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Specific Host Defense Mechanisms: An Introduction to Immunology BY Prof. DR. Zainalabideen A. Abdulla, DTM&H., MRCPI, Ph.D., FRCPath. (U.K.) Learning Objectives/First Lecture Learning Objectives/Second Lecture Immunology Is the scientific study of the immune system and immune response. • Immune system: Third line of defense/Specific • Immune response (IR): Complex interactions Details given below Antigens (Ag) Are molecules that stimulates the immune system to produce antibodies. They are commonly proteins (most potent antigens). Antibodies (Ab) Are protein molecules that are produced by the immune system in response to antigens. Functions of the immune system 1. Differentiate between “self” and “non-self” (foreign) antigens 2. Destroy the non-self antigens Arms of the immune system 1. Humoral immunity 2. Cell-mediated immunity (CMI) N.B: “Danger-Model” is a new theory to explain IR on the basis of damaged tissues?! Humoral immunity (Antibody-Mediated Immunity “AMI”) • Antibodies (Ab): Play a major role • Ab: Present in blood/plasma/serum, lymph, body secretions/extracellular fluid, and on surface of some lymphocytes (B-cells) Cell-Mediated Immunity (CMI) • Involve various types of cells • Ab play ONLY a minor role Types of acquired immunity (AI) 1. Active: Ab produced the body, long: A. Natural: Infections; protective Ab B. Artificial: Vaccination Edward Jenner, Cowpox Vacca = Cow 2. Passive: Ab “received”; short-lasting A. Natural: Mother to fetus (IgG, IgA; 6 m ) B. Artificial: Preformed Ab to patients, e.g. HBV exposure Natural Passive Acquired Immunity • IgG is the only Ab can cross the placenta • Colostrum (Milk few days before/after delivery Rich in secretory IgA) Artificial Passive Acquired Immunity • Temporary protection • Gamma globulin (pooled immune serum globulin “ISG”) e.g. Measles, Mumps, Polio • Hyperimmune serum (high level) e.g. HBIG, tetanus, rabies, botulism Vaccine Material that can artificially induce immunity to infectious disease; injected or ingested. • Produce Ab and memory cell • Ideal Vaccine: - Enough antigenic determinants - Against all causative strains - Not cause a disease Types of vaccines 1. Living organisms (harmless or attenuated) - Attenuated = Modified/ Weakened - Most effective - Some given at birth (Hepatitis A & B, Rota, DTaP, Hib, Polio, MMR, Chickenpox, Influenza, Pneumococcal, Meningo - Others: On need, e.g. cholera - Antigenic variation: e.g. Influenza virus 2. Inactivated (Killed): Weaker/shorter e.g. Hepatitis A, Rabies, Polio cont./… cont./… types of vaccines 3. Subunit vaccines (acellular) - Part of a microbe , e.g. Pertussis - Genetically produced part, e.g. HBsAg/yeast 4. Conjugate vaccine, e.g. Hib, Pneumococcal 5. Toxoid (detoxified) e.g. Diphtheria, Tetanus 6. DNA vaccines (still experimental): Gene Plasmid Human Ag/Ab 7. Autogenous vaccines: Isolated m.o. Killed Injected Ab How vaccines work 1. Antibodies: • Anti-Toxin, e.g. anti-tetanus toxin • Anti-surface Ag/Pili; Prevent attachment • Opsonization • C activation Lysis 2. Memory cells (lymphocytes) Cells of the immune system 1. T lymphocytes (T cells) 2. B lymphocytes (B cells) 3. Natural Killer (NK) cells 4. Macrophages B.M. Lymphoid Stem Cells Lymphocytes T- cells 1. T helper (TH ) = CD4 - TH1: Help CMI; produce type 1 cytokines - TH2: Help B cells (Ab-production), produce type 2 cytokines 2. T cytotoxic (Tc)- CD8 - Killer: Virally infected cells, foreign cells, tumor cells Location of immune response • Ag in the blood Spleen • Ag in tissues Local L.N. • Ag via mm Mucosal-associated lymphoid tissues Examples: • Intranasal/inhaled Ag Tonsils/Adenoids • Ingested Ag Microfold (M) cells Peyer’s patches of the intestine Humoral Immunity Antigens • Antibody-generating substances are called antigenic or immunogenic. • Proteins (> 10,000 Da), Polysaccharides (> 60,000 Da), or larger DNA or RNA and combinations: glycoproteins, lipoproteins, nucleoproteins • Best antigen: Proteins (more immunogenic) Antigenic determinants (AD) Are the surface molecules that stimulate the antibody production (> AD // > Immunogenicity) Haptens Are antigens that can bind antibodies, but can not stimulate their production unless coupled to a larger carrier molecule such as protein. Example: Penicillin (hapten) + Serum albumin (carrier) Allergy (Type-I Hypersensitivity) in some