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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Allergy and hypersensitivity

Allergy and Hypersensitivity


I introduction

I. Introduction


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


Allergy and hypersensitivity

  • 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)


Ii type i anaphylaxis hypersensitivity

II. Type I (Anaphylaxis) Hypersensitivity


A pathway

A. Pathway

  • 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


Allergy and hypersensitivity

High affinity FceRI 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

degranulation.


Allergy and hypersensitivity

  • Induces degranulation  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


Allergy and hypersensitivity

  • Tachyphylaxis

    • 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


Allergy and hypersensitivity

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

    • Wheal and flare reaction


Allergy and hypersensitivity

  • Mucosal mast cells

    • Inhalation – low dose  Activated by inhaled allergen

      • Smooth muscle contraction of lower airways

      • Bronchoconstriction

        • Asthma

        • Allergic rhinitis (hay fever)

      • Increased mucosal secretions

        • Irritations


Allergy and hypersensitivity

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.


Allergy and hypersensitivity

Fig. 10.14

Properties of inhaled

allergens that favor TH2

priming that promotes

IgE isotype switching.


Allergy and hypersensitivity

Fig. 10.15

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.


Allergy and hypersensitivity

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).


Allergy and hypersensitivity

  • Ingestion – Activated by ingested allergen

    • Food allergy

    • Gut epithelial cells are involved

    • Intestinal smooth muscle contraction

      • Vomiting

      • Diarrhea

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


Allergy and hypersensitivity

Fig. 10.25: Ingested allergen can cause vomiting, diarrhea and urticaria.


Allergy and hypersensitivity

Summary of Type I Hypersensitivity Reactions

Fig 10.12


C hereditary predisposition for ige synthesis

C. Hereditary predisposition for IgE synthesis

  • 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


Allergy and hypersensitivity

  • Acute – Immediate

    • 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


Allergy and hypersensitivity

Mast cell stained for protease

chymase demonstrating

abundant granules residing

in the cytoplasm.


Allergy and hypersensitivity

  • Chronic – Late

    • Caused by influx of inflammatory leukocytes (including eosinophils)

    • Chronic allergic inflammation

    • Tissue damage

    • Edema, long-lasting


Allergy and hypersensitivity

  • Chemokines

  • 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


Allergy and hypersensitivity

Fig. 10.5: Mast cell products involved in allergic reactions.


Allergy and hypersensitivity

Fig. 10.7

Mast cell

production of

prostaglandins

and leukotrienes

by different enzyme pathways starting with arachidonic

acid.


Allergy and hypersensitivity

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.


Allergy and hypersensitivity

Fig. 10.9:

Products of

activated

eosinophils.


Allergy and hypersensitivity

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

  • 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


Allergy and hypersensitivity

  • Arterioles dilate

    • 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


Allergy and hypersensitivity

  • Examples of allergens:

    • 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


Allergy and hypersensitivity

  • 2. Localized anaphylaxis

    • 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


Allergy and hypersensitivity

  • Bronchial asthma = allergic asthma – LRT

    • 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


Allergy and hypersensitivity

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.


Allergy and hypersensitivity

  • In vivo skin testing can help to identify responsible allergens  rapid inflammation

    • Diameter of swelling measured

    • Wheal-and-flare reactions

    • Cutaneous allergic response

    • Develops within 1-2 minutes  lasts ~30 minutes


F desensitization

F. Desensitization

  • 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

  • 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)


Allergy and hypersensitivity

  • Block allergic response effector pathways

    • 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


Allergy and hypersensitivity

Figure 10.20: Effect of epinephrine on blood pressure

Time 0 = point at which anaphylactic response began.

Arrows = times when epinephrine was administered.


Iii type ii cytotoxic hypersensitivity

III. Type II (Cytotoxic) Hypersensitivity


Allergy and hypersensitivity

  • A. Host cells are killed or lysed

    • 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


Allergy and hypersensitivity

  • FcR bind Ig:Ag complexes

    • 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


Allergy and hypersensitivity

  • 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


Allergy and hypersensitivity

  • Examples

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


Allergy and hypersensitivity

Hemolytic Disease of the

Newborn (Erythroblastosis

fetalis)

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:

  • 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)


Allergy and hypersensitivity

  • 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)


Allergy and hypersensitivity

Penicillin may also bind to surface proteins

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.


Allergy and hypersensitivity

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.


Allergy and hypersensitivity

  • RBC and platelets are especially susceptible to lytic effects of Type II hypersensitivity, owing to reduced levels of C’ regulatory proteins than other cells have.


Allergy and hypersensitivity

  • Ab can alter signaling properties of cells in autoimmunity

    • 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

    • MORE LATER - AUTOIMMUNITY


Iv type iii immune complex hypersensitivity

IV. Type III (Immune complex) Hypersensitivity


A description of immune complexes

A. Description of immune complexes

  • 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

  • Blood vessels  Vasculitis

  • Kidney glomerular basement membrane  Glomerulonephritis

  • Synovial tissue of joints  Arthritis or Arthralgia

  • Skin  Butterfly rash in SLE


Allergy and hypersensitivity

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


Allergy and hypersensitivity

  • Mechanism:

    • 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

  • 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

  • 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


Allergy and hypersensitivity

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

hypersensitivity reaction.


Allergy and hypersensitivity

  • Serum Sickness

    • 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


Allergy and hypersensitivity

  • Examples:

    • 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)


Allergy and hypersensitivity

  • Serum sickness is usually a self-limited disease

    • 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


Allergy and hypersensitivity

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


Allergy and hypersensitivity

  • Persistent viral, bacterial or protozoan infections

    • Results in chronic immune complex formation (IC)

    • Examples:

      • Subacute bacterial endocarditis

      • Acute glomerulonephritis

      • Chronic viral hepatitis


Allergy and hypersensitivity

  • Autoantibody produced continuously

    • Prolonged IC formation

    • Systemic lupus erythematosus (SLE)

      • Glomerulonephritis, arthritis, vasculitis

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


Allergy and hypersensitivity

  • Immune complex formed at body surfaces (lungs) (IgG not IgE)

    • Exposure to very large doses of inhaled allergens  Inflammation of alveolar wall of lung

    • Farmer’s lung  Inhalation of hay dust or mold spores  Gas exchange compromised


V type iv hypersensitivity

V. Type IV Hypersensitivity


A features

A. Features

  • T-cell mediated immune responses

    • Includes:

      • Delayed-type hypersensitivity

      • Contact hypersensitivity

      • Gluten-sensitive enteropathy (Celiac disease)


B mechanism

B. Mechanism

  • 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


Allergy and hypersensitivity

  • Cytokines, chemokines and cytotoxins made by TH1 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


Allergy and hypersensitivity

  • Cytotoxins – TNFa 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


Allergy and hypersensitivity

  • Tcyt 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)


Allergy and hypersensitivity

  • The time course of a delayed type hypersensitivity reaction

    • 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

  • 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


Allergy and hypersensitivity

  • 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.)


Allergy and hypersensitivity

  • Allergic contact dermatitis

    • Haptens combine with skin proteins

      • Pentadecacatechol (poison ivy)

      • Cosmetics

      • Metals (jewelry)

        • Nickel

        • Gold

  • Transplantation (Graft) Rejection


Allergy and hypersensitivity

  • Autoimmune diseases

    • 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


Allergy and hypersensitivity

Fig. 10.33: Summary


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