2. The immune system multiple strategies to reduce damage to
self tissue by turning off responses when pathogen is cleared
However, these checks and balances can break down, leading
to immune-mediated adverse reactions that are more
detrimental – HYPERSENSITIVITY
Inappropriately vigorous innate and/or adaptive response to
antigens that pose little or no threat.
3. Paul Portier and Charles Richet
Vaccine against Toxin (8 kDa protein)
1st immunization in dog in very low dose - alive
2nd immunization in dog even in lesser dose – vomiting,
asphyxiation, and death immediately
Weeks later
Anaphylaxis as opposed to Prophylaxis
5. TYPE I Hypersensitivity
Classic allergy
•Mediated by IgE attached to the
surface of Basophil and Mast cells.
• The symptoms resulting from allergic responses are known as
anaphylaxis.
• Includes: Hay fever, asthma, eczema, bee venom stings, food
allergies.
6. General mechanism underlying an immediate type I
hypersensitivity reaction
1. Initial Exposure to an allergen activates TH2 cells that stimulate
B cells to form IgE-secreting plasma cells.
2. The secreted IgE molecules bind to IgE-specific Fc receptors
(FcRI) on tissue resident mast cells and blood basophils. (IgE is
polyclonal)
3. Second exposure to the allergen leads to cross-linking of the
bound IgE, triggering the release of pharmacologically active
mediators (vasoactive amines) from mast cells and basophils.
4. The mediators cause smooth muscle contraction, increased
vascular permeability, and vasodilation.
8. 1. IgE Antibodies (mediators)
1. K. Ishizaka and T. Ishizaka
2. Lowest conc. (0.1-0.4 µg/ml) in blood among all the Ab
classes in healthy and 1 µg/ml in allergic patients
3. Half life – 2-3 days (circulating) to weeks or months
(receptor bound)
4. P-K Ab or Reagins or Reaginic Ab
5. 190 kDa (two epsilon H-chains and 2 light chans)
9. P-K test could be neutralized by rabbit antiserum against
whole atopic human sera but not by rabbit antiserum specific
for the four human immunoglobulin classes known at that
time (IgA, IgG, IgM, and IgD)
Discovery by P-K reaction (wheal and flare
reaction)
12. 2. Allergens (triggers)
• Allergens are nonparasite antigens that can stimulate a
type I hypersensitivity response.
• Usually harmless but can elicit adverse reaction in
atopic individual
• Allergens bind to IgE and trigger degranulation of
chemical mediators.
14. Characteristics of allergens
• Usually small 15 to 40,000 Da MW proteins (?).
• Proteins or glycoproteins components
• Often enzymes (eg. protease) or Pathogen-associated
molecular patterns (PAMPs).
• Low dose of allergen
• Mucosal exposure.
• Most allergens promote a Th2 immune response.
17. Two phases of allergic response
1. Sensitization phase (priming but no symptoms)
First few exposures to allergens initiates immune
response that generates IgE isotype. Th2 cells required
to provide the IL-4 required to get isotype switching to
IgE. Mast cells are primed wit IgE on surface
2. Effector phase (allergic reaction occurs)
• Subsequent exposures when Allergen binds and
cross-links IgE to activate a signaling cascade with
tyrosine phosphorylation, Ca++ influx, degranulation and
release of mediators.
19. 3. The IgE Receptor, FcƐR
A. The High-Affinity IgE Receptor, FcƐRI
1. Mast cells and basophils
2. KD = 1–2X10^–9 M
3. 40,000 and 90,000 receptors on a single basophil
4. One α and one β chain and two identical disulfide-linked γ
chains
20. 1. CH3/CH3 and CH4/CH4 domains of IgE interacts with α chain
2. β chain spans the plasma membrane four times and is thought
to link the α chain to the γ homodimer.
3. γ-chain has a conserved sequence in its cytosolic domain
known as an immunoreceptor tyrosine-based activation
motif (ITAM)
4. ITAM interacts with protein tyrosine kinases to transduce an activating
signal to the cell.
5. Allergen binding cross-links the bound IgE that’s results in aggregation
of the FcRI receptors and rapid tyrosine phosphorylation, which initiates
the process of mast-cell degranulation
21. B The Low-Affinity IgE Receptor, FcƐRII (CD23)
1. KD = 1X10^–6 M
2. Interacts with only CH3/CH3 domain
of IgE
3. Allergen cross-linkage of IgE bound
to FcRII has been shown to activate B
cells, alveolar macrophages, and
eosinophils.
