Allergy and hypersensitivity
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Allergy and Hypersensitivity. I. Introduction. A. Definitions. Allergy Immune-mediated response to innocuous environmental antigen Can be humoral or cell-mediated reaction Usually involves prior exposure to antigen resulting in sensitization of individual Allergen Innocuous antigen

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A definitions
A. Definitions

  • Allergy

    • Immune-mediated response to innocuous environmental antigen

    • Can be humoral or cell-mediated reaction

    • Usually involves prior exposure to antigen resulting in sensitization of individual

  • Allergen

    • Innocuous antigen

    • Universal

    • Non-reactiving to most people

  • Hypersensitivity reactions

    • Harmful IRs that cause tissue injury and may cause serious pathologies

  • Atopy

    • State of increased susceptibility to immediate hypersensitivity usually mediated by IgE Abs

    • Over-react to common environmental Ags

B four types of immune mediated hypersensitivity reactions causing tissue damage
B. Four types of immune-mediated hypersensitivity reactions causing tissue damage

  • Type I = Anaphylaxis hypersensitivity (TH2 = IgE)

  • Type II = Cytotoxic hypersensitivity (IgG)

  • Type III = Immune complex hypersensitivity (IgG)

  • Type IV = Cell-mediated hypersensitivity (TH1, TH2, CTL)

A pathway
A. Pathway causing tissue damage

  • IgE made during primary response to soluble Ag  Binds to high affinity FceRI on mast cells, basophils and activated eosinophils

    • Sensitizes individual (become allergic)

    • IgE aka reagin

  • Secondary exposure  allergen binds to IgE on sensitized mast cells, basophils or eosinophils

    • IgE Ab crosslinking on leads to rapid release of preformed inflammatory mediators

High affinity Fc causing tissue damageeRI is functional

on mast cells, basophils, and

activated eosinophils. It is

composed of a,b and two g

chains. Crosslinking of FceRI

on cells by Ag and IgE induces


  • Induces degranulation causing tissue damage Release of inflammatory mediators [pre-formed substances including histamine, slow reacting substance of anaphylaxis (SRS-A), heparin, prostaglandins, platelet-activating factor (PAF), eosinophil chemotactic factor of anaphylaxis (ECF-A), and various proteolytic enzymes]

  • Eosinophils release major basic protein which induces degranulation of mast cells and basophils

  • Tachyphylaxis causing tissue damage

    • Depletion of mast cell granules

    • Accounts for unresponsiveness of a patient to a skin test following an anaphylactic reaction (lasts 72-96 hours after a reaction)

B ig e mediated reactions differ depending on route of administration and dose
B. Ig-E mediated reactions differ depending on route of administration and dose

  • Connective tissue mast cells

    • Associated with blood vessels

    • IV-high dose  Activated by allergen in the bloodstream  systemic

      • Systemic release of histamine

      • Systemic anaphylaxis

  • SC-low dose administration and dose subcutaneous injection  local release of histamine

    • Wheal and flare reaction

  • Mucosal mast cells administration and dose

    • Inhalation – low dose  Activated by inhaled allergen

      • Smooth muscle contraction of lower airways

      • Bronchoconstriction

        • Asthma

        • Allergic rhinitis (hay fever)

      • Increased mucosal secretions

        • Irritations

Fig. 10.24: Allergen-induced release of histamine by mast cells in skin

causes localized swelling. Swellings (wheals) appear 20 min. after

intradermal injection of ragweed pollen (R), histamine (H). Saline bleb (S) is due to volume of fluid.

Fig. 10.14 cells in skin

Properties of inhaled

allergens that favor TH2

priming that promotes

IgE isotype switching.

Fig. 10.15 cells in skin

Sensitization to an inhaled allergen.

Soluble allergen is processed by APC and displayed to TH2 T cells.

T cells help B cells to produce IgE which then binds to mast cells. IL-4 promotes isotype switching to IgE.

Fig. 10.21: Allergic rhinitis (hay fever) is caused by inhaled allergen entering the respiratory tract. Sneezing, runny nose – nasal discharge is full of eosinophils. Allergic conjunctivitis results if the conjunctiva of the eye is affected (itchy, watery, and swelling of eyes).

