allergic reactions, hypersensitivity

1. 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.

2. 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

3. Hypersensitivity Reactions

4. Type I Hypersensitivity: Sensitization
B-cell
MHCII-Peptide
MHCII
Peptide
B7
TCR
CD4
CD3
CD28
TH-2
Memory
B-Cell
Plasmacyte
IgE Production
MHCII
Peptide
B7

5. Type I Hypersensitivity: Sensitization
Plasmacyte
IgE Production
IgE Binding
to Mast Cell
Sensitized
Mast Cell
Fc/IgE
Receptor
Sensitized Mast Cell

6. Type I Hypersensitivity: Effector
Sensitized
Mast Cell
Calcium
Influx
Degranulation
(enzymes, histamine)
Histamine
Cytokines
Lipid Mediators
Eosinophil &
Neutrophil Attraction
Allergen

7. Type I Hypersensitivity

8. Type I Hypersensitivity

9. 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

10. 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

11. 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

12. Type I Hypersensitivity
Lipid
Mediators
: formed and
secreted after
mast cells 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
prostaglandins

13. 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

14. Type I Hypersensitivity
N
S CH3
CH3
CO2H
O
O
CO2H
SH
SH
Self
Protein
NH
S CH3
CH3
CO2H
S
O
CO2H
O
SH
Self
Protein

15. 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.

16. 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

17. 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

18. Type I Hypersensitivity
4. 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

19. Type I Hypersensitivity: Immunomodulation

20. Type I Hypersensitivity
Allergen 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 Route
Progressive, escalating dose, modified to patient needs; SC
Indications
Treatment of patients with allergies upon natural exposure to allergens.
Effective against rhinitis, allergic asthma from cat, dog, grass, dust mite.
Adverse Reactions
Most common cause of systemic anaphylaxis, managed by dosing with epinephrine and in
some cases antihistimines.
Efficacy
7~90% of patients demonstrate improvement in symptoms within 12 weeks and
continuing for 1-2
years
Allergen extracts, Aqueous & Glycerinated

21. 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.

22. Type I Hypersensitivity
Benzylpenicilloyl 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.

23. 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-B
B anti-A
AB none
O 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.

24. Type II Hypersensitivity
Blood Groups

25. Type II Hypersensitivity
Blood Group Compatability

26. Type II Hypersensitivity
Rh+
Rh-
Placenta
Mother
Fetus
Placenta
tears
during
Delivery
Rh iRBC
mRBC
Mother's
B-cell
Rh iRBC
B-Cell
Mother's
Memory Cells
Plasmacytes
IgM, IgG
Second
PregnancyRh iRBC
Mother's Anti-Rh
ADCC & Complement
Distruction of iRBC
Rhogam
Rh iRBC
Rhogam

27. Type II Hypersensitivity
Rho(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 given
Dosage 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 rare
Efficacy
Sensitizaiton 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%

28. 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 complement
at specific
receptors and are
activated
Neutrophils are
attracted to the
site leading to
tissue damage
1. Mechanism

29. 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

30. 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.

31. 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.

32. Classical Pathway
.
Bacteria
or Tissue
Antigen
or
IgM IgG
Or
C1qr2s2

33. Classical Pathway
.
Or
C1qr2s2
C2 C4
C2a
+
C2b
C4
+
C4b
C2b•C4b
C3C3b + C3a
C2b•C4b•C3b
C2/C4 Convertase
C3 Convertase

34. Classical Pathway
.
C2b•C4b
C3C3b + C3a
C2b•C4b•C3b
C5C5b + C5a
Mast Cell
Histamine Release
C2b•C4b•C3b
Bacteria
or Tissue
Cell
C5b
C5 Convertase

35. Classical Pathway
C2b•C4b•C3b
Bacteria
or Tissue
Cell
C5b
C5b + C6 + C7 + C8
C2b•C4b•C3b
C5b•C6•C7•C8
MAC
Loss of
Membrane
Integrity
Cell Lysis
Poly C9
C5b very Labile
T1/2 = 2 min
if C6 doesn’t
bind

36. Classical Pathway

37. Classical Pathway
.
MAC
or
Or
Bacteria
or Tissue
C2 C4
C2a
+
C2b
C4
+
C4b
C2b•C4b
C3C3b + C3a
C2b•C4b•C3b
C2b•C4b•C3b C5C5b + C5a
Loss of
Membrane
Integrity
C5b
Antigen
IgM IgG
C2b•C4b•C3b
C5b•C6•C7•C8
Bacteria
or Tissue
Cell
C5b + C6 + C7 + C8
Cell Lysis
Poly C9
Mast Cell
Histamine Release
Mast Cell
Histamine Release
C1qr2s2

