Upload
walter-rose
View
225
Download
2
Tags:
Embed Size (px)
Citation preview
Hypersensitivity Reactions Gell & Coombs 1963
CLASSIFICATION OF HYPERSENSITIVITY REACTIONS (GELL AND COOMBS)
Based on effector mechanisms and antigensType I
Mediated by IgE on mast cells, basophils and eosinophils (time: 2-30 min)
Type IIMediated by IgG and IgM against cell surface / matrix antigens (time: hours- 1 day)
Type IIIMediated by IgG against soluble antigens (time: hours- days)
Type IVMediated by CD4 and CD8 cells against soluble and cell surface antigens (time: 24-72 hours)
HYPERSENSITIVITY AFTER GELL & COOMBS 1963
Subtypes IV a ‐ eczematous IV b – maculopapular or bullous exanthem IV c – Eczematous, maculopapular,
bullous, pustular exanthem IV d – Pustular exanthem.
Type V: Stimulation of Receptors
TYPE I - IMMEDIATE HYPERSENSITIVITY IGE MEDIATED
* Normal physiological role of IgE* Defense against parasites
* Pathophysiological role of IgE* Type I hypersensitivity reaction
* Type I reactions follow sensitization to allergens
* Sensitization* First exposure to allergen elicits an IgE response* Genetic predisposition (Atopy - 10% of population
are atopic)
Sensitization
TYPE I HYPERSENSITIVITY:
History of Discoveries• Anaphylaxis: Portier and Richet, 1902• Histamine: Dale and Laidlaw, 1911• Mast cells as main tissue source of
histamine: Riley and West, 1952• IgE immunoglobulin: Ishizaka and
Ishizaka, 1966
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
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
TYPE I - IGE MEDIATED REACTION
Atopic Diseases (Triad of atopy): Allergic Asthma, Allergic Rhinoconjunctivitis- Hay Fever,Allergic Dermatitis (eczema),
&Urticaria *, Food allergy
Allergen Primary
Individual Generation
IgE
Adhesion
IgE binds to the FceRI on mast cell and basophil Secondary
Allergen binds to the IgE on primed target cell
Crosslikage of FceRI
Degranulate and release the biological mediators
Preformed granule mediators New generated mediators
Histamine Bradykinin Leukotrienes PAF Prostaglandin D2
Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle
Systemic anaphylaxis
Skin Respiratory tract GI tract
Mechanism of type I hypersensitivity
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)
EARLY PHASE RESPONSE
MAST CELL• DEGRANULATION- Release of preformedmediators• SYNTHESIS OF LIPID MEDIATORS
MEDIATORS & CELLS
Mast cells
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
MAST CELL MEDIATORS
• Preformed– Vasoactive amines: histamine– Neutral proteases: tryptase, chymase– Acid hydrolases: β-hexoseaminidase– Proteoglycans: heparin, chondroitin sulfate• Newly formed– Eicosanoids: PGD2, LTC4– Cytokines: TNFα, IL-4, IL-5, IL-6
PREFORMED MEDIATORS
HISTAMINE• Stimulation of irritant nerve receptors• Smooth muscle contraction• Increase in vascular permeabilityKALLIKREIN• Activates bradykinin - similar actions to
histamineTRYPTASE - role unclear
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
HISTAMINE
• Produced almost exclusively by basophilsand mast cells (3-8 pg/cell)• Immediate pharmacologic effects:– pruritus (H1)– ↑ vascular permeability/vasodilatation (H1)– smooth muscle contraction (H1)– gastric acid secretion (H2)
MAST CELL TRYPTASE
Tetrameric serine protease• Found only in mast cells, not basophils• Peaks in 1-2 hours and remains elevated 4-6-
12 hours in serum following release in anaphylaxis
• Alpha isoform is predominant in blood: mostmastocytosis patients with systemic disease
havetotal tryptase levels that are elevated (> 20
ng/ml)and are at least 10-fold greater than their βtryptase level.
