Hypersensitivity

Disorders

Parameth Thiennimitr, M.D., Ph.D.

Department of Microbiology
Faculty of Medicine, Chiang Mai University
2016

Learning Objectives
- 4 types of hypersensitivity
- Immunological Mechanisms
- Important Clinical Syndromes
- Hypersensitivity Tests

DEVIL

GOD

Hypersensitivity Disorders
Hypersensitivity diseases = Disorders caused by
immune response
Classification of hypersensitivity disorders

Type I

IgE-mediated (immediate or anaphylactic)

hypersensitivity (= Allergy, Atopy)

Type II

Antibody-mediated hypersensitivity

Type III

Immune complex-mediated hypersensitivity

Type IV Cell-mediated (delayed-type) hypersensitivity

(DTH)

Causes of Hypersensitivity Diseases

Self antigen
(due to failure of self tolerance)
e.g. SLE

Microbes

Immune
responses to

(excessive reaction and

unusually persistent infection)

e.g. granuloma formation

in TB infection

Environmental
antigens
(20% of population react
against common antigen)
e.g. allergic to pollen
(Hay fever or allergic rhinitis)

Common Environmental Allergens

Inhaled allergen

Ingested allergen

Injected allergen

Contacted allergen

Type I
IgE-Mediated (Immediate)
Hypersensitivity

= Allergy

Risk factors for Allergy

= Genetics + Environment
Allergy

Parasitic
Infection

http://www.fortressbiotech.com/research-development/hygiene-hypothesis.cfm

More parasite, less allergy ??

Hygiene Hypothesis
Traditional lifestyle

microbes

Hygienic lifestyle
(Too clean)

TH1 dominate

TH2 dominate

Less allergy

More allergy

IFN-, TNF-

(IL-4, IL-5, IL-6)

Over-antibiotic use in an early life leads

to hypersensitivity disorders (and others)
antibiotic

Gut
microbiota

antibiotic

Gut
dysbiosis

asthma

TH 2

dominate
Infant
(< 1 year)
Toddler
(1-3 years)
Immune development
TH1 VS. TH2

eczema

obesity
Tamburini et al. Nat Med Rev, 2016

Type I Hypersensitivity:

IgE-mediated hypersensitivity
(1) The first
allergen
exposure
(2) APC uptakes
allergen

(8) Mast cell

releases
mediators
(3) T cell
activation

(TH2 cells)

(4) Activation of
IgE-producing
B cell

(7) Activation of
sensitized mast
cell

(6) The second

allergen
exposure

(5) IgE binds to FcR on mast

cells SENSITIZATION
(ready for the next encounter)

Type I Hypersensitivity:

Sensitization and Degranulation Phases

Sensitization phase
(1) First exposure
to the allergen

(2) Allergen
uptake by APC

(3) TH2-cell
activation

(4) IgE-specific
B cell activation

(5) IgE
binds to
FcR on
mast cell

Degranulation phase
(6) Second exposure
to the same allergen

(7) Activation of
sensitized mast cell

Symptoms of
allergy
(8) Mast cell
releases mediators
(histamine,
leukotrienes)

Non-IgE mediated Allergy

Physical stimuli
- Cold
- Heat
- Pressure

Anaphylatoxin
- C3a, C5a

Drug
- Codeine
- Morphine
- Iodinated radio contrast
dye

Others
- Inflammatory products
Reviewed in Yu Y et al, Eur J Pharmacol 2016

Mast cell degranulation

by the unknown certain
mechanisms?

