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OVER-REACTIONS OF THE IMMUNE SYSTEM Hypersensitivity Reactions and Allergic Diseases OVER-REACTIONS OF THE IMMUNE SYSTEM • Hypersensitivity reactions – Adaptive immune response to harmless molecules – Sensitization of immune system required – Mediated by antibody and effector T cells – Allergic diseases • • Disease following immune response to allergens Allergens – Harmless molecules which cause type 1 hypersensitivity reactions CLASSIFICATION OF HYPERSENSITIVITY REACTIONS (GELL AND COOMBS) Based on immune reactant, antigen and effector mechanism Type I Mediated by IgE against soluble antigens with mast cells, basophils and eosinophils Type II Mediated by IgG and IgM against cell surface / matrix antigens with complement and phagocytes CLASSIFICATION OF HYPERSENSITIVITY REACTIONS (GELL AND COOMBS) Based on immune reactant, antigens and effector mechanism Type III Mediated by IgG against soluble antigens with complement and phagocytes Type IV Mediated by CD4 and CD8 cells against soluble and cell surface antigens with macrophages and CD 8 T cells TYPE I HYPERSENSITIVITY REACTIONS * Normal physiological role of IgE * Defense against parasites * Pathophysiological role of IgE * Allergy * Greater knowledge * Type I reactions follow sensitization to allergens * Sensitization * First exposure to allergen elicits an IgE response * Genetic predisposition (Atopy) TYPE I HYPERSENSITIVITY REACTIONS THE IgE RECEPTOR * IgE binds (Fc fragment) with high affinity to FceRI receptor * FceRI receptor * Mast cells, basophils, activated eosinophils * Binding of IgE results in sensitization of cells * IgE functions as allergen receptor ANTIGEN RECEPTORS ON MAST CELLS, BASOPHILS AND ACTIVATED EOSINOPHILS * Different from receptors on T and B cells * Effector function becomes operational immediately following antigen binding * Cell proliferation and differentiation not required * Receptors are not restricted to a single antigen specificity * Features provide a strong and quick response to antigens for a sensitized person MAST CELLS (MASTOCYTES) * Originate in bone marrow from CD34 progenitor * Basophils may have same progenitor * Development of immature cells at tissue sites * Types * Mucosal * Tryptase production * Development T cell dependent * Connective tissue * Chymotryptase production * Express high levels of IgE receptor MECHANISM OF TYPE I HYPERSENSITIVITY REACTIONS * FceRI receptor expressed constitutively * Mast cells and Basophils * Activated eosinophils * Allergen binding results in cross-linking of receptors * Cross-linked receptors signal degranulation of cytoplasmic granules * Degranulation results in release and synthesis * Inflammatory mediators, toxins, enzymes Figure 10-5 HISTAMINE (BIOGENIC AMINE) * Exerts a variety of physiological effects following binding to specific receptors (H1, H2, H3) * Allergic reactions * Histamine binds to H1 receptors * Physiological effects * * * * Constriction of bronchial / intestinal smooth muscle Increased permeability of blood vessels Increased secretion of mucus by goblet cells Leukocyte chemotaxis LEUKOTRIENES * Classified as lipid mediators of inflammation * Derived from arachidonic acid via lipoxygenase pathway * Produced by mast cells, monocytes and granulocytes * Leukotrienes (LTA4 – LTE4) * Sustain inflammatory response in allergic disease * Autocrine and paracrine mechanisms * C, D and E are cysteinyl leukotrienes * Increased levels induce anaphylaxis * Physiological effects similar to histamine * More potent / longer lasting than histamine * Vasodilation, bronchoconstriction, neutrophil chemotaxis PROSTAGLANDINS * Classified as lipid mediators with a variety of physiologic effects * Normal * Inflammation * Derived from arachidonic acid * Cyclooxygenase pathway * Act locally and rapidly metabolized * Produced