Arachidonic acid pathway
Allergen
Degranulation ,release and synthesis of biological mediators of primed target cells
LOXCOXAcetyl-transferases
Phosphoration of ITAM
MAPK
Lipid mediatiors
Endoplasmic reticulum
Degranulation
Myosin
Phosphoration of Light chain
Cell membrane
Activation of PTK
Phosphatidylcholine
Histamine
Arachidonic acid
Inactivated PKC
ActivatedPKC
Hydroxyl phosphalipid Phosphalipid
LIPID MEDIATORS- 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 formation
* Cox-2 involved in inflammatory response
LIPID MEDIATORS PROSTAGLANDINS
* Classified as lipid mediators of inflammation* Derived from arachidonic acid* Act locally and rapidly metabolized* Located in virtually all tissues / organs
* Produced following activation of* Mast cells, basophils, macrophages
* PGD2 is major mediator* Levels increased by Cox-2 in inflammation
* Physiological effects similar to histamine* Vasodilation, bronchoconstriction, neutrophil chemotaxis
LIPID MEDIATORS LEUKOTRIENES
* Synthesized and released following activation of * Mast cells, eosinophils, basophils, neutrophils, macrophages
* Classified as lipid mediators of inflammation* Derived from arachidonic acid
* Leukotrienes (LTA4 – LTE4)* Sustain inflammatory response in allergic disease* C, D and E are cysteinyl leukotrienes
* Receptors (CysLT 1 & 2) on mast cells, eosinophils, endothelial cells
* Increased levels induce anaphylaxis* Physiological effects similar to histamine
* More potent / longer lasting than histamine* Vasodilation, bronchoconstriction, neutrophil chemotaxis
LATE-PHASE RESPONSE -
BASOPHILS• Similar properties to mast cells over longer time
scale
EOSINOPHILS• granules contain cytotoxic proteins (ECP)• In tissues, release contents of granules – major
source of tissue damage in allergic response T cells• cytokine- activity is the major source of
pathogenesis in allergic responses
EOSINOPHILS
* Granulocytic leukocytes (1 – 6% in blood)* Level variation (down in a.m., up in p.m.)
* 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
ACTIONS OF MEDIATORS
• Irritation of nerve endings• Blood vessels dilate and leak• Airways contract• Hypersecretion• Recruitment of immune cells
CONSEQUENCES
• Irritation of nerve endings - Itch• Blood vessels dilate, leak - Urticaria /
angio oedema, low blood pressure• Airways contract - Wheeze /asthma• Hypersecretion - Runny nose /eyes• Recruitment of immune cells - Late
phase reaction
ALLERGIC RHINITIS (HAY FEVER)
* Inflammation of mucous membranes caused by inhaled allergens
* Genetic predisposition for offspring* 1 (30%) or 2 (50%) parents with AR
* Classification * Seasonal (tree, grass, ragweed pollens) * Perennial (dust mites, cockroaches, animal
dander)* Symptoms
* Sneezing, itching, rhinorrhea and nasal congestion
* Nasal discharge rich in eosinophils
ALLERGIC RHINITIS (HAY FEVER)
Skin Prick Testing Used in the diagnosis of allergic disorders. A panel of potential allergens are intradermally
“pricked” into the skin. After 15-20 minutes if a wheal or flare is seen this is
suggestive of IgE allergy against the allergen.
