CASE

STUDY 5:
HYPERSENSITIVITY
Jasmine Reggiani, Victoria
Defelippe & Sinad Clarke

Thomas
9 year olf son of amateur bee keeper.
Bee s6ng
Angioedema on his face
Shortness of breath

Previous bee s6ngs:

Local swelling
Redness
Severe itching

Hypersensi6vity reac6ons

Classica6on proposed by Gell and Coombs.

Types I - IV
Humoral and cell-mediated
Iden6es pathogenic immune system, cells and
mediators involved.

Type I
IgE-mediated
Allergen induced
degranula6on of mast
cells and basophils
15 to 30 minutes
Allergic asthma, hay
fever, insect s6ng, food
allergies.

Kuby et al. Immunology 6th ed.

Type II
An;body-mediated
cytotoxic
An6body binds to cell
surface an6gen
ac6va6ng complement
or ADCC
IgM and IgG
Minutes to hours
Blood transfusion
reac6ons,
erythroblastosis fetalis
Kuby et al. Immunology 6th ed.

Type III
Immune complex-
mediated
hypersensi;vity
Accumula6on of immune
complexes in 6ssues >
ac6va6on of complement
-> neutrophil inltra6on
IgM and IgG
3 to 8 hours
Farmers lung disease,
Serum sickness
Kuby et al. Immunology 6th ed.

Type IV
Delayed-type
hypersensi;vity
Sensi6zed Th1 cells
Macrophages
48 to 72 hours
Gra] rejec6on,
granuloma

Kuby et al. Immunology 6th ed.

Thomas
Previous bee s6ng
Anaphylac6c shock
Smooth muscle contrac6on
Blood pressure drops
Edema

IgE-mediated hypersensi6vity
Time passes and mast cells
remain sensi;zed to allergen

Kuby et al. Immunology 6th ed.

Second exposure to allergen causes

faster and more severe response due
to sensi;za;on

Response
Histamine
Vasopermeability
Vasodila6on
Smooth muscle
contrac6on

Leukotrienes and
prostaglandins
More pronounced and
long las6ng eects

IL-3 and IL-4 s6mulate

Th2 response and
increase IgE produc6on
by B cells
IL-5 recruitment of
eosinophils
TNF- shock

Early

Late

15 to 30 minutes

4 to 6 hours 1 to 2 days

Cell types

Mast cells, basophils

Neutrophils, eosinophils,
basophils, macrophages, Th2
cells

Mediators

Histamine, ECF-A, NCF-A,

leukotrienes,
prostraglandins

IL-4, TNF-, PAF, IL-5, ECF

Eects

anaphylaxis or localized
hypersensi6vity reac6on
An6histaminics +
Epinephrine

Inamma6on 6ssue damage

Time frame

Treatment

Cor6costeroids

Thomas
Sensi6zed mast cells and basophils
Anaphylac6c shock
Smooth muscle contrac6on
Blood pressure drops
Edema

Treatment: an6histaminic
Block histamine receptors
Inhibit enzyma6c ac6vity of his6dine
decarboxylase

B or T cell deregula6on?

Kuby et al. Immunology 6th ed.

Gene;c component
Atopy: a hereditary predisposi6on to the development of
immediate hypersensi6vity reac6ons against common
environmental an6gens.
- 20% of the popula6on in developed countries
2 allergic parents 50% chance
1 allergic parent 30% chance
high levels of circula6ng IgE + elevated numbers of circula6ng
eosinophils
normal individuals: 0.1-0.4 micrometers/ml
atopic individuals: 10x normal concentra6on

 Chromosome 5 a variety of cytokines

including IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF
Chromosome 11 chain of the high-anity FceR1 IgE
receptor.
IgE responses have also been linked to MHC genes
(chromosome 6)
Other possibili;es: inamma6on genes + cytokine receptors
(IL-4 receptor) + T-cell deciency

IgE
Two heavy chains and two light chains
IgE produc6on by B cells
Allergen presenta6on by APCs +
coopera6on between B cells and TH2
cells.
Addi6onal constant region domain: C2
replaces the hinge region in IgG
Bind to glycoprotein receptors -
basophils and mast cells

 allergic subjects limited selec;on of VH

genes
variable region + the pamern of soma6c
hypermuta6on in heavy chains.

Half life of IgE (in the serum) -- 2-3 days

IgE on mast cells and basophils
Stable for a number of weeks
protects IgE from destruc6on by serum
proteases

Important characteris;c ability to bind to

a receptor on mast cells and basophils for
the Fc region

IgE Structure

Alberts, B., et al. (1983). Molecular Biology of the Cell. Garland Publishing, Inc., New York, NY.