4. Soluble form (sCD23) can enhance
IgE-production by B-cells
22. IgE Cross-linkage Initiates Degranulation
IgE-mediated degranulation begins when an allergen
crosslinks IgE that is bound to the FcƐ receptor on the
surface of a mast cell or basophil.
In itself, the binding of IgE to FcRI apparently has no effect
on a target cell. It is only after allergen crosslinks the fixed
IgE-receptor complex that degranulation proceeds.
Monovalent allergen (one IgE epitope) cannot degranulate
Cross-linking of receptor is the critical step
Can be allergen or IgE-independent
25. 1. Allergen crosslinkage of bound IgE results in FcRI aggregation and activation of protein
tyrosine kinase (PTK). PTK phosphorylates phospholipase-C, which converts
phosphatidylinositol-4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and inositol
triphosphate (IP3). DAG activates protein kinase C (PKC), which along with Ca2+ triggers
microtubular assembly and the fusion of the granules with the plasma membrane. IP3 is
a potent mobilizer of intracellular Ca2+ stores.
2. Crosslinkage of FcRI also activates an enzyme that converts phosphatidylserine (PS) into
phosphatidylethanolamine (PE). Eventually, PE is methylated to form
phosphatidylcholine (PC) by the phospholipid methyl transferase enzymes (PMT I and
II). The accumulation of PC on the exterior surface of the plasma membrane causes an
increase in membrane fluidity and facilitates the formation of Ca2+ channels. The influx
of Ca2+ activates phospholipase A2, which promotes the breakdown of PC into lyso PC
and arachidonic acid. Arachidonic acid is converted into potent mediators: the
leukotrienes and prostaglandin D2.
3. FcRI crosslinkage also activates the membrane adenylate cyclase, leading to a transient
increase of cAMP within 15 seconds. A later drop in cAMP levels is mediated by protein
kinase and is required for degranulation to proceed. cAMP-dependent protein kinases
are thought to phosphorylate the granule-membrane proteins, thereby changing the
permeability of the granules to water and Ca2+. The consequent swelling of the
granules facilitates fusion with the plasma membrane and release of the mediators.
26.
27. Classification of type-1 hypersensitivity based on time of
onset of inflammatory reaction
1. Immediate early reaction (1st phase): within minutes of allergen
exposure and involvement of primary mediators eg. histamine,
leukotrienes, and prostaglandins released by basophils and mast
2. Late-phase reaction (2nd phase): hours after allergen exposure
when immeadiate reaction starts to subside. Cytokines (secondary
mediators eg. IL1, IL3, IL5, GM-CSF) released from mast cells
facilitate the influx, growth, and differentiation of eosinophil and
neutrophils. These inflammatory cells undergo further
degranulation.
3. 3rd phase: 3 days after allergen exposure and peak on day-4.
Degranulation of basophils stimulate tissue-resident fibroblast cells
to secret chemkines which in turn trigger degranulation of
eosinophils.
28. antibody-mediated (other than IgE)
Fc and complement
Type II hypersensitivity
Protective roles of Ab
1. ADCC (Tc cells)
2. Activation of complement system
3. Opsonin and phagocytosis
Adversely affect self or healthy cell instead of disputed cell
1. Cytotoxix mode
2. Non-cytotoxic mode
(autoimmunity)
34. Group A blood
A
B
Anti-B Ab induction
Tolerance
If a type A individual is transfused with blood containing type B
cells, a transfusion reaction occurs in which the anti-B
isohemagglutinins (IgG) bind to the B blood cells and mediate
their destruction by means of complement-mediated lysis.
35. Eg. 2: Hemolytic Disease of the Newborn
Maternal IgG antibodies specific for fetal blood-group antigens
cross the placenta and destroy fetal red blood cells
Erythroblastosis fetalis
36. Rhogam or Anti-D: Ab against Rh antigen
injected to mother 24-48 h after delivery to clear
fetal Rh+ RBCs before activation of B cells and
memory cells of mother.
Plasmapheresis: Mother’s blood
Cells Plasma with Rh+ Ab
Discarded
Fresh plasma
37.
38. Eg. 3: Drug-Induced Hemolytic Anemia
1. Antibiotics (e.g., penicillin, cephalosporin, and
streptomycin) nonspecifically adsorb to proteins on RBC
membranes, forming a complex similar to a hapten-carrier
complex.
2. Induce Ab formation.
3. Complement mediated RBC lysis and thus progressive
anemia.
4. Drug is withdrawn and anemia disappears.
39. Ab against the drug
Ab against the drug
+ RBC antigens
(recognized as
foreign body)