  • Ingestion – Activated by ingested allergen inhaled allergen entering the respiratory tract. Sneezing, runny nose – nasal discharge is full of eosinophils. Allergic conjunctivitis results if the conjunctiva of the eye is affected (itchy, watery, and swelling of eyes).

    • Food allergy

    • Gut epithelial cells are involved

    • Intestinal smooth muscle contraction

      • Vomiting

      • Diarrhea

    • Dissemination through bloodstream causes urticaria (hives) or anaphylaxis (rare)

C hereditary predisposition for ige synthesis
C. Hereditary predisposition for IgE synthesis and urticaria.

  • FceR genes

  • Cytokine genes involved in

    • Isotype switching

    • Eosinophil survival

    • Mast cell proliferation

    • Example: IL-4 promoter mutation which leads to elevated IL-4 can favor IgE

  • MHC class II

    • MHC:peptide combinations may favor TH2 response

    • Example: ragweed pollen associates with HLA-DRB1*1501

D type i hypersensitivity reactions can be divided into immediate and late stages
D. Type I hypersensitivity reactions can be divided into immediate and late stages

  • Acute (minutes) versus Chronic (5-12 hours) Reactions

    • Immediate allergic reactions is then followed by a late-phase response

  • Acute – Immediate immediate and late stages

    • Peaks within minutes after allergen injection or inhalation and then subsides

    • Wheal and flare

    • Bronchial constriction in asthma

    • IgE crosslinking  rapid degranulation

      • Release of preformed inflammatory mediators

        • Histamine, serotonin

        • Mast cell chymase, tryptase, carboxypeptidase and cathepsin G  breaks down tissue matrix proteins (remodeling of connective tissue matrix)

        • TNF-a

Mast cell stained for protease immediate and late stages

chymase demonstrating

abundant granules residing

in the cytoplasm.

  • Chronic – Late immediate and late stages

    • Caused by influx of inflammatory leukocytes (including eosinophils)

    • Chronic allergic inflammation

    • Tissue damage

    • Edema, long-lasting

  • Chemokines immediate and late stages

  • Heparin

  • Lipid mediators derived from membrane phospholipids

    • Form a precursor called arachidonic acid

      • Many anti-inflammatory agents inhibit arachidonic acid metabolism (e.g. aspirin)

    • Arachidonic acid forms:

      • Leukotrienes

      • Prostaglandins

      • Thromboxanes

      • Platelet activating factor

Fig. 10.7 reactions.

Mast cell

production of


and leukotrienes

by different enzyme pathways starting with arachidonic


Fig. 10.8: Eosinophils display a unique staining pattern with bilobed

nuclei and stain pink with eosin.

Eosinophils are specialized granulocytes that release toxic mediators

in IgE-mediated responses.

Fig. 10.9: with bilobed

Products of



Fig 10.16: Immediate and late-phase reactions to house dust mite

allergen (HDM) injected intradermally. Saline injection = control.

Wheal = raised area of skin around injection site; flare = redness

(erythema) spreading out from the wheal.

Two types of anaphylaxis
Two types of anaphylaxis mite

  • 1. Systemic anaphylaxis

    • Generalized response to systemically administered Ag (e.g. IV) or rapidly absorbed from gut

    • Immediate: a lot of mast cell products released quickly

    • Smooth muscle constriction of bronchioles  breathing difficulties

      • Epiglottal swelling  Asphyxiation

      • Can be fatal

  • Arterioles dilate mite

    • Arterial blood pressure decreases

    • Capillary permeability increases (increases vascular permeability

      • Fluid loss into tissue spaces

      • Edema

      • Late phase reaction = sustained edema

    • Circulatory shock

      • Can be fatal

  • Examples of allergens: mite

    • Penicillin (or cephalosporins)

      • Penicillin = hapten  beta lactam ring reacts with amino groups on host proteins  conjugates form

    • Bee, wasp or hornet venom

    • Peanuts or brazil nuts

    • Anti-sera

  • 2. Localized anaphylaxis mite

    • Atopic (out of place) allergy

    • Examples:

      • Allergic rhinitis (hay fever) – URT

        • Airborne allergens: pollen, spores, animal dander, house dust mite feces

        • Allergens diffuse across the mucus membranes of nasal passages

          • Mast cells sensitized in mucus membrane upon primary exposure

          • Upon secondary exposure – itchy, runny eyes and nose, sneezing coughing

  • Bronchial asthma = allergic asthma – LRT mite

    • Air sacs (alveoli) fill with fluid and mucus

    • Wall of bronchi constricted

    • Bronchodilators relax muscles, making breathing easier (inhalers)

      • Anticollinergic

      • Sympathetic activators

      • Metaproterenol

      • Albuterol

  • Hives (food allergy)

    • Vomiting and diarrhea = local response

    • Urticaria = systemic response

Fig. 10.23: Inflammation of the airways in chronic asthma restrict breathing

A = section through bronchus of individual who died from asthma.