FcRI
Mast cells + basophils (eosinophils,
Langerhans cells, monocytes + platelets)
High anity for IgE
Tetrameric receptor complex

1 alpha (FcRI), 1 beta (FcRI), 2 disulphide

connected gamma (FcRI)
ITAM mo6fs ( and chains)
FcRI interacts with both CH3 domains of one IgE
molecule (via two Ig-like domains of the receptor
chain).

 ITAM mo6f:
immunoreceptor tyrosine-
based ac6va6on mo6f
binds to protein tyrosine
kinases transduce an
ac6va6ng signal to the cell

Allergen-mediated cross-
linkage of bound IgE
results in aggrega6on of
FcRI + rapid tyrosine
phosphoryla6on
induces mast-cell
degranula;on
FcRII
Zhang, 2003.

FcRI + FcRII molecule

Kuby et al. Immunology 6th ed.

Mast cell degranula6on

Kuby et al. Immunology 6th ed.

How can the reac6on to the very same an6gen

dier per person?
Rela6ve levels of TH1 and TH2 key to regula6on
of type I hypersensi6ve reac6ons
TH1 reduce the response
Produce IFN-y (inhibits type I response)
TH2 enhance the response
Codes for interleukins
Including class switching, clonal
expansion regula6on, mast cell
produc6on
Atopic + nonatopic individuals qualita6vely
dierent type I responses to an allergen

Thomas (Epipen)
Thomas is given Epipen as take-home rst aid kit
Epinephrine autoinjector to prevent or treat
anaphylac6c shock onset
Maintains high cAMP levels in mast cells
High cAMP prevents degranula6on

Thomass future
In case of bee s6ng he has to be able to reach
a hospital within 30 mins
Can Thomas prevent another allergic reac6on?
Avoidance of allergen
Immunotherapy

Venom Immunotherapy (VIT)

Small, increasing doses of allergen administered
subcutaneously
AIM: s6mulate normalised immune response and
counteract hypersensi6vity
NEW: Sublingual Immunotherapy role of Lagerhans
Cells of oral mucosa

VIT protocol dura6on

Ultra-rush and Semi-rush
5 days
5 weeks

Maintenance dose
3 years

Hypersensi6vity-overview

Bonifazi, 2011.

VIT main players

Treg IL10 and TGF
IgG4
FcRI IgE high-anity receptor on
granulocytes
Histamine and receptors (HR2 and HR1)

Treg
Peripheral T-cell tolerance
Secre6ng IL-10 and TGF
Inhibits TH2
Inhibits IgE
Decrease FcRI

IL-10 class switch to IgG4

Marker for allergen introduc6on in VIT
Forms complex with an6gen for phagocytosis

Changes to FcRI
High-anity IgE receptor on granulocytes
Down-regulated expression during VIT
Before Maintenance Dose
Lack of FcRI No degranula6on No histamine
release

VIT overview

Bonifazi, 2011.

Eec6veness tests
IgG4 response to allergen
Skin tests
Venom-specic IgE/Total IgE

Hymenoptera venom immunotherapy. Bil BM, Bonifazi F.

Bibliography

Alberts, B., et al. (1983). Molecular Biology of the Cell. Garland Publishing, Inc., New
York, NY
Bieber, T. and Simon, H.-U. (2011), Allergen-specic immunotherapy: current
concepts and future direc6ons. Allergy, 66: 709712.
Bilo, MB. "Anaphylaxis Caused by Hymenoptera S6ngs: From Epidemiology to
Treatment." European Journal of Allergy and Clinical Medicine (2011)
Bonifazi, Floriano. "Hymenoptera Venom Immunotherapy." Future Medicine Ltd,
2011
Celesnik. "Short-term Venom Immunotherapy Induces Desensi6za6on of FcRI-
mediated Basophil Response." Short-term Venom Immunotherapy Induces
DesensiKzaKon of FcRI-mediated Basophil Response. University Clinic of
Respiratory and Allergic Diseases Golnik, Slovenia., Oct.-Nov. 2012.
Kuby, Janis, Thomas J. Kindt, Richard A. Goldsby, and Barbara A.
Osborne. Immunology. 6th ed. . New York: W.H. Freeman and Company, 2007.
371-397. Print.
Roim, Ivan M., Jonathan Brosto, and David K. Male. Immunology. London: Mosby,
1998. Print.
Zhang, Wenliang. "Hypersensi6vity Diseases." HypersensiKvity Diseases. University
of Georgia, Oct.-Nov. 2007. Web. 15 Feb. 2013.