by all nucleated cells except lymphocytes CYCLOOXYGENASE PATHWAY * Prostaglandins produced by two different enzymes * Cyclooxygenase-1 (Cox-1) * Cyclooxygenase-2 (Cox-2) * Cox-1 involved in normal physiological functions * Stomach mucus production * Kidney water excretion * Platelet function * Cox-2 involved in inflammatory response NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) * Reduce pain, inflammation and fever by inhibition of cyclooxygenase pathway * Non-Selective (Cox-1 and Cox-2 inhibitors) * * * * Acetylsalicyclic acid (Aspirin) Ibuprofen (Motrin, Advil) Indomethacin (Indocin) Naproxen (Naprosyn, Aleve) * Selective (Cox-2 inhibitors) * Celecoxib (Celebrex) * Rofecoxib (Vioxx) * Valdecoxib (Bextra) EOSINOPHILS * Granulocytic leukocytes (1 – 6% in blood) * Level variation (down in am, up in pm) * Granules * Orange to reddish-orange in color * Uniform in size and evenly distributed * Toxins, enzymes, cytokines and inflammatory mediators * Mature cells reside in * Blood and lower GI tract Figure 10-9 EOSINOPHILS * Eosinophil response * * * * Parasites (Helminths) Main effector cell in allergy and asthma Induced by drugs, diseases and radiation Eosinophilia potentially toxic to host * Control mechanism for host toxicity * Limiting bone marrow production * Regulated expression of Fc-epsilon-RI * IgE receptor not expressed in resting state CASE STUDY – 58 YEAR OLD FEMALE • Presents to family physician with 1 month history – – – – Fever Cough Weight loss Dyspnea • Past and present medical history – Non-smoker – Childhood asthma – Rheumatoid arthritis CASE STUDY – 58 YEAR OLD FEMALE • Laboratory – CBC with differential 12,000 leukocytes with 10% eosinophils – Sputum for eosinophils Unable to produce • Radiology – CXR and CT • Endoscopy – Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) CASE STUDY – EOSINOPHILIC PNEUMONIA • Pulmonary eosinophilia or eosinophilic lung disease • Classification – Primary (idiopathic) – Secondary Parasitic or fungal infection Immunological or systemic disease » Asthma, HIV, malignancy Drugs » Antibiotics, NSAIDS, L-tryptophan • Mechanism of disease is unknown CASE STUDY – 23 YEAR OLD MALE • Presents to family physician with 2 year history of – Dysphagia – Episodes of food impaction Breads and meats • Past and present medical history – Seasonal allergic rhinitis – Non-smoker CASE STUDY – 23 YEAR OLD MALE • Laboratory – CBC with differential 12,000 leukocytes with 11% eosinophils • Endoscopy with esophageal biopsy – Endoscopy showed “ringed esophagus” • Surgical Pathology Report – > 20 eosinophils/HPF (proximal and distal) – Areas of basal cell hyperplasia suggests reflux – No viral CPE, dysplasia or malignancy CASE STUDY – EOSINOPHILIC ESOPHAGITIS • Etiology is unknown – Associated with food allergy Milk, eggs, soy, corn, wheat, beef, chicken – Acid reflux – Medications stuck in esophagus • Mechanism – Decrease stretching of esophagus • Treatment is evolving – Prednisone, antihistamines, Mast cell stablizers – Avoidance of implicated food – Proton pump inhibitors (Nexium) ? BASOPHILS * Granulocytic leukocytes (0 – 1% in blood) * Granules * Violet-blue in color * Variable in size and unevenly distributed * Contents similar to mast cells * Mature cells reside in blood * Basophils similar to mast cells * Constitutive expression of IgE receptor * Significant source of IL-4 * Both interact with eosinophils IgE MEDIATED ALLERGIC REACTIONS * IgE production is favored following * Chronic exposure to proteins or chemicals bound to proteins * Low molecular weight, soluble, glycosylated proteins * Allergens promote CD4 TH2 response when interleukin-4 is present * Interleukin-4 promotes IgE isotype switch in cognate interaction with B cells * IgE response amplified following release of IL-4 by activated mast cells and basophils SENSITIZATION TO AN INHALED ALLERGEN * Majority of allergens are components of dried particles derived from plant and animals * Majority of allergens in US are proteases * Cysteine protease in feces from house dust mite * Dermatophagoides pteronyssimus * Papain from papaya fruit * Significance of enzymatic activity of allergens is unknown GENETIC PREDISPOSITION TO TYPE I HYPERSENSITIVITY * Atopy * Genetic propensity to produce IgE antibodies in response to allergens * Atopic response characterized by elevated levels * IgE and eosinophils * Multiple genes are involved * Chromosome 2 * Regulation of T cell activation * Chromsome 5 * Gene cluster for IL-3, IL-4 and IL-13 * Chromosome 11 * Beta chain of FceRI receptor TWO STAGES OF TYPE I HYPERSENSITIVITY REACTIONS * Immediate reaction (Stage 1) * Appears within 30 minutes * Subsides within 30 minutes * Late phase reaction (Stage 2) * Appears 6 to 8 hours after immediate reaction has subsided * Subsides within 24 hours * Examples * Wheal and flare (skin) * Breathing capacity (lungs) * Forced expiratory volume in 1 second (FEV1) SPECTRUM OF TYPE I ALLERGIC DISEASES * * * * * Allergic rhinitis (hay fever) Allergic conjunctivitis Allergic rhinoconjunctivitis (ARC) Allergic asthma Eczema * Atopic dermatitis * Allergic contact eczema (dermatitis) * Allergic urticaria (hives) and angioedema * Food allergy * Anaphylaxis (Anaphylactic shock) ALLERGIC RHINITIS (HAY FEVER) * Inflammation of mucous membranes of * Nose * Eyes, eustachian tubes, ears, sinuses, pharynx * Symptoms * Sneezing, itching, rhinorrhea, nasal congestion, fatigue * Tearing, postnasal drip, earache, sinus pressure * Genetic predisposition for offspring * 1 (30%) or 2 (50%) parents with AR * Classification * Seasonal (tree, grass, ragweed pollens) * Perennial (dust mites, cockroaches, animal dander) ALLERGIC RHINITIS (HAY FEVER) * Prevalence in US of 20% * Diagnosis * History and physical * Laboratory studies * Differential diagnoses * * * * * * Sinusitis Viral rhinosinusitis Vasomotor or non-allergic rhinitis Hormonal rhinitis Rhinitis medicamentosa NARES LABORATORY DIAGNOSIS OF ALLERGIC RHINITIS (HAY FEVER) * Nasal cytology * Wright stained smear of nasal secretions * CBC with differential * Serum IgE (total) * Allergy testing * Skin test * Prick or puncture techniques * Blood test * ImmunoCAP system IMMUNOCAP SPECIFIC IgE BLOOD TEST * Quantitative measurement of specific IgE levels to numerous allergens by FEIA * Fluoresence Enzyme Immunoassay (FEIA) * Consists of reaction chamber with solid phase of cellulose sponge matrix * Specific allergens covalently linked to solid phase * Specific IgE levels expressed as kU/L * Interpretation * Seven concentration classes (0-6) from < 0.35 to > 100.00 * Negative, equivocal, positive (2), strongly positive (3) PREVENTION AND TREATMENT OF ALLERGIC RHINITIS * Prevention * Avoidance of offending allergens * Treatment / Prevention * * * * * * Antihistamines Decongestants Leukotriene receptor antagonists Anti-inflammatory agents Mast cell stabilizing agents Immunotherapy (Hyposensitization / Desensitization) ANTIHISTAMINES (ORAL) FOR ALLERGIC RHINITIS * Mechanism of action * Prevent binding of histamine to H1 receptors * Blood vessels, GI tract, respiratory tract * Antihistamines (1st generation) * Sedating * Chlorpheniramine (Chlortrimeton) * Diphenhydramine (Bendryl) ANTIHISTAMINES (ORAL) FOR ALLERGIC RHINITIS * Antihistamines (2nd generation) * Low-sedating or non-sedating * Cetirizine (Zyrtec) * Levocetirizine (Xyzal) * Fexofenadine (Allegra) * Loratadine (Claritin) * Loratadine (Alavert) * Desloratadine (Clarinex) NASAL ANTIHISTAMINE FOR ALLERGIC RHINITIS • Azelastine (Astelin, MedPointe Pharmaceuticals) – First intra-nasal antihistamine – Reduces nasal congestion • Indicated for seasonal allergic rhinitis – 1 to 2 sprays per nostril BID • Adverse events – Bitter taste, headache, somnolence • Precaution – Avoid concurrent use with alcohol and other CNS depressants DECONGESTANTS FOR ALLERGIC RHINITIS * Mechanism of action * Decrease hyperemia by vasoconstriction * Activate alpha-adrenergic receptors of respiratory tract * Decongestants (oral) * Pseudoephedrine (Sudafed) * No longer OTC but BTC * Phenylephrine (Sudafed PE) * Phenylpropanolamine * AR of hemorrhagic stroke * Decongestants (intranasal) * Oxymetazoline ANTIHISTAMINE / DECONGESTANT COMBINATIONS FOR ALLERGIC RHINITIS * First generation * Chlorpheniramine + pseudoephedrine (Chlortrimeton-D) * Diphenhydramine + pseudoephedrine (Bendryl-D) * Second generation * Cetirizine + pseudoephedrine (Zyrtec-D) * Fexofenadine + pseudoephedrine (Allegra-D) * Loratadine + pseudoephedrine (Claritin-D) ANTI-LEUKOTRIENE AGENTS FOR ALLERGIC RHINITIS * Leukotriene receptor antagonists * Montelukast (Singulair) * Mechanism of action * Binds to CysLT1 receptor with no agonist activity * Precautions * Avoid aspirin (NSAIDS) if aspirin sensitive * Neuropsychiatric events * Changes in behavior and mood NASAL STEROIDS FOR ALLERGIC RHINITIS AND ARC * Considered most effective for prevention and treatment * Mechanism of action is unknown * Wide range of effects on many inflammatory cells and mediators * Control all major symptoms * Corticosteroids * * * * * Fluticasone propionate (Flonase) Fluticasone furoate (Veramyst) Mometasone furoate (Nasonex) Triamcinolone acetonide (Nasacort) Beclomethasone dipropionate (Beconase) MAST CELL STABILIZING AGENTS FOR ALLERGIC RHINITIS • Cromolyn sodium – Cromolyn (Nasalcrom) by nasal spray • Mechanism of action – Calcium ion channel blocker Intracellular Ca++ essential for degranulation • Not as effective as corticosteroids • Frequent dosing (1 spray q6h) IMMUNOTHERAPY (ALLERGY SHOTS) FOR ALLERGIC RHINITIS * Immunotherapy (allergy shots) indications * Allergic rhinitis, allergic asthma and insect stings * Allergy shot phases * Build-up (1-2 visits a week for 3-6 months) * Maintenance (1 visit every 2-4 weeks for 3-5 years) * Mechanism * Generation of allergen-specific regulatory T cells * Secretion of IL-10 and TGF-beta * Suppression of IgE and stimulation of IgG4 and IgA by B cells ASTHMA * Disease of the lower respiratory tract * Types * Allergic (extrinsic) asthma * Symptoms triggered by inhalation of allergens * Non-Allergic (intrinsic) asthma * Symptoms triggered by factors not related to allergy * Anxiety, stress, exercise, viruses, smoke and other irritants * Symptoms for two types are similar ALLERGIC AND NON-ALLERGIC ASTHMA * Symptoms * Shortness of breath (SOB), wheezing, chest tightness, cough, fatigue * Pathophysiology * Characterized by inflammation, constriction and mucus in tracheobronchial tree * Prevalence in US * 1 in 15 (20 m) MANAGEMENT AND TREATMENT OF ALLERGIC ASTHMA * Bronchodilators (beta-antagonists) * Albuterol (Proventil) * Short acting * Salmeterol (Serevent) * Long acting * Mast cell stabilizing agents * Cromolyn (Intal) for inhalation * Corticosteroids (oral, IV, inhaled) * Prednisone (PO), Methylprednisolone (IV), inhaled fluticasone (Flovent) MANAGEMENT AND TREATMENT OF ALLERGIC ASTHMA * Leukotriene receptor antagonists * Montelukast (Singulair) * Zafirlukast (Accolate) * Leukotriene synthesis inhibitors * Zileuton (Zyflo) * Anti-IgE monoclonal antibody * Omalizumab (Xolair) OMALIZUMAB (XOLAIR) IN ALLERGIC ASTHMA * Indication * Persons >12 years with moderate to severe disease not controlled with ICS * Positive for perennial aeroallergen * IgG1 kappa monoclonal antibody to IgE * Mechanism of action * Reduces binding of IgE to FceRI receptors * Reduces number of receptors on basophils * Administration * Subcutaneous every 2 to 4 weeks * Bioavailability of 62% ALLERGIC REACTIONS IN SKIN * Urticaria (Hives) * * * * Red and itchy swelling of superficial skin Allergic and non-allergic