MP = mucus plug – restricts airway. White plug depicts remaining passageway in bronchial lumen.

B = Bronchial wall at higher magnification demonstrating presence of inflammatory infiltrate consisting of eosinophils, neutrophils, and lymphocytes. L = lumen of bronchus.

F desensitization
F. Desensitization allergens

  • Subcutaneous injections of Ag  to produce IgG Abs  can compete with IgE Ab, and neutralize allergens before they reach mast cells

  • Tiny amounts injected initially, then dose is increased  Diverts IR from TH2 to TH1  Decreases IgE production

  • 65-75% effective treatment of inhaled allergens

G treatment
G. Treatment allergens

  • Inhibit allergic reactions – Examples

    • Desensitization (described above)

    • Experimental:

      • Inhibit IL-4, IL-5 and/or IL-13 or CD40L to reduce IgE responses

      • Use cytokines that enhance TH1 responses

        • gIFN, aIFN, IL-10, IL-12, and TGF-b

      • Block FceR (e.g. with modified Fc components that lack variable domains)

  • Block allergic response effector pathways allergens

    • Epinephrine

      • Endothelial tight junctions reform

      • Relaxation of smooth muscle

      • Stimulation of heart (increase BP)

    • Anti-histamines

      • Block histamine receptors

      • Decrease urticaria (hives)

    • Corticosteroids

      • Reduce inflammation

Figure 10.20: Effect of epinephrine on blood pressure allergens

Time 0 = point at which anaphylactic response began.

Arrows = times when epinephrine was administered.

  • A. Host cells are killed or lysed allergens

    • Cell surface antigens

  • B. IgG (mainly) or IgM Abs react with cell surface receptors, matrix associated Ag or modified cell membranes

  • Complement is activated

    • C’ binds Ig (C1q)

    • C’ cascade results in formation of membrane attack complex (MAC)

    • Holes are punched in target cells  Death

  • FcR bind Ig:Ag complexes allergens

    • FCR-bearing accessory cells are activated (e.g. macrophages, neutrophils and NK cells)

      • Especially important mechanism used by splenic macrophages  clearance of cells

    • Opsonization induced via FcR + CR1

  • Antibody-dependent cell-mediated cytotoxicity (ADCC) is induced in NK cells

    • NK cells secrete preformed perforin and granzyme from cytoplasmic granules

    • Perforin forms a pore in target cell – transmembrane polymerization

    • Granzyyme (aka fragmentin) = 3 serine proteases – digest host proteins and activate endonucleases  DNA is degraded into ~200 by multimers (subunits) = APOPTOSIS

  • Examples induced in NK cells

    • Hemolytic disease of the newborn (Erythroblastosis fetalis) (Abs to Rh Ags)

Hemolytic Disease of the induced in NK cells

Newborn (Erythroblastosis


Type II hypersensitivity

Alloantibodies resulting

from Rh incompatibilities

between mother and father

Spacing of Rh antigen is

too far to activate C’ or

cause agglutination.

Fetal RBC destroyed by macro-

phages causing edema.

This may in turn lead to heart

failure, edema and fetal death

(hydrops fetalis).

More examples
More examples: induced in NK cells

  • Mismatched blood transfusion (Abs to A/B Ags)

  • Autoimmune hemolytic anemia (Abs to self Ag on RBC)

  • Autoimmune thrombocytopenia purpura (Abs to platelet integrin  abnormal bleeding/hemorrhaging)

  • Goodpastuer’s Syndrome (renal failure due to anti-basement membrane collagen Abs)

  • Pemphigus vulgaris (skin blisters – anti-epidermal cadherin Abs)

  • Acute rheumatic fever (cross-reactive Abs to cardiac muscle generated following Streptococcus group A infection  myocarditis, arthritis, heart valve scarring)

  • Drug allergies (e.g. penicillin) (drug combines with cell proteins)

Penicillin may also bind to surface proteins cadherin Abs)

on human cells (RBC = most common).