Type I Hypersensitivity:

Immediate & Late Phase Reactions

Histamine and
lipid mediators

Cytokines

Immediate
reaction

Late phase
reaction

Vascular &
Smooth
muscle
response

Inflammation

Vascular &
Smooth
muscle
response

Inflammation

Type I Hypersensitivity:

Effector Cells: Mast cell, Basophil and Eosinophil

Mast cells

Basophil

Eosinophil

cytoplasmic granules contain

mediators of allergic reaction

Type I Hypersensitivity:

Biologic Functions of Mediators

Vasodilation
Histamines
Leukotrienes

Vascular leakage

Bronchoconstriction
Intestinal hypermotility

Mast cell
or
Basophil

Eosinophil

Cytokines
Lipid
mediators

Inflammation

Enzymes

Tissue damage

Cationic
granule
proteins

Killing parasite

Enzymes

Tissue damage

Type I Hypersensitivity:

Clinical Syndromes (I)

(1) Allergic Rhinitis

(2) Bronchial asthma

Vasodilatation and
increased vascular
permeability in nasal,
conjunctival mucosa

Sneezing

Watery rhinorrhea

Itching at nose, eyes

Difficult to breath (dyspnea)

Bronchial constriction (Contraction

smooth muscle at bronchus or bronchiole)

Type I Hypersensitivity:

Clinical Syndromes (II)

(3) Food Allergy

Activated GI mast cells

GI symptoms: nausea,
vomiting, diarrhea
Skin symptom: urticaria
Most common food allergens =
peanut, egg, shrimp, milk

(4) Anaphylaxis

- Life threatening
condition!
-

Systemic allergic reaction

Generalized vasodilatation
(CVS, Respi, GI systems)
Anaphylactic shock

Type I Hypersensitivity Testing:

Intradermal Skin Test (IDT)

Inject test-allergen + Tissue mast cell
15 minute

Wheal (edema from plasma leakage)

&
Flare (vasodilatation at edge of lesion)

Type I Hypersensitivity Testing:

Skin Prick Test (SPT)

http://www.medbroadcast.com/Procedure/GetProcedure/Allergy-Skin-Test

Type I Hypersensitivity Testing:

Provocative Test
Bronchoprovocative test
- For asthma diagnosis
- Pulmonary function test
after suspected antigen
challenge
spirometer

Oral food challenge

- For food allergy diagnosis
- Skin & GI symptoms after
suspected antigen
consumption

Type II
Antibody (IgG, IgM)-Mediated
Hypersensitivity

Type II Hypersensitivity:

Antibody (IgG,IgM)-mediated hypersensitivity (I)

(1) Antibody act as an opsonin to enhance phagocytosis

(2) Antibody forms immune complex then activate

complement system

Type II Hypersensitivity:

Antibody (IgG,IgM)-Mediated hypersensitivity (II)

(3) Antibody cause abnormal physiologic response
without cell damage

Antibody stimulates
receptor

Antibody inhibits
binding

Type II Hypersensitivity:

Drug-induced Hemolytic Anemia

penicillin drug

1. binding

2. Complement
binding

Normal RBC

RBC lysis

Abnormal RBC
(Penicillin-modified)

3. Phagocytosis by
macrophage

7. Complement
activation (C1-C9)
5. B cell activation

6. Plasma cell secretes

penicillin-specific IgG

4. TH2 cell activation

Type II Hypersensitivity:

Hemolytic Disease of the Newborn (HDN)

First Pregnancy
Rh- mother pregnant with Rh+ child

Second Pregnancy
Rh- mother pregnant with Rh+ child

Anti-Rh Ig
cross
placenta
First child is safe

Anti-Rh Ig in
maternal serum

Maternal anti-Rh IgG

Hemolytic
Maternal antiRh Ig binds to
Rh antigen on
fetal RBC

Type II Hypersensitivity Testing

Coombs Test (= Coombs test, Antiglobulin test)

Direct Coombs test (detect bound anti-RBC Ab)

Indirect Coombs test (detect free anti-RBC Ab)

http://en.wikipedia.org/wiki/Coombs_test

Type III
Immune Complex-Mediated
Hypersensitivity

Type III Hypersensitivity

Immune Complex-Mediated Hypersensitivity

Type III Hypersensitivity

Clinical Syndromes are Depend on Sites of Immune Complex Deposition

Arthus Reaction
Localized form of Immune Complex-Mediated Hypersensitivity
(1) Locally injected
antigen in immune
individual