Diagnosis of atopy
PREVENTION AND TREATMENT OF ALLERGIC RHINITIS
* Prevention * Avoidance of offending allergens
* Treatment / Prevention* Antihistamines* Leukotriene receptor antagonists * Anti-inflammatory agents (GCS) * Mast cell stabilizing agents * Immunotherapy (Hyposensitization /
Desensitization)
ANTIHISTAMINES FOR ALLERGIC RHINITIS
* Mechanism of action * Prevent binding of histamine to H1 receptors
* Antihistamines (1st generation)* Antazolinum (Phenazolinum), Clemastinum,
Hydroxyzinum, Prometazinum- per os, i.m., i.v.* Chlorpheniramine (Chlortrimeton)* Diphenhydramine (Bendryl)
* Antihistamines (2nd generation) * Cetirizine (Zyrtec, Allertec) Levocetirizine (Xyzal)* Fexofenadine (Allegra, Fexofast, Telfast)* Loratadine (Claritin), Desloratadine (Clarinex,
Aerius)
NASAL ANTIHISTAMINE FOR ALLERGIC RHINITIS
Azelastine (Astelin,Allergodil) First intra-nasal antihistamine FDA approval in 1996
Indicated for seasonal allergic rhinitis 1 spray per nostril (FDA approval in 2006)
Adverse events Bitter taste, headache, somnolence
Precaution Avoid concurrent use with alcohol and other CNS depressants
ANTI-LEUKOTRIENE AGENTS FOR ALLERGIC RHINITIS
* Leukotriene receptor antagonists * Montelukast (Singulair) * Zafirlukast (Accolate)
* Mechanism of action * Binds to CysLT1 receptor with no agonist activity
* Leukotriene synthesis inhibitors * Zileuton (Zyflo)
* Mechanism of action * Inhibits 5-lipoxygenase (5-LO)
NASAL STEROIDS FOR ALLERGIC RHINITIS
* Considered most effective for prevention and treatment
* Mechanism of action: * Wide range of effects on many inflammatory cells and
mediators * Maximum benefit following several days of use* Steroids
* Fluticasone propionate (Flonase, Flixonase) * Mometasone furoate (Nasonex) * Triamcinolone acetonide (Nasacort) * Beclomethasone dipropionate (Beconase)
MAST CELL STABILIZING AGENTS FOR ALLERGIC RHINITIS
Cromolyn sodium Cromolyn (Intal) by metered-dose inhaler (MDI) Cromolyn (Nasalcrom) by nasal spray
Mechanism of action Calcium ion channel blocker
Intracellular Ca++ essential for degranulation
Not as effective as corticosteroids
IMMUNOTHERAPY FOR ALLERGIC RHINITIS
* Goal is to shift immune response from IgE to IgG
* Achievement of goal by allergy shots * Injection of small, then increasing doses of allergen
* Shots gradually divert TH2 IgE response to * TH1 and / or IgG response
* Potential complication* Anaphylaxis
TYPE II - CYTOTOXIC REACTION
Binding of antibody to cell surface leads to activation of complement and damage to host cell eg. blood cells (penicillin, methyldopa, quinidine)
Examples of Diseases:• Transfusion reactions• Hemolytic disease of the newborn (Rh
incompatibility)• Hyperacute graft rejection• Drug-induced hemolytic anemia
Allergen
Stimulate
Antibody
A. Opsonic phagocytosis
D. ADCC of NK
C. Effect of complement
Combined opsonic activities
Cell injury ways of type II hypersensitivity
Cell
HYPERSENSITIVITY TYPE II
IgM, IgG1, IgG3 activate complement
Antigen or hapten on cell
Antibody (IgG, IgM)
Activate complement
Lyse target cell
Opsonic phagocytosis NK , phagocyte Stimulate / block
Destroy target cell ADCC
Target cell injuryChange the function ofTarget cell
Mechanism of Type II hypersensitivity
TRANSFUSION REACTIONS
TRANSFUSION REACTIONS
HEMOLYTIC DISEASE OF THE NEWBORN(RH INCOMPATIBILITY)
HEMOLYTIC DISEASE OF THE NEWBORN(RH INCOMPATIBILITY)
HEMOLYTIC DISEASE OF THE NEWBORN(RH INCOMPATIBILITY)
DRUG-INDUCED HEMOLYTIC ANEMIA
* Drugs (soluble, small molecules) covalently linked to cell surface proteins of human cells
* Common drugs * Penicillin (erythrocytes)* Sulfamethoxazole (thrombocytes- platelets)
* Results in altered antigen and IgG response with cell lysis :
Penicillin RBC hemolytic anemia
Quinin Platelet thrombocytopenic purpura
Pyramidone Granulocyte agranulocytosis
TYPE III - IMMUNE COMPLEX REACTION
Formation of complexes between antigen & antibody leads to tissue damage as a result of deposition in blood vessels (vasculitis) and activation of inflammatory pathways (serum sickness, farmers lung).