This creates a new epitope that can act

like a foreign Ag.

Penicillin interferes with the

bacterial enzyme transpeptidase

after binding to the active site in

the enzyme.

Fig. 10.27: Penicillin-protein conjugates stimulate the production of

anti-penicillin antibodies.

Penicillin-modified RBC get coated with C3b as a bystander effect of C’ activation by bacterial activating surfaces for which the penicillin was administered. This initiates the process by inducing opsonization by macrophages.

  • Ab can alter signaling properties of cells in autoimmunity effects of Type II hypersensitivity, owing to reduced levels of C’ regulatory proteins than other cells have.

    • Grave’s Disease

      • Agonist Ab  Hyperthyroidism

      • Ab = anti TSH receptor specific  overproduction of thyroid hormone

    • Myasthenia Gravis (MG)

      • Antagonist Ab  Blocks neuromuscular transmission

      • Anti-acetylcholine receptor specific  progressive weakness


Iv type iii immune complex hypersensitivity

IV. Type III (Immune complex) Hypersensitivity effects of Type II hypersensitivity, owing to reduced levels of C’ regulatory proteins than other cells have.

A description of immune complexes
A. Description of immune complexes effects of Type II hypersensitivity, owing to reduced levels of C’ regulatory proteins than other cells have.

  • Form through association of Ab with multivalent soluble Ag

  • Complexes become deposited on blood vessel walls or tissue sites and activate C’  Inflammation induced (C5a)

  • Pathogenicity depends on size of complex

    • Large = cleared by C’ fixation (Ab excess)

    • Small = deposited (Ag excess)

B damage to host tissue
B. Damage to host tissue effects of Type II hypersensitivity, owing to reduced levels of C’ regulatory proteins than other cells have.

  • Blood vessels  Vasculitis

  • Kidney glomerular basement membrane  Glomerulonephritis

  • Synovial tissue of joints  Arthritis or Arthralgia

  • Skin  Butterfly rash in SLE

The pathology of type III hypersensitivity reactions is determined by the sites of immune-complex deposition.

  • Mechanism: determined by the sites of immune-complex deposition.

    • C’ is activated

    • Basophils and platelets degranulate

    • Histamine and other inflammatory mediators are released

    • Vascular permeability increases

    • Platelets aggregate and form microthrombi (blood clots) on vessel walls

      • Burst, hemorrhaging of skin

    • Recruitment of PMNL by chemotaxis

      • Further degranulation, enzyme release and host damage  vasculitis

C five types of disease
C. Five types of disease determined by the sites of immune-complex deposition.

  • Arthus reaction

  • Serum sickness

  • Persistent viral, bacterial or protozoan infection in face of weak Ig response

  • Continuous autoantibody production

  • Immune complexes formed at body surfaces

D examples
D. Examples determined by the sites of immune-complex deposition.

  • Arthus Reaction

    • A skin reaction occuring in sensitized (already immune) individuals where Ag is injected into the dermis and reacts with IgG in extracellular spaces

    • This in turn leads to C’ fixation/activation (mast cell degranulation) and recruitment of phagocytic cells leading to inflammation

      • Increased fluid and protein release

      • Increased phagocytosis

      • Blood vessel occlusion by platelets

    • Experimental model for I.C. disease

Localized deposition of immune complexes within a tissue causes a type III

hypersensitivity reaction.

  • Serum Sickness causes a type III

    • Systemic reaction to a large dose of Ag (7-10 days after injection)

      • Ag is poorly catabolized and remains in circulation long enough to be available following primary immune response

    • Chills, fever, urticaria, arthritis and glomerulonephritis

  • Examples: causes a type III

    • Horse serum used to treat pneumococcal pneumonia prior to antibiotics usage

    • Anti-venin – horse anti snake venom

    • Mouse anti-lymphocyte globulin used for immunosuppression of transplantation (mouse MoAb)

    • Streptokinase (bacterial enzyme) to treat heart attack victims

    • Antibiotics (penicillin or cephalosporin)

  • Serum sickness is usually a self-limited disease causes a type III

    • Symptoms improve as host Abs increase to zone of Ab excess

    • Can be fatal if kidneys shut down or hemorrhaging occurs in brain

    • Treatment

      • Prednisone (anti-inflammatory – corticosteroid) and Benadryl (anti-histamine)

    • Prior sensitization is NOT prerequisite  Reaction can occur on first encounter if Ag isn’t readily cleared from circulation and is present at high concentration

Serum sickness is a classic example of a transient immune-complex mediated syndrome.

