Allergic reactions

Hypersensitivity Reactions:Take Home Message

1. Allergic or Hypersensitivity reactions result from an non-desirable immune response.

2. Both CMI and AMI are involved in allergic reactions.

3. Complement is an important part of the immune responses ability to combat bacterial infections.

4. Hypersentivity reactions are a major reseason for drug induced pathologies.

Hypersensitivity Reactions

1. Immediate hypersensitivity reactions • result from an AMI based interaction (antibody- antigen) • take minutes to hours to develop after first encounter with antigen

Type I. Type II. and Type III.2. Delayed hypersensitivity reactions

• result from an CMI based interaction (cell-cell) • symptoms do not develop for days after exposure to antigen

Type IV

Hypersensitivity Reactions

Type I Hypersensitivity: Sensitization

B-cellMHCII-Peptide

MHCIIPeptide

B7

TCR

CD4

CD3

CD28

TH-2

MemoryB-Cell

Plasmacyte

IgE Production

MHCIIPeptide

B7

Type I Hypersensitivity: Sensitization

Plasmacyte

IgE Production

IgE Bindingto Mast Cell

SensitizedMast Cell

Fc/IgEReceptor

Sensitized Mast Cell

Type I Hypersensitivity: Effector

SensitizedMast Cell

Calcium Influx

Degranulation(enzymes, histamine)

HistamineCytokines

Lipid Mediators

Eosinophil &Neutrophil Attraction

Allergen

Type I Hypersensitivity



Preformed Mediators:

stored in granules in mast cells

1) Histamine - most important

mediator in humans,

although a similar function is performed by

serotonin in other species, e.g.,rodents

most of the characteristics of anaphylaxis

can be mimicked in humans by injection of histamine

alone

present in granules at very high

concentrations as an electrostatic complex with heparin. After fusion of the

granules histamine is released from

the heparin complex by ion-exchange effects

stimulates contraction in most smooth

muscle, vasodilation and permeability in post-capillary

venules, drop in blood pressure


Preformed Mediators:• 2) Eosinophil chemotactic factor - attracts

and prevents further migration of eosinophils and neutrophils

• 3) Neutrophil chemotactic factor - attracts and prevents further migration of neutrophils

• 4) Degradative enzymes including: Arylsulfatase - inactivates leukotrienes chymase - degrades proteins N-acetylglucosaminidase - degrades heparin


2. Causes and Results•for humans can result from, bee or wasp sting, seafood, nuts.•can also result from cross linking of drug to self protein (i.e., penicillin, insulin)•can result in asthma, hayfever, systemic or localized anaphylaxis


Lipid Mediators: formed

and secrete

d afte

r mas

t cell

s are activated

• 1) Leukotrienes B4, C4, D4: formerly known as SRS-A, slow reacting substance of anaphylaxis

• arachidonic acid metabolites structurally related to prostaglandins

• contracts bronchioles and increases capillary permeability

2) Platelet-activating Factor (PAF):

• synthesized from phospholipids in the cell membranes active at l0l0 M

• potent hypotensive agent

• most potent bronchorestricting agent in asthma and allergic rhinitis (hay fever)

• aggregates and lyses platelets releasing serotonin and other mediators

• promotes eosinophil infiltration

• PAF antagonists represent an active area of research, particularly for drugs to prevent abnormalities in reproduction

3) Prostaglandin D2 and

other prostaglan

dins


Cytokines

:

•stimulates production of lymphokines (IL-3, IL-4, IL-5, IL-6, GM-CS~), which stimulate production of leukocytes, more mast cells ‑ stimulates production of bradykiniin, which causes vasodilation, hypotension


N

S CH3

CH3

CO2HO

O

CO2H

SH

SH

SelfProtein

NH

S CH3

CH3

CO2HS

O

CO2H

O

SH

SelfProtein


Systemic

Anaphylaxis:

•most severe and life‑threatening type of allergic response •characteristics:•- generalized flush, palpitations, dizziness, apprehension, urticaria, angioedema and abdominal cramps•- may proceed to dyspnea, seizures, cyanosis, shock, and/or death•- begins 3 to 4 min after administration •causes:•-xenogenic sera, allergenic extracts, dextrans, therapeutic enzymes, polypeptide hormones, penicillins and cephalosporins.•localized anaphylaxis affects only certain vasodilation smooth muscles most common is hayfever (allergic rhinitis) and asthma (localized brochial constriction)

Skin grids are useful for

detecting if a person will

respond to an allergen;

Risk of sensitizing

the individual as

well as leading to

shock.