38. Alternative Pathway
Bacteria or Tissue Cell
C3 C3b + C3a
C3b
Mast Cell
Histamine Release
C3b
Bacteria or Tissue Cell
Ba
Bb
B Factor
D
Ba
Bb•C3b
Bacteria or Tissue Cell
Spontaneous
Chemical
Reaction
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

39. Alternative Pathway
Bb•C3b
Bacteria or Tissue Cell
2 million C3b molecules are
produced on surface in 5 min
Pp
C3b•Bb•C3b Pp
Bacteria or Tissue Cell
C5C5b + C5a
Mast Cell
Histamine Release
C3b•Bb•C3bC5b Pp
Bacteria or Tissue Cell
C5 convertase

40. Alternative Pathway
C3b•Bb•C3bC5b Pp
Bacteria or Tissue Cell
C5b + C6 + C7 + C8
C2b•C4b•C3b
Poly C9
C5b•C6•C7•C8
MAC
Loss of
Membrane
Integrity
Cell
Lysis

41. Alternative Pathway
D
Ba
Ba
C3 C3b + C3a
C3b•Bb•C3b
C5C5b + C5a
C5b
C5b + C6 + C7 + C8
Mast Cell
Histamine Release
Mast Cell
Histamine Release
Pp
C3b
Bacteria or Tissue Cell
C3b•Bb
•C3b
Pp
Bacter
ia 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
MAC
Loss of
Membrane
Integrity
Cell Lysis

42. Alternative Pathway
Bacteria or Tissue Cell
C3b
C3b Receptor
Phagocyte

43. Type III Hypersensitivity
Attack of Bystander Tissues
Bacteria
or Immune complex under
Complement Attack
Normal Tissues
Neutrophil/Eosinophil
Attraction and Attack
Examples: Serum Sickness, Arthus Reaction, Rheumatic Fever, Rheumatoid Arthritis
Farmer’ and Pigeon’s Lung

44. Type III Hypersensitivity

45. Type III Hypersensitivity

46. Type III Hypersensitivity

47. Type III Hypersensitivity

48. 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.

49. Type IV Delayed Hypersensitivity
APC
TCR
TH-1
MHCII-Peptide
CD4
CD3
MHCII
Peptide
B7 CD28
TDTH
TDTH
Differentiation &
Proliferation
APC Ag
Lymphatics
Langerhans Cells
Antigen
SkinAPC TDTH
Cytokines Macrophage
Attraction
7-10 days 72 hr

50. Type IV Delayed Hypersensitivity

51. 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

52. Type IV Delayed Hypersensitivity
Allergen Patch Test Kit
Antigen Source Group of substances associated with
contact dermatitis, such as benzocaine, phenylenediamine,
lanolin, neomycin, epoxy resins, etc.
Dosage and Route
Apply from 1 to 20 allergens as a test battery to a patch test
device; Topical
Indications
For accessment of contact dermatitis
Adverse Reactions
Mild and localized to the site, anaphylaxis rare
Efficacy
22% false positives

53. Type IV Delayed Hypersensitivity
Poison Ivy Extract, for Oral Desensitization
Antigen Source
Leaf extracts from Toxicodendron
Dosage and Route
Daily ingestation of gradually increasing amounts of
extract. Treatment should be started only when the patient
is free of skin rash; oral
Indications
For prevention of contact dermatitis, also called poison ivy
or poison oak dermatitis.
Adverse Reactions
Pruritus ani (a burning sensation in the rectum) occurs
briefly during the first weeks.
Efficacy
Adequately potent as judged by the FDA

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

55. Hypersensitivity Induced Drug
Immunopathology
Drug
Drug
Drug
Drug
Sensitized
Mast Cell
Self
Protein
Type I= Can cause allergic anaphylactic reaction
due to allergen complexation with sensitized Mast
cell

56. Hypersensitivity Induced Drug
Immunopathology
Type II= Can cause blood cells that are labelled to be
removed by complement or ADCC
RBC
Drug
DrugDrug
B-Cell
and/or
APC
Complement
Initiation

57. Hypersensitivity Induced Drug
Immunopathology
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

58. Hypersensitivity Induced Drug
Immunopathology
Type IV= Can cause tissues to be labelled (i.e., skin)
and inducing cytotoxic T cell response
Drug
APC
TCR
TDTH
MHCII-Peptide
CD4
CD3
MHCII
Peptide
B7 CD28

59. 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.