  • Autoantibody produced continuously immune-complex mediated syndrome.

    • Prolonged IC formation

    • Systemic lupus erythematosus (SLE)

      • Glomerulonephritis, arthritis, vasculitis

      • AutoAbs to DNA, RNA and proteins associated with nucleic acids

V type iv hypersensitivity

V. Type IV Hypersensitivity immune-complex mediated syndrome.

A features
A. Features immune-complex mediated syndrome.

  • T-cell mediated immune responses

    • Includes:

      • Delayed-type hypersensitivity

      • Contact hypersensitivity

      • Gluten-sensitive enteropathy (Celiac disease)

B mechanism
B. Mechanism immune-complex mediated syndrome.

  • Delayed-type hypersensitivity = DTH

    • TDTH recruited

    • Soluble Ag  macrophages, TH1 activation

    • Cell-associated Ag  TH1 activation  Tcyt cytotoxicity

    • Cytokines and chemokines produced

      • IL-2, gIFN, IL-3, TNFa, TNFb and GM-CSF

    • Other cells recruited

      • Macrophages, basophils, other lymphocytes

    • Tissue can be severely damaged

  • Cytokines, chemokines and cytotoxins made by TH immune-complex mediated syndrome.1 during Type IV Hypersensitivity Reactions

    • Chemokines

      • Recruitment of macrophages to the site of Ag deposition

    • Cytokine

      • gIFN

        • Macrophage activation, release of inflammatory mediators

      • IL-3/GM-CSF

        • Increased monocyte synthesis in bone marrow

  • Cytotoxins – TNF immune-complex mediated syndrome.a and TNFb

    • TNFa activates macrophage

    • TNFa and TNFb blood vessel adhesion molecules expressed (activation of endothelial cells)  cells infiltrate, edema

    • TNFb cytotoxic to macrophages and other cells

  • T immune-complex mediated syndrome.cyt may also be involved in Type IV hypersensitivity reactions

    • Cell-mediated cytotoxicity and gIFN production

    • Modified peptides associate with class I (e.g. pentadecacatechol of poison ivy = lipid soluble)

  • The time course of a delayed type hypersensitivity reaction immune-complex mediated syndrome.

    • Acquired IR

      • 1st phase:

        • Uptake, processing and presentation of Ag

      • 2nd phase:

        • Previously primed TH1 cells migrate to site of infection and become activated

        • T cells secrete mediators that result in recruitment of macrophages  Inflammation ensues fluid and protein accumulate  Lesion  Induration

C examples
C. Examples immune-complex mediated syndrome.

  • Tuberculin hypersensitivity

    • Tuberculosis skin test (Mantoux test, Heath test – multipronged skin prick)

    • Purified protein derivative (PPD) from Mycobacterium tuberculosis

      • Injected intradermally

      • After 48 hours, induration (swelling/lesion) indicates positive reaction

        • Related to degree of sensitivity

          • Indicates prior exposure to M. tuberculosis

  • Other microbial products used in Type IV skin testing include

    • Histoplasmic (for histoplasmosis – Histoplasma capsulatum – fungus)

    • Coccidiodin (for coccidiodomycosis – fungus)

    • Lepromin (for Hansen’s disease – Mycobacterium leprae)

    • Brucellergen (for brucellosis – bacteria – Brucella spp.)

  • Allergic contact dermatitis include

    • Haptens combine with skin proteins

      • Pentadecacatechol (poison ivy)

      • Cosmetics

      • Metals (jewelry)

        • Nickel

        • Gold

  • Transplantation (Graft) Rejection

  • Autoimmune diseases include

    • Rheumatoid arthritis (joint inflammation)

    • Multiple sclerosis and Experimental allergic encephalomyelitis (EAE) (demyelination)

    • Diabetes mellitus (IDDM) (pancreatic beta cell destruction)

    • Gluten-sensitive enteropathy – Celiac disease

      • Ag = Gliadin

      • Malabsorption results from villous atrophy in small intestine