3. Drugs that Affect TYPE I• -Antihistamines Block Hl&H2

receptors• -Cromolyn Sodium Blocks

Calcium influx• -Theophyllin Prolongs cAMP

levels (inhibits phosphodiesterases). Degranulation is increased by lowering levels of cAMP

• -Epinephrine Stimulates cAMP production through b-adrenergic receptor

• -Cortisone Blocks histimine production, stimulates mast cell cAMP production


· smooth muscle cells - Constriction· small blood vessels - Vasodilation · mucous glands - Mucous secretion· blood platelets · sensory nerve endings

Histamine Receptors(H1 and H2 receptors

Histamine Causes a Wide Array of Effects

Type I Hypersensitivity4. Therapeutic Immediate‑Hypersensitivity Antigens

Therapy for allergies based on hyposensitivity

Typical therapy depends on the injection of known quantities of an allergen in the hope of increasing the amount of IgG over IgE capable of reacting with the

allergen

IgG blocks the binding of the allergen with IgE

Type I Hypersensitivity: Immunomodulation

Type I HypersensitivityAllergen extracts, Aqueous & Glycerinated Antigen Source FDA licenses over 600 distinct allergen extracts as safe and effective for immunotherapy. Composed of proteins and other components ‑Foods: Chicken egg albumin, casein, almond, scallops, etc. ‑Animals: cat, dog, horse, rat, chicken, duck, pigeon feathers, etc. ‑Grasses: Kentucky blue, red top, perennial rye, Bermuda, fescue, etc. ‑Insects: Cockroach, house‑dust mite ‑Molds:Aspergillus, Rhizopus, etc. ‑Trees: White oak, cypress, cottonwood, maple, elm ‑Weeds:Ragweed, sagebrush, saltbush, wingsscalel, etc.Dosage and RouteProgressive, escalating dose, modified to patient needs; SCIndicationsTreatment of patients with allergies upon natural exposure to allergens.Effective against rhinitis, allergic asthma from cat, dog, grass, dust mite.Adverse ReactionsMost common cause of systemic anaphylaxis, managed by dosing with epinephrine and in some cases antihistimines.Efficacy7~90% of patients demonstrate improvement in symptoms within 12 weeks and continuing for 1‑2years

Allergen extracts, Aqueous & Glycerinated


Hymenoptera (Bee) Venom

Protein

Antigen Source • Venoms of the

following flying insects: Honey bee, Wasp, White‑faced hornet, Yellow hornet, Yellow jacket‑, Composed of purified venom.

Dosage and Route • Progressive,

escalating dose, modified to patient needs; SC

Indications • Treatment

of patients with history of systemic reaction to stings

• Adverse Reactions Anaphylaxis without warning within 20 mins. of injections, managed by dosing with epinephrine and in some cases antihistimines.

Efficacy • 97% of patients

have reduced anaphylaxis from stings, without therapy 60% will develop anaphylaxis with next sting.

Type I HypersensitivityBenzylpenicilloyl Polylysine

Antigen Source Hapten(Benzylpenicilloyl moiety‑polypeptide (lysine) containing Dosage and Route Sterile skin test area on upper or outer arm,

5‑10 mins. reaction time.

Indications Used to assses risk of administering benzylpenicillins (i.e., penicillin G)

Adverse Reactions Allergic reactions occur in <1% of recipients and is usually characterized by intense 1ocali inflammation.

Efficacy The test is 89‑96% sensitive and specific. Consequently, 4‑11%

of patients who test negative will react to treatment with penicillins.

Type II Hypersensitivity· Antibodies react with foreign antigens on surface of blood cells ‑

Blood groups are sugars connected to lipid (glycolipid) or protein (glycoprotein); have antibodies to groups that are lacking.

Blood Group Serum Abs (IgM)A anti‑BB anti-AAB noneO anti‑A

anti‑B

· Blood cells deemed to be foreign are removed by ADCC · Reason for blood transfusion reaction

· Other blood antigen Rhesus blood group (Rh(D); 85% are RhD+ and 15% are RhD-) results in Rh incompatability (erythroblastosis fetalis); treatable with RhoGam.