(2), (3) Immune complex

formation and complement
activation leading to tissue
mast cell degranulation

(4) Local
inflammation

Injected Ag

Immune
complex

Mast cell

IgG

Immune
complex binds
to mast cell via
FcR

C5a bind to C5aR on

mast cell

Blood vessel
occlusion

Type III Hypersensitivity

Serum Sickness

Skin hemorrhage from vasculitis in serum sickness patient

Serum Sickness
Systemic and Transient form of Immune Complex-Mediated Hypersensitivity

7-14 days

Type III Hypersensitivity Testing

Immunofluorescence Microscopy in the

Detection of Immune Complex Deposition
Immunofluorescence microscope

Lumpy bumpy
deposits

Immune complex
deposition in the
glomeruli

Type IV
Cell-Mediated (Delayed-type)
Hypersensitivity (DTH)

Type IV Hypersensitivity:

Cell-Mediated (Delayed-type) hypersensitivity

(1) Cytokine-mediated inflammation (TH1 cytokines)
TH1 cytokines

Inflammatory
cells
Tissue damage

(2) T cell-mediated inflammation (CD8+ CTL)

Cell killing
(cytotoxic) and
tissue damage

Type IV hypersensitivity
Cell-Mediated (Delayed-type) Hypersensitivity
(1) Skin APCs uptake
antigen

(2) TH1 cell activation and

secrete TH1 cytokines

(3) More T cells and

phagocytes infiltration

antigen
APC

TH1

TH1
cytokines

Redness and Induration

Within 24-72

TH1 cells play a major role in type IV hypersensitivity

Activated
macrophage

TH1 cell
Chemokines Cytokines

Cytotoxin

IFN- = Interferon gamma

TNF- = Tumor necrosis
factor alpha
LT = lymphotoxin

Type IV Hypersensitivity:

Poison Ivy Contact Dermatitis

Skin protein

Pentadecacatechol
(hapten)
Poison Ivy

First exposure

Pentadecacatechol combined
with skin protein
(antigen)
Second exposure

7-10 days

TH1 cells

1-2 days
Ag-specific memory
TH1 cells

Many active TH1 cells

Type IV Hypersensitivity:

Delayed-type Hypersensitivity (DTH): Lung Granuloma Formation

Human
pulmonary
tuberculosis

Prolonged production of IFN-

and TNF- by TH1 cells

Mycobacterium
tuberculosis
(intracellular bacteria)

Granulomatous formation in
pulmonary TB patients lymph node

Granuloma formation
(Macrophage and
lymphocyte
infiltration)

Type IV Hypersensitivity Testing:

Purified Protein Derivative (PPD or Tuberculin) Skin Test

Intradermal
injection of
PPD

Wait for 24-72

Redness and
Induration

Mycobacterium
tuberculosis
(intracellular bacteria)

PPD (Purified protein

derivative)
= Poor defined mixture of
antigens from Mycobacterium
tuberculosis, M. bovis, or M.
avium
Interpretation: Diameter of induration
Human
pulmonary
tuberculosis

>10 mm = Positive

5-10 mm = Borderline
< 5 mm = Negative

Induration
diameter

Type IV Hypersensitivity Testing:

Skin Patch Test

Wait for
24-72 h

Positive
(Ag-Specific TH1 cells)
(Erythematovesicular lesion)

Testing allergens are spotted in

the separated area on the patch.

SUMMARY

References
1.

Abbas Ak, Litchman AH and Pillai S. Cellular and Molecular Immunology, 8th
ed. Philadelphia:Elsevier Sauder; 2014

2.

Abbas Ak, Litchman AH and Pillai S. Cellular and Molecular Immunology, 7th
ed. Philadelphia:Elsevier Sauder; 2012

3.

Murphy KP. Janeways Immunobiology. 8th ed. New York: Garland Science;
2012

4.

Parham P. The Immune System. 3rd ed. New York: Garland Science; 2009