TYPE III HYPERSENSITIVITY REACTIONS
* Pathophysiology related to portal of entry of antigen
1. Subcutaneous injection (Arthus reaction) * Localized erythema and induration
2. I.V. 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 and deposition on
alveolar membranes
Soluble antigen Body Antibody
Immune complex
Small molecular soluble Immune complex
intermediate molecular soluble Immune complex
Large molecular insoluble Immune complex
Deposit on the basement of capillaries
Combine and activate complement system
C3a,C5a,C3b
Infiltration of neutrophils
Phagocytose complex
Release the enzymes in lysosome
Tissue injury
Eliminate by phogacytosis
Platelets
Thrombus
Aggregation of platlets
Blood Clotting MechanismsRelease of vasoactive amine
Increase vascular permeability
Bleeding Edema
Basophils and mast cells
Release of vasoactive amine
Increase vascular permeability
Edema
Local or systemic immune complex diseases
THE ARTHUS REACTION
• Occurs with introduction of antigen intoan individual with high level antibody• Requires both complement & phagocytes• Peaks at 3-6 hours after exposure• Histology: massive influx of neutrophils,edema, sometimes necrosis
THE ARTHUS REACTION
HYPERSENSITIVITY PNEUMONITIS
Syndromes and Associated Antigens• Farmer’s lung (thermophilic actinomycetes)• Malt worker’s lung (Aspergillus spores)• Pigeon raiser’s disease (avian proteins)• Cheese washer’s lung (Penicillium spores)• Furrier’s lung (fox fur)• Laboratory technician’s lung (rat urine proteins)
hypersensitivity pneumonitis (extrinsic allergic alveolitis) is an inflammation of the alveoli within the lung caused by hypersensitivity to inhaled organic dusts.
SERUM SICKNESS
• Fever, rash, joint pain, lymphadenopathy,occasionally glomerulonephritis
• Time: days to weeks after introduction of foreign antigen
• Causes: allogenic serum, drugs, infections,autoimmune disorders
SERUM SICKNESS
TYPE IV - CELL MEDIATED REACTION (DTH)
Activation of T cells around site of antigen leads to T cell cytotoxicity & activation of macrophages, causing tissue damage (contact sensitivity).
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
HYPERSENSITIVITY TYPE IV
* Examples :* Tuberculin skin test* Sarcoidosis, Wegener’s granulomatosis, Crohn’s* Contact dermatitis - nickel, latex , contact with poison ivy
HYPERSENSITIVITY TYPE IV
HYPERSENSITIVITY TYPE IV
Antigen T cell(CD4+,CD8+)
Secondary contact
Induce
Primed T cell
CD4+ T cell
CD8+ T cell
ReleaseCytokines
IL-2TNF-bINF-g
TFMCFMIFMAFSRF
Directly kill target cells
Infiltration of monocyte and Mf
Proliferation of T cell
Exudation and edema
Cytotoxicity
Inflammation characterized by infiltration of Mf, monocyte, and tissue injury
Mechanism of type IV hypersensitivity
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)
TUBERCULIN SKIN TEST (TST)
*
TUBERCULIN SKIN TEST (TST)
*
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
NONSTEROIDAL ANTI-INFLAMMATORY 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)
* Adverse reactions with both categories
FIGURE 10-5
FIGURE 10-9