.
Involves specialized set of lymphocytes called T cells that recognize foreign antigens on the surface of cells, organisms, or tissues:
T cells regulate proliferation and activity of other cells of the immune system: B cells, macrophages, neutrophils, etc. Defense against:
Bacteria and viruses that are inside host cells and are inaccessible to antibodies. Fungi, protozoa, and helminths Cancer cells Transplanted tissue
Cellular Immunity
T cells regulate the immune response Helper T cells secrete cytokines that regulate the immune response IL-2 - induce proliferation of T cells IL-4, IL-5, IL-6 - activate B cells (and T cells) -interferon - T cell activation IL-1 is secreted by macrophages; this helps activate cells also Macrophages present antigen to T cells T
Matures inbone marrowthymus Type of immunityhumoralcell-mediated Secretesantibodiescytokines Antigen receptorsurface IgT cell receptor Where foundspleenblood, lymph nodes Targetsbacteria, infected cells virusestumor cells? Memory?YesYes
Interleukins: Communication between WBCs. Interferons: Protect against viral infections. Chemokines: Attract WBCs to infected areas.
T cells are key cellular component of immunity. T cells have an antigen receptor that recognizes and reacts to a specific antigen (T cell receptor). T cell receptor only recognize antigens combined with major histocompatability (MHC) proteins on the surface of cells.
MHC Class I: Found on all cells. MHC Class II: Found on phagocytes.
T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces
Most are CD4+ Recognize antigen on the surface of antigen presenting cells (e.g.: macrophage). Activate macrophages Induce formation of cytotoxic T cells Stimulate B cells to produce antibodies.
Most are CD4 negative (CD4 -). 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.
Release protein called perforin which forms a pore in target cell, causing lysis of infected cells. Undergo apoptosis when stimulating antigen is gone.
Stimulated by ingestion of antigen Larger and more effective phagocytes. Enhanced ability to eliminate intracellular bacteria, virus-infected and cancerous cells. Lymphocytes that destroy virus infected and tumor cells. Not specific. Dont require antigen stimulation. Not phagocytic, but must contact cell in order to lyse it.
Antigen-Presenting cells (macrophages) place antigen on their cell surface in combination with the MHC II complex Antigen is presented to a specific helper T cell that has receptors that match the antigen MHC II complex
Summary
T and B cells recognise antigen differently Antigen must be catabolised before T cells can recognise it Antigen processing generates antigenic peptides Exogenous antigen processing takes place in lysosomes Endogenous processing is non-lysosomal The mechanism of antigen processing depends upon the compartment in which the pathogen replicates Endogenous and exogenous antigen processing both involve uptake, degradation, complex formation and presentation Pathogens can evade immunity by disrupting antigen processing
After binding, the APC produces Interleukin -1 (IL-1) which stimulates the TH Cell to produce IL-2 and/or IL-4 Interleukin-2 has an autocrine function, causes TH Cell to clone itself, and make more IL-2 and /or IL-4
Helper T cells
TH1 cells produce IL -2 and IFN- and influence cell-mediated immunity TH2 cells produce IL -4 (and other ILs)and influence antibody-mediated (humoral) immunity
When B cell comes in contact with the antigen and IL-4, the B cell produces plasma cells and memory cells Tc Cells come in contact with the antigen on the surface of infected cells in combination with the MHC 1 complex. When also have binding with IL-2, cells produce activated Tc Cells and memory cells.
Antibody production requires assistance from T helper cells. A macrophage cells ingest antigen and presents it to TH cell. TH cell stimulates B cells specific for antigen to become plasma cells. Antigens are mainly proteins on viruses, bacteria, foreign red blood cells, and hapten-carrier molecules. Antibody production does not require assistance from T cells. Antigens are mainly polysaccharides or lipopolysaccharides with repeating subunits (bacterial capsules). Weaker immune response than for T-dependent antigens.
T-Independent Antigens:
Target cell is covered with antibodies, leaving Fc portion sticking outwards. Natural killer and other nonspecific cells that have receptors for Fc region are stimulated to kill targeted cells. Target organism is lysed by substances secreted by attacking cells. Used to destroy large organisms that cannot be phagocytosed.