etiology Acute and chronic (idiopathic) onset Chronic idiopathic urticaria * 35% have autoimmune etiology * Angioedema * Swelling of skin with pain and burning * Mouth, lips, tongue, hands * Lower dermis and subcutaneous * Allergic and non-allergic etiology ALLERGIC REACTIONS IN SKIN * Reactions occur following mast cell activation * Direct inoculation into skin * During systemic anaphylaxis * Following ingestion of food or drug carried to skin by bloodstream ALLERGIC REACTION TO FOOD * Food allergy * A reaction involving the immune system * IgE * Prevalence of 2% of adults and 6% of children * Symptoms * * * * * * Tingling in mouth Swelling of lips, tongue, throat and face Abdominal pain, N/V/D Urticaria, eczema Dizziness, syncope Wheezing, SOB ALLERGIC REACTION TO FOOD * Top eight foods * Milk, eggs, peanut, tree nuts (almonds, pecans,walnuts), soybean, wheat, fish and shellfish * Shellfish allergy * Usually develops in young adults and is life-long * Types of shellfish * Crustaceans (shrimp, crab, lobster) * Mollusks (clams, oysters, scallops) ALLERGIC REACTION TO FOOD * Fish allergy * One of most common and most dangerous * Tendency to be life-long * Canned fish (tuna, salmon) less antigenic than fresh * Peanut allergy * One of most common and most dangerous * Tendency to be life-long * 35% show allergy to tree nuts ALLERGIC REACTION TO FOOD * Egg allergy * One of most common in children * Tendency to outgrow * White contains allergenic proteins * Milk (cow) allergy * The most common in infants and young children * Majority outgrow * Not to be confused with lactose intolerance ALLERGIC REACTION TO FOOD * Oral allergy syndrome * Fruits and vegetables trigger a mild allergic reaction due to protein cross-reactivity * Allergy to ragweed pollen * Reaction to melons, bananas, tomatoes * Allergy to grass pollens * Reaction to melons, kiwis, tomatoes * Allergy to birch pollen * Reaction to apples, peaches, plums, cherries, nectarines, carrots, celery FOOD INTOLERANCE AND MALADSORPTION * A reaction to foods (containing lactose and fructose) not involving the immune system * Same signs and symptoms as food allergy * Lactose intolerance * Results from lactase deficiency * Fructose * Intolerance * Results from Adolase B deficiency * Maladsorption * Results from defective intestinal transport mechanism ALLERGIC REACTION TO FOOD * Food Allergy Initiative (www.faiusa.org) * National 501 (c) non-profit organization founded in 1998 by concerned parents and grandparents * Played major in passage of * Food Allergen Labeling and Consumer Protection Act (FALCPA) of 2004 * FALCPA (August, 2004) * Under FDA * January 1, 2006 start date * August of 2008 to include gluten ALLERGIC REACTION TO FOOD * Gluten * Proteins in wheat, barley, rye and sometimes oats * Mixture of prolamins and glutelins * Prolamins trigger reaction in small intestine * Celiac disease * Celiac disease * Autoimmune disease * Inflammation of mucosa leads to atrophy of villi * Maladsorption ANAPHYLAXIS * Acute, systemic (multi-system) reaction * Caused by allergens which reach bloodstream * Venomous insect stings * IV and IM drugs * PO drugs (rapid absorption and high bioavailability) * Foods * Anaphylactoid reactions * Non-IgE mediated * Clinical manifestations are same * Cause is NSAIDS, radiographic dyes or idiopathic SIGNS AND SYMPTOMS OF ANAPHYLAXIS * Appear within minutes to hours of exposure * Order of appearance * Skin and soft tissue * Flushing, pruritis, urticaria and angioedema * Cardiovascular * Syncope, tachycardia, irregular or no pulse * Nervous * Apprehension, convulsions * Gastrointestinal * Vomiting, diarrhea, abdominal cramps * Respiratory * Wheezing, dyspnea TREATMENT OF SYSTEMIC ANAPHYLAXIS * Epinephrine is drug of choice * Catecholamine drug (stress hormone) acting on * Alpha receptors of vascular endothelium * Beta receptors