individuals T-dependent antigens Are antigens that depend on TH-cells in their processing (involve also macrophages & B cells) T-independent antigen Are antigens which require only B cells (do not require TH-cells) in their processing Processing: Stimulation of B-cells to become plasma cells that produce antibodies Immune response (IR) 1. Primary response: • 10-14 days after Ag stimulation • IgM mainly • Memory cells: B and T cells 2. Secondary response (Anamnestic/Memory): • Rapid, larger Ab quantities • IgG mainly • Memory cells also generated . Booster Ag dose: Stronger Antibodies • Microbial Ag/AD: Capsule, cell wall, cell membrane, pili, flagella, etc. • Ab: - Each specific to one AD (Lock & Key) - Cross-reacting Ab to similar Ag (AD) • Proteins “glycoprotein” (immunoglobulin) • Resembled = Y Antibody structure Monomer • Two identical Heavy chains (H) + Two identical Light chains (L) • H chain heaver & more a. a. than L chain • Chains connected by disulfide –S-S- bonds • L chain located at the top of the Y • The tops of both H & L are the Antigenbinding sites (Fab) - Bivalent in which a.a. sequences are variable (VH, VL) • The sequences of the rest: Constant (Fc) Fc receptors • Neutrophils, macrophages, basophils, mast cells AND NK cells (for ADCC) Classes of immunoglobulins • IgA, IgD, IgE, IgG, IgM • IgA and IgG: Subclasses . IgG & IgM = Complement-Fixing Ab (+ and +++ respectively); Why? • See details in the Table Antigen-Antibody Complexes • Ab + Ag = Immune complexes (IC) • IC can activate the complement (activation of leukocytes, lysis, opsonization) • Acute extracellular infections: AMI • IC Type III Hypersensitivity Role of antibodies in protection I. Microbial toxin Neutralizing anti-toxin II. Viral adhesin (vaccine) Anti-adhesin prevent attachment of virus III. Bacterial Pili Anti-Pili antibodies prevent attachment IV. Bacterial capsule (polysaccharides) Anti-capsule Ab Opsonization ( phagocytosis) Monoclonal antibodies • Single plasma cell Single antibody • Tumor cells (e.g. myeloma) Life long • Plasma cell + Myeloma Hybridoma • 1 cell divide 1 clone daughter of cells • Applications: - Immunodiagnostic Procedures (IDPs) - Killing tumors - Boost immune system - Prevent organ rejection - Fight diseases, e.g. autoimmune/infectious Cell-Mediated Immunity (CMI) • Intracellular organisms • Cells: TH, Tc, NK, macrophages, granulocytes • Step 1: Macrophages/phagocytosis/ APC • Step 2: TH bind one AD on macrophages Cytokines Tc and NK (Effector) • Step 3: Effector cells bind target cell • Step 4: Effector cells Vesicular factors (perforin, enzymes, TNF, NK cytotoxic factor) • Step 5: Effector cell Toxins DNA, Cell dies AMI and CMI • Viral infection (e.g., herpes infections) • Ab & C Neutralize & destroy virus • CMI Destroy virus infected cells • Latent (e.g. Shingles) Not destroyed • Tc and NK cells Killer (cytotoxic) e.g. infected liver cells killed in viral hepatitis • AIDS (HIV): Destroy TH cells AMI/CMI Susceptible to infections/malignancy Natural Killer cells (NK cells) • Large granular lymphocytes • Lack B and T cell markers • Not involved in antigen-specific recognition • Kill: Foreign, virus-infected, tumor cells • Have receptor for Fc region of IgG Kill (Antibody-Dependent Cell Mediated Cytotoxicity “ADCC”) • How?: Perforin (pores) Granzymes (Cytotoxic granules inserted) • Involve in immune surveillance system to destroy tumor/mutated cells Hypersensitivity Overly sensitive or overly immune system causing irritation or damage to cells or tissues Types of hypersensitivity 1. Immediate Hypersensitivity (Types I, II, III) - Antibody-mediated reactions 2. Delayed-Type Hypersensitivity (Type IV) - Cell mediated reaction Type I Hypersensitivity/Anaphylactic • Allery: Hay fever, asthma, hives, food allergy, insect stings, drug allergy, anaphylactic shock. • IgE antibody + (Reagin antibody) chemical mediators from basophils/mast cells • Atopic patient = Allergic patient with IgE • Allergen = Antigen causing allergy • Basophil/mast cells contain IgE Fc receptors cont./… allergic reactions • First exposure Reagin antibody • Second exposure Degranulation of basophil/mast cells • Basophils: Anaphylaxis, Mast: Local Allergy • Release of mediators: Histamine, PG, serotonin, bradykinin, SRS-A, Leukotrienes, ECF • Allergens: e.g. Pollens, dust, fungal spores • Anti-histamine blocks histamine binding Systemic