allergic reactions
TRANSCRIPT
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
Type I Hypersensitivity
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
Type I Hypersensitivity
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
Type I Hypersensitivity
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
Type I Hypersensitivity
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
Type I Hypersensitivity
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
Type I Hypersensitivity
N
S CH3
CH3
CO2HO
O
CO2H
SH
SH
SelfProtein
NH
S CH3
CH3
CO2HS
O
CO2H
O
SH
SelfProtein
Type I Hypersensitivity
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.
Type I Hypersensitivity
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
Type I Hypersensitivity
· 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
Type I Hypersensitivity
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
Mast CellHistamine Release
Mast CellHistamine Release
C1qr2s2
Alternative Pathway
Bacteria or Tissue Cell
C3 C3b + C3a
C3b
Mast CellHistamine Release
C3b
Bacteria or Tissue Cell
Ba
BbB Factor
DBa
Bb•C3b
Bacteria or Tissue Cell
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
Bacteria or Tissue Cell
2 million C3b molecules areproduced on surface in 5 min
PpC3b•Bb•C3b Pp
Bacteria or Tissue Cell
C5C5b + C5a
Mast CellHistamine Release
C3b•Bb•C3bC5b Pp
Bacteria or Tissue Cell
C5 convertase
Alternative Pathway
C3b•Bb•C3bC5b Pp
Bacteria or Tissue Cell
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
Mast CellHistamine Release
Mast CellHistamine Release
Pp
C3b
Bacteria or Tissue Cell
C3b•Bb•C3b
Pp
Bacteria or
Tissue Cell
Bacteria or Tissue Cell
C3b
Bacteria or Tissue Cell
Bb Bb•C3b
Bacteria or Tissue Cell
B Factor
C2b•C4b•C3b
Poly C9
C5b•C6•C7•C8
MACLoss of
MembraneIntegrity
Cell Lysis
Alternative Pathway
Bacteria or Tissue Cell
C3b
C3b Receptor
Phagocyte
Type III Hypersensitivity
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 III Hypersensitivity
Type III Hypersensitivity
Type III Hypersensitivity
Type III Hypersensitivity
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.
Type IV Delayed Hypersensitivity
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
Type IV Delayed Hypersensitivity
Type IV Delayed Hypersensitivity
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
Type IV Delayed Hypersensitivity
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
Type IV Delayed Hypersensitivity
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.
Hypersensitivity Induced DrugImmunopathology
Drug
Drug
Drug
DrugSensitizedMast Cell
SelfProtein
Type I= Can cause allergic anaphylactic reaction due to allergen complexation with sensitized Mast cell
Hypersensitivity Induced DrugImmunopathology
Type II= Can cause blood cells that are labelled to be removed by complement or ADCC
RBC
Drug
DrugDrug
B-Celland/orAPC
ComplementInitiation
Hypersensitivity Induced DrugImmunopathology
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
Hypersensitivity Induced DrugImmunopathology
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.