Type II HypersensitivityBlood Groups

Type II HypersensitivityBlood Group Compatability

Type II Hypersensitivity

Rh+

Rh-Placenta

Mother

FetusPlacenta

tearsduring Delivery

Rh iRBC

mRBC

Mother'sB-cell

Rh iRBCB-Cell

Mother's

Memory CellsPlasmacytes

IgM, IgG

SecondPregnancyRh iRBC

Mother's Anti-Rh

ADCC & ComplementDistruction of iRBC

Rhogam

Rh iRBC

Rhogam

Type II HypersensitivityRho(D) Immune Globulin (RhIG) Antigen Source Human erthrocytes with Rho(D) surface antigen. Production Process RhoD‑ men or sterile women are imunized with Rho(D) cells in order to produce anti‑Rho(D) antibodies. The antibodies are harvested from plasma collected from these donors. Indications Used for passive, transient protection against development of anti‑Rho(D) antibodies in nonsensitized Rho of negative persons woho receive Rho+ blood due to fetomaternal hemorrhage, aminocentesis, fetal surgery or manipulation, or transfusion accident. For administration during pregnancy: 1) the mother must be Rho(D)‑, 2) the mother should not have been previously sensitized to the Rh factor, 3) the infant must be Rho(D) + and direct antiglobulin negative, 4) If father is Rho(D) ‑, Rho(D)IG need not be givenDosage and Route One to multiple vials given the conditions; IM within 72 hours postpartum or exposure.Adverse Reactions Mild, transient pain at point of injection. Anaphylaxis is rareEfficacySensitizaiton rate is 12% to 13% without Rho(D)IG; if given 72 hours postpartum incidence drops to 1% to 2%; incidence if given 28 weeks gestation and immediately after birth then 0.1% and 0.7%

Type III Hypersensitivity

1. Mechanism

Large immune complexes are formed from

complement

Complexes are deposited on blood vessel

walls or tissues

Mast-cells

bind the complem

ent at specific receptors and are

activated

Neutrophils are attracted to the

site leading to tissue damage

1. Mechanism

Complement

Development of Complement

· There are three major biological activities associated with complement

1) Activation of phagocytes, including macrophages and neutrophils

2) Lysis of target cells

3) Opsonization (i.e., deposition of antibody and C3b) on microorganisms and immune complexes, for

recognition by cells with complement receptors

Complement

· The Complement system is a group of at least 20 proteins found in plasma

· The 20 proteins can be classified into two groups in two ways: as enzymes or non-enzymes or as components or regulators:

7 enzymes 13 components 20 proteins

13 non-enzymes 7 regulators

· components are part of a complex that forms at the site of complement fixation and results in punching holes in membranes.

Complement

. · there are two pathways:

(1) The Classical Pathway - initiated by bound antibody or antibodies

(2) The Alternative Pathway - initiated by bacterial cell surface components

· Both pathways undergo an amplification phase and converge on a final pathway

· Both generate a macromolecular membrane attack complex (MAC), which lyses a variety of cells, bacteria and

viruses.

Classical Pathway

.

Bacteriaor Tissue

Antigen

orIgM IgG

Or

C1qr2s2

Classical Pathway

.

Or

C1qr2s2C2 C4

C2a+C2b

C4+C4b

C2b•C4b

C3C3b + C3a

C2b•C4b•C3b

C2/C4 Convertase

C3 Convertase

Classical Pathway

.

C2b•C4b

C3C3b + C3a

C2b•C4b•C3b

C5C5b + C5a

Mast CellHistamine Release

C2b•C4b•C3b

Bacteriaor Tissue

Cell

C5b

C5 Convertase

Classical Pathway

C2b•C4b•C3b

Bacteriaor Tissue

Cell

C5b

C5b + C6 + C7 + C8

C2b•C4b•C3b

C5b•C6•C7•C8MACLoss of

MembraneIntegrity

Cell Lysis

Poly C9

C5b very LabileT1/2 = 2 minif C6 doesn’t

bind

Classical Pathway

Classical Pathway

.

MAC

or

Or

Bacteriaor Tissue

C2 C4

C2a+C2b

C4+C4b

C2b•C4b

C3C3b + C3a

C2b•C4b•C3b

C2b•C4b•C3b C5C5b + C5a

Loss ofMembrane

Integrity

C5b

Antigen

IgM IgG

C2b•C4b•C3b

C5b•C6•C7•C8

Bacteriaor Tissue

Cell

C5b + C6 + C7 + C8

Cell Lysis

Poly C9



C1qr2s2

Alternative Pathway

Bacteria or Tissue Cell

C3 C3b + C3a

C3b


C3b


Ba

BbB Factor

DBa

Bb•C3b


SpontaneousChemicalReaction

Sialic Acid on Surface of Mammalian

Tissues destabilizes C3b on surface.