anaphylaxis • Anaphylactic shock: Fatal • Allergens: Drugs, insect venom Example: Penicillin (hapten) + Blood protein (carrier) IgE • Reaction occurs within 20 minutes (immediate) • Treatment: Epinephrine (adrenaline) + Anti-histamine Latex Allergy 1. Irritant contact dermatitis Dry, itchy, irritated hand skin, Not allergy most common reaction to latex 2. Allergic contact dermatitis Chemicals added to latex and poison ivy This is DTH 3. Latex allergy Latex, more severe, mild to severe, type-I Allergy skin testing • Scratch or intradermal • Wheal and Flare (cutaneous anaphylaxis) Hyposensitization (immunotherapy) • Injection of small doses of allergens • Blocking IgG antibodies; prevent attachment of allergen to mast/basophils • Used for: plants, insect venom, cat dander Type II Hypersensitivity (Cytotoxic) • IgG and IgM antibodies involved • Complement may/may not involved • Three mechanisms: 1. C- activation 2. Opsonization 3. NK cells (ADCC) • Examples: ABO/Rh incompatibility Myasthenia gravis (Anti-Ach Ab) Drugs (bind Anti-drug Ab C- activation Lysis) Type III Hypersensitivity (IC hypersensitivity) • IgG and IgM antibody, C, and N • Serum Sickness: Anti-sera (e.g. horse antiClostridium botulinum toxin) “foreign” Anti-horse Ab (IC) Deposited in joints, skin, kidney, Choroid plexus (brain) • Similar in SLE, Rheumatic fever (Anti- M protein of S. pyogenes cross react with cardiac muscles/valves, glomerulonephritis, arthritis Type IV Hypersensitivity/CMI • DTH (24 – 48 hours or longer) • Examples: Tuberculin (Mantoux) & fungal skin tests, contact dermatitis, transplant rejection, intracellular microbes • Contact dermatitis To metals, cosmetics, topical medication Mantoux test - PPT = Purified Protein Derivative used - Steps: 1. PPD PMN influx in 2-3 h 2. L & M; PMN disperse 3. Erythematous & edematous area 12-18 h 4. Increased intensity 24-48 h 5. Cells and manifestations disperse Positive Mantoux (TB skin) test • Active TB • Past/recovered TB • Cured TB (no live m.o.); isoniazid for 6 m • Latent TB (no actual TB, but harbor m.o.); isoniazid 6 m • Bacillus Calmette-Guerin (BCG) vaccine = attenuated strain of Mycobacterium bovis (gives 50% protection) N.B.: Gamma-Interferon Releasing Tests (IGRA) are new alternatives to TB skin test Autoimmune diseases (AID) • Immune system reacts against self antigens • > 80 diseases • 1. Organ-specific: e.g. Thyrotoxicosis, DM-1 pernicious anemia, Addison’s disease 2. Organ-nonspecific: e.g. RA, SLE, myasthenia gravis, scleroderma • Multiple mechanisms Hypersensitivity I, II, III • Sequestered tissues: Eye lens, brain, spinal cord, sperms. Exposed AID IgM and IgG against tissues Immunosuppression • Immunosuppressed, immuno-depressed, immunocompromised = Immune system • Acquired, or inherited • Acquired: Drugs, irradiation, HIV, aging • Inherited: Ab production, C activity, NK/ phagocytic functions Examples: DiGeorge syndrome (No thymus and no parathyroid glands) Hypo- or Agammaglobulinemia The Immunology Laboratory • With CML or separate • Functions: - Diagnosis of infectious diseases - Immune system disorders - Tissue compatibility for transplantation - Immunochemical procedures Immunodiagnostic Procedures (IDP) • Rapid tests to detect Ag or Ab in infectious diseases (vs culture: takes a long time) • Serological procedures: When serum used • Detection of Ag: Direct evidence of microbes (Best Proof) Detection of Ab: Indirect evidence: - Currently infected - Past infection - Vaccination - Cross reactivity (reaction) IDPs general rules and tests • IgM: Current infection (why?) • Paired sera: To detect or in Ab titer (1st: Acute serum ; 2nd: Convalescent serum) • Detect Ag by Ab (specific) & Vice Versa • Tests: See Figure - Agglutination (clumping) - Precipitation - Immunofluorescence (IF) - ELISA Antigen detection procedures • Ab used to detect Ag e.g. H. influenza (Ag) in CSF + Ab: Meningitis Blood typing • Major blood groups (ABO) & Rh factor • Agglutination test Antibody detection procedures • Ag used to detect Ab e.g. Ab (serum of patient) + Ag (bacteria): Dx Allergy tests • Radio-allergosorbent test (RAST) to detect specific IgE against allergens • Intradermal skin test to allergy to allergens Skin testing/diagnostic tool • Subcutaneous or intradermal tests • Example: TB diagnosis by Mantoux skin test Diagnosis of immunodeficiency disorders • B, T, Phagocytic cells, Complement