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