Bacteria and yeast have very low levels

of Sialic acid on their surfaces.

Pp

Alternative Pathway

Bb•C3b


2 million C3b molecules areproduced on surface in 5 min

PpC3b•Bb•C3b Pp


C5C5b + C5a


C3b•Bb•C3bC5b Pp


C5 convertase

Alternative Pathway

C3b•Bb•C3bC5b Pp


C5b + C6 + C7 + C8

C2b•C4b•C3b

Poly C9

C5b•C6•C7•C8

MACLoss of

MembraneIntegrity

Cell Lysis

Alternative PathwayD

Ba

BaC3 C3b + C3a

C3b•Bb•C3b

C5C5b + C5a

C5b

C5b + C6 + C7 + C8



Pp

C3b


C3b•Bb•C3b

Pp

Bacteria or

Tissue Cell


C3b


Bb Bb•C3b


B Factor

C2b•C4b•C3b

Poly C9

C5b•C6•C7•C8

MACLoss of

MembraneIntegrity

Cell Lysis

Alternative Pathway


C3b

C3b Receptor

Phagocyte


Attack of Bystander Tissues

Bacteriaor Immune complex under

Complement Attack

Normal Tissues

Neutrophil/EosinophilAttraction and Attack

Examples: Serum Sickness, Arthus Reaction, Rheumatic Fever, Rheumatoid ArthritisFarmer’ and Pigeon’s Lung





Type IV Delayed Hypersensitivity

· Thought to be a response to tissue harboring bacteria or parasites.

· Occurs most commonly with topical agents which react with the skin (contact dermatitus), such as cosmetics, poison oak, chemicals (e.g., pentadecacatechol)

· Development of sensitized TDTH cells, which secrete cytokines capable of activating and attracting macrophages.


APC

TCR

TH-1MHCII-Peptide

CD4

CD3MHCIIPeptide

B7 CD28

TDTH

TDTH

Differentiation & Proliferation

APC Ag

Lymphatics

Langerhans Cells

Antigen

SkinAPC TDTH

Cytokines MacrophageAttraction

7-10 days 72 hr



E. Therapeutics Based on Type IV Hypersensitivity

• Type IV hypersensitivity is associated with several diseases and conditions, such as tuberculosis, leprosy, leishmaniasis, deep fungal infections, etc.

• Type IV is also associated with allergic reactions to contact antigens like poison ivy and poison oak


Allergen Patch Test KitAntigen Source Group of substances associated with contact dermatitis, such as benzocaine, phenylenediamine, lanolin, neomycin, epoxy resins, etc.Dosage and RouteApply from 1 to 20 allergens as a test battery to a patch test device; TopicalIndicationsFor accessment of contact dermatitisAdverse ReactionsMild and localized to the site, anaphylaxis rareEfficacy22% false positives


Poison Ivy Extract, for Oral DesensitizationAntigen SourceLeaf extracts from ToxicodendronDosage and RouteDaily ingestation of gradually increasing amounts of extract. Treatment should be started only when the patient is free of skin rash; oralIndicationsFor prevention of contact dermatitis, also called poison ivy or poison oak dermatitis.Adverse ReactionsPruritus ani (a burning sensation in the rectum) occurs briefly during the first weeks.EfficacyAdequately potent as judged by the FDA

Hypersensitivity Induced DrugImmunopathology

Each of the four Types of Hypersensitivity can lead to deleterious affects when a drug is administered.


Drug

Drug

Drug

DrugSensitizedMast Cell

SelfProtein

Type I= Can cause allergic anaphylactic reaction due to allergen complexation with sensitized Mast cell


Type II= Can cause blood cells that are labelled to be removed by complement or ADCC

RBC

Drug

DrugDrug

B-Celland/orAPC

ComplementInitiation


Type III= Can cause complement complexation which can lead to innocent bystander reaction in tissues where complexes lodge (i.e., kidney)

Tissue Space

IgM/Ag Complex


Type IV= Can cause tissues to be labelled (i.e., skin) and inducing cytotoxic T cell response

Drug

APC

TCR

TDTHMHCII-Peptide

CD4

CD3MHCIIPeptide

B7 CD28

Hypersensitivity Reactions:Take Home Message

1. Allergic or Hypersensitivity reactions result from an non-desirable immune response.

2. Both CMI and AMI are involved in allergic reactions.

3. Complement is an important part of the immune responses ability to combat bacterial infections.

4. Hypersentivity reactions are a major reseason for drug induced pathologies.

Health & Medicine

Allergic reactions