Disorders of Immunity
Hypersensitivity
Exaggerated Immune Response
Hypersensitivity Types
Allergy
Isoimmunity (alloimmunity)
Autoimmunity
Hypersensitivity Mechanisms
Type I: IgE mediated Type II: Tissue specific Type III: Immune complex mediated Type IV: Cell mediated
Type I
Type I: Mechanism
Repeated antigen exposure causes increased IgE production IgE binds to mast cells Sensitization occurs
Type I: Mechanism
Antigen binds to IgE on mast cell membrane Mast cell releases histamine, chemotaxic factors Inflammatory response occurs
Type I: Signs/Symptoms
Clinical signs, symptoms = response to histamine release GI, skin, respiratory system
Type I: Signs/Symptoms
Histamine effects
Type I: Signs/Symptoms
Skin: flushing, itching, edema, urticaria Respiratory: bronchospasm, laryngospasm, laryngeal edema Cardiovascular: tachycardia, hypotension GI: nausea, vomiting, cramping, diarrhea
Type I: Atopia
Allergy prone individuals Genetic predisposition More IgE More mast cell receptors for antibodies than normal
Type I: Anaphylaxis
Severe, generalized Type I reaction Life-threatening
Type II
Tissue specific Reaction to tissue-specific antigens Causes target cell destruction, dysfunction Exogenous or endogenous antigen
Type II
Most commonly affected cells
Antibody binds to cell membrane, causes alterations in target cell function Example: Graves' disease
Antibody binds to thyroid cell membrane Mimics Thyroid Stimulating Hormone action Causes production of excessive amounts of thyroid hormone Results in common form of hyperthyroidism
Type III
Mediated by antigen/ antibody complex deposition in tissues Exogenous or endogenous antigen
Type III
Immune complex quantity varies over time Symptomatic periods alternate with periods of remission
Temperature governs immune complex deposition in peripheral circulation Exposure to cold causes redness, pain of fingers, toes followed by numbness, cyanosis, gangrene
Occurs after repeated LOCAL exposure to exogenous antigen Immune complexes in vessel walls Examples
Celiac disease from wheat protein Hemorrhagic alveolitis from moldy hay inhalation
Type IV
Type IV
Examples
Hypersensitivity Targets
Allergins
Autoimmune Disease
Clinical disorder produced by immune response to normal tissue component of patients body
Graves Disease
Antibody stimulates thyroid hormone over production Produces hyperthyroidism Antibody, disease can be passed through placenta
Rheumatoid Arthritis
Antibody reaction to collagen in joints Causes inflammation, destruction of joints
Myasthenia Gravis
Antibodies destroy acetylcholine receptors on skeletal muscle Produce episodes of severe weakness Antibodies can cross placenta, affect newborn
Isoimmune Neutropenia
Antibodies attack, destroy neutrophils Can cross placenta, affect newborn
Disorders of Immunity
Immunodeficiency Diseases
Immunodeficiency Disease
Patient unable to fight off infection Hallmarks
Immunodeficiency Disease
Most are defects in T cells or B cells
T cells, macrophage defects = fungal, viral infections B cells, complement defects = bacterial infections
Immunodeficiency Disease
Congenital Acquired
Congenital
B-cell Deficiency IgA Deficiency DiGeorges Syndrome Severe Combined Immunodeficiency
B Cell Deficiency
Agammaglobulinemia Hypogammaglobulinemia
IgA Deficiency
Most common immune deficiency disorder Genetic condition Failure of IgA synthesis Patient has repeated, recurrent sinus, lung, GI infections
DiGeorges Syndrome
Thymic hypoplasia Severe decrease in T-cell production, function Defects of face, ears, heart
Thymus development arrested at ~6-8 weeks gestation. Deficiency, defective maturation of stem cells that produce B and T cells Little to no antibody production
Acquired
Nutritional deficiency Iatrogenic (drugs, radiation) Trauma (prolonged hypoperfusion) Stress Infection (HIV)