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 Universal Non-reactiving to most people

Hypersensitivity reactions Harmful IRs that cause tissue injury and

may cause serious pathologiesAtopy

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

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

A. Pathway IgE made during primary response to soluble

Ag Binds to high affinity FcRI 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 FcRI is functionalon mast cells, basophils, and activated eosinophils. It is composed of and two chains. Crosslinking of FcRIon cells by Ag and IgE induces degranulation.

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

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

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 subcutaneous injection local release of histamine

Wheal and flare reaction

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

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. 10.14Properties of inhaled allergens that favor TH2 priming that promotes IgE isotype switching.

Fig. 10.15Sensitization 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 Food allergy Gut epithelial cells are involved Intestinal smooth muscle contraction

Vomiting Diarrhea

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

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

Fig 10.12

Summary of Type I Hypersensitivity Reactions

C. Hereditary predisposition for IgE synthesis FcR 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

Acute (minutes) versus Chronic (5-12 hours) Reactions Immediate allergic reactions is then

followed by a late-phase response

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-

Mast cell stained for protease chymase demonstrating abundant granules residing in the cytoplasm.

Chronic – Late Caused by influx of inflammatory

leukocytes (including eosinophils) Chronic allergic inflammation Tissue damage Edema, long-lasting

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

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

Fig. 10.7

Mast cell production of prostaglandins and leukotrienes by different enzyme pathways starting with arachidonic acid.

Fig. 10.8: Eosinophils display a unique staining pattern with bilobednuclei and stain pink with eosin. Eosinophils are specialized granulocytes that release toxic mediators in IgE-mediated responses.

Fig. 10.9:Products of activated eosinophils.

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.

E. 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

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

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

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

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

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

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 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 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 IFN, IFN, IL-10, IL-12, and TGF-

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

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

Figure 10.20: Effect of epinephrine on blood pressureTime 0 = point at which anaphylactic response began. Arrows = times when epinephrine was administered.

III. Type II (Cytotoxic) 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

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

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 Hemolytic disease of the newborn

(Erythroblastosis fetalis) (Abs to Rh Ags)

Hemolytic Disease of the Newborn (Erythroblastosis fetalis)

Type II hypersensitivity

Alloantibodies resulting from Rh incompatibilities between mother and father

Spacing of Rh antigen istoo 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: 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 interferes with the bacterial enzyme transpeptidase after binding to the active site in the enzyme.

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.

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.

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.

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

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 tissueBlood vessels VasculitisKidney glomerular basement membrane

GlomerulonephritisSynovial tissue of joints Arthritis or

ArthralgiaSkin Butterfly rash in SLE

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

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 diseaseArthus reactionSerum sicknessPersistent viral, bacterial or protozoan

infection in face of weak Ig responseContinuous autoantibody production Immune complexes formed at body

surfaces

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

Localized deposition of immune complexes within a tissue causes a type III hypersensitivity reaction.

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

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)

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

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

Persistent viral, bacterial or protozoan infections Results in chronic immune complex

formation (IC) Examples:

Subacute bacterial endocarditis Acute glomerulonephritis Chronic viral hepatitis

Autoantibody produced continuously Prolonged IC formation Systemic lupus erythematosus (SLE)

Glomerulonephritis, arthritis, vasculitis AutoAbs to DNA, RNA and proteins associated

with nucleic acids

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

A. FeaturesT-cell mediated immune responses

Includes: Delayed-type hypersensitivity Contact hypersensitivity Gluten-sensitive enteropathy (Celiac disease)

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, IFN, IL-3, TNF, TNF and GM-CSF Other cells recruited

Macrophages, basophils, other lymphocytes Tissue can be severely damaged

Cytokines, chemokines and cytotoxins made by TH1 during Type IV Hypersensitivity Reactions Chemokines

Recruitment of macrophages to the site of Ag deposition

Cytokine IFN

Macrophage activation, release of inflammatory mediators IL-3/GM-CSF

Increased monocyte synthesis in bone marrow

Cytotoxins – TNF and TNF TNF activates macrophage TNF and TNF blood vessel adhesion

molecules expressed (activation of endothelial cells) cells infiltrate, edema

TNF cytotoxic to macrophages and other cells

Tcyt may also be involved in Type IV hypersensitivity reactions Cell-mediated cytotoxicity and IFN

production Modified peptides associate with class I

(e.g. pentadecacatechol of poison ivy = lipid soluble)

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. ExamplesTuberculin 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 Haptens combine with skin proteins

Pentadecacatechol (poison ivy) Cosmetics Metals (jewelry)

Nickel Gold

Transplantation (Graft) Rejection

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

Fig. 10.33: Summary