of bronchial smooth muscles * Administered by IM injection into anterolateral thigh * Do not inject into buttock * Do not inject IV * Cerebral hemorrhage * Epinephrine Auto-Injector (EpiPen) * Adult (0.3 mg) and pediatric (0.15) ALLERGY TESTING * Methods of testing * Skin and blood * Skin testing * Prick, puncture or scratch technique * Skin reaction (wheal and flair) within 15 minutes * Blood testing * Measure serum IgE level * Measure serum IgE level for allergen(s) * CBC with differential TYPE II HYPERSENSITIVITY REACTIONS * Antibody mediated (IgG and IgM) cell destruction * Mechanisms of cell destruction * Activation of complement * ADCC * Opsonization * Clinical settings * Blood transfusion reactions * Hemolytic disease of the newborn * Drug-induced hemolytic anemia TRANSFUSION REACTIONS * Transfusion of blood is a type of transplantation * ABO blood group antigens * Glycoproteins on surface of erythrocytes * Blood types based on ABO and Rh antigens * A, B, AB, O * Rh + or – * Natural antibodies associated with ABO antigens * Isohemagglutinins * Mechanisms * IgM mediated response to ABO antigens * IgG mediated response to Rh antigen DRUG-INDUCED HEMOLYTIC ANEMIA * Drugs (soluble, small molecules) covalently linked to cell surface proteins of human cells * Drugs and cells * Penicillin to erythrocytes * Sulfamethoxazole to platelets * Results in altered antigen and IgG response with cell lysis * Hemolytic anemia * Thrombocytopenia Figure 10-27 Figure 10-28 TYPE III HYPERSENSITIVITY REACTIONS * Mediated by immune complexes * Formed by IgG and soluble antigens * IC cleared by phagocytes following complement fixation * Complement fixation influenced by size of IC * Small * CF is inefficient * Circulate in blood and deposited in tissues * Large * CF is efficient * Removed from blood with no tissue deposition * Size of IC influenced by concentration of antigen and antibody TYPE III HYPERSENSITIVITY REACTIONS * Pathophysiology related to portal of entry of antigen 1. Subcutaneous injection (Arthus reaction) * Localized erythema and induration 2. IV administration (Serum sickness) * Occurs 7 to 10 days following * Horse serum, mouse monoclonal antibodies * Characterized by fever, chills, skin rash…. 3. Inhalation (Hypersensitivity pneumonitis) * Continued exposure to antigen with IC formation and deposition on alveolar membranes TYPE IV HYPERSENSITIVITY REACTIONS * Delayed-type hypersensitivity reactions (DTH) * Occur 1 – 3 days following antigen contact * Large amount of antigen required * Mechanism of action * Presentation of antigen to memory T cells * CD4 TH1, CD4 TH2 and CD8 * Effector T cells secrete cytokines * Macrophage activation, inflammation, tissue destruction * Examples * Tuberculin skin test * Contact with poison ivy TUBERCULIN SKIN TEST (TST) * Synonym * PPD (purified protein derivative) skin test * Identify infection with Mycobacterium tuberculosis * Test procedure and interpretation * Injection of TB protein intradermally * Read reaction at 48 to 72 hours for induration (mm) * Interpret induration based on risk factors * 5 mm (high risk) * 10 mm (moderate risk) * 15 mm (low risk) QuantiFERON-TB GOLD TEST (Interferon-gamma release assay) * Blood test for * Tuberculosis * Latent tuberculosis infection (LTBI) * Test procedure * Whole blood mixed with M. tuberculosis antigens (peptides) * ESAT-6 * CFP-10 * TB7.7 (p4) * Incubation for 16 to 24 hours * Measure quantity of interferon-gamma (IFN-gamma) * Interpretation * IFN-gamma indicates CMI (memory T cells) CONTACT WITH POISON IVY * A contact dermatitis * Involves both CD4 TH1 and CD8 T cells to * Pentadecacatechol (urushiol oil) * Langerhans’ cells process and present modified proteins * Extracellular * CD4 TH1 cells * Intracellular * CD8 cells * Transfer of pentadecacatechol from initial site of contact * Delayed nature of reaction