OS 216: Hematopoiesis and the Immune Response
Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics
Dr. Cherie Ocampo-Cervantes
1
November 20, 2013
TOPIC OUTLINE
I.
II.
III.
IV.
V.
VI.
The Four Types of Hypersensitivity Reactions
Type I: Immediate Hypersensitivity
Type II: Antibody-Mediated Hypersensitivity
Type III: Immune Complex-Mediated Hypersensitivity
Type IV: Delayed Hypersensitivity
Allergic History and Physical Examination
A. History
B. Physical Examination
Legends:
From the Powerpoint presentation
From the lecturer and from other sources (textbook, Internet, etc.)
I. THE FOUR TYPES OF HYPERSENSITIVITY REACTIONS
A. INTRODUCTION
Figure 1. Types of Immune Responses
 Autoimmunity – failure of normal mechanisms or self-tolerance
resulting to reactions against one’s cell or tissues
 Reaction Against Microbes – may cause disease if the reaction is
excessive or if they are persistent
 Reaction Against Environmental Antigens – about 20% of the
population are abnormally responsive to environmental antigens
ALLERGENS
 Antigens that elicit immediate hypersensitivity
 Usually common environmental proteins and chemicals (e.g. food,
animal hair, dust mites, pollens, certain medication)
II. TYPE 1: IMMEDIATE HYPERSENSITIVITY
 IgE-mediated
 a rapid immunologic reaction occurring within minutes after the
combination of an antigen with antibody bound to mast cells in
individuals previously sensitized to the antigen
 may occur as a systemic disorder or as a local reaction
 The development of immediate hypersensitivity reactions is
dependent on the coordinated actions of a variety of chemotactic,
vasoactive, and spasmogenic compounds
Figure 2. Sequence of Events in Immediate Hypersensitivity
Immediate hypersensitivity reactions are initiated by the introduction of
an allergen, which stimulates TH2 responses and IgE production in
genetically susceptible individuals. IgE binds to Fc receptors (FcεRI)
on mast cells, and subsequent exposure to the allergen activates the
mast cells to secrete the mediators that are responsible for the
pathologic manifestations of immediate hypersensitivity.
(Release of cytokines by the mediators would result to late phase
reaction which happen 2-4hours after repeated exposure to the
allergen) (sorry di maedit ung pictue box na late phase)
Sequence of Events in Immediate Hypersensitivity
 Upon first exposure to an allergen, TH2 cells are activated stimulating
the B cells to produce IgE antibodies
 IgE binds to Fc receptors (FcεRI) on mast cells
 Upon subsequent exposure to an allergen, the allergen crosslinks to
IgE receptors on mast cells leading to its activation
 The activated mast cell releases the mediators (vasoactive amines
and lipid mediators) which leads to immediate hypersensitivity after
repeated exposure
Sensitization
 Occurs when a specific IgE antibody produced against the allergen
binds to the mast cell
Figure 3. Biological Effects of Mediators of Type 1
Hypersensitivity
Lorvin, Roms, Deni
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Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics
A. The Immediate and Late Phase Reactions (from Robbins, 2016)
Immediate or Initial Reaction
 Wheal and flare reactions
 Vasodilation, vascular leakage, and depending on the location,
smooth muscle spasm or glandular secretions.
 Changes usually become evident within 5 to 30 minutes after
exposure to an allergen and tend to subside in 60 minutes.
Late Phase Reaction
 Mainly inflammation and edema
 Occurs in allergic rhinitis and bronchial
 sets in 2 to 24 hours later without additional exposure to antigen and
may last for several days
 infiltration of tissues with eosinophils, neutrophils, basophils,
monocytes, and CD4+ T cells as well as tissue destruction, typically in
the form of mucosal epithelial cell damage
B. IMMEDIATE HYPERSENSITIVITY DISEASES
1. Anaphylaxis
 A life threatening response of a sensitized human that appears within
minutes after administration of a specific antigen
 Manifestations of anaphylaxis include the following:
o Wheals
o Respiratory Involvement

Laryngeal edema with or without bronchospasm

Bronchial asthma (BA): predisposed to severe lower airway
involvement

Difficulty in breathing due to airway constriction
o Cardiovascular

Lowered blood pressure

Cardiac malfunction

tachycardia
o Gastrointestinal

Diarrhea

Abdominal pain and vomiting
2. Allergic Rhinitis
3. Atopic Dermatitis (early phase)
4. Bronchial Asthma
5. Urticaria
C. DIAGNOSTIC TESTS
Anaphylaxis
 Diagnosis is clinical
 Laboratory tests are NOT specific for anaphylaxis
 Histamine
o Onset
 Total tryptase
o Obtain blood sample within 15min to 30hours of symptom onset
Allergy Tests
 Adjuncts to thorough exposure history that indicates the presence of
relevant IgE-mediated symptoms or signs and the physical exam
In Vivo Allergy Skin Test
 Most sensitive
 Most cost-effective
 Based on mast cell degranulation due to the patient’s skin’s being
exposed to specific allergens
 Wheals and flare reaction
OS 213
o Food allergy
o Drug allergy
o insect sting hypersensitivity
In Vivo Testing of Total Serum IgE
 identify persons with high likelihood of atopy
 should not be used as a diagnostic or screening test on its own
 measures total circulating IgE, and not amount of IgE responsible for
clinical symptoms
 variations of levels with age
 considerable overlap between normal and abnormal values
Antigen-Specific IgE
 ELISA
o Quantitatively measures IgE antibodies to specific allergens
 Inhaled allergens
 Food allergens
 Drugs
 Latex
Table 1. Comparative Advantage of Skin Tests VS In Vitro Tests
Comparative Advantage
Skin Tests
In Vitro Tests
 high sensitivity
 Inhaled allergens
 results
available
in  Food allergen
minutes
 no risk of anaphylaxis
 greater
selection
of  medications do not effect results
allergen
(not
necessary
to
withhold
 cheaper than in vitro tests
antihistamine, unlike in skin test)
 minimal
equipment  not dependent on skin condition
needed
 convenient for patient afraid of
needles
 perceived by patients as more
scientific
D. TREATMENT
 Antihistamines – against biologic amines
 Bronchodilators (B2 agonist) – for bronchoconstriction
 Steroids (topical, inhaled, intranasal, oral)– addresses
inflammation
 Epinephrine IM – drug of choice for anaphylaxis (IMPORTANT)
o 0.01mg/kg of a 1mg/mL (1:1000) aqueous dilution
o Adults: 0.5mg maximum
o Children: 0.3mg maximum
the
E. MANAGEMENT
 Allergen avoidance
F. IMMUNOTHERAPY OR DESENSITIZATION
 For IgE-mediated reactions
 Administration of increasing doses of the allergen to induce a shift
from TH2 to TH1
III. TYPE II: ANTIBODY-MEDIATED (Hypersensitivity)



Hypersensitivity reaction produced by antibodies that react with
antigens present on cell surfaces or in the extracellular matrix
Antigenic determinants may be intrinsic to the cell membrane or
matrix or an exogenous antigen (i.e. drug metabolite)
Results from the binding of antibodies to normal or altered cell
surface antigens
A. ANTIBODY-MEDIATED DISEASES



Produce by antibodies that bind to antigens in particular cells or
extracellular tissues
Often not systemic
Usually autoantibodies
o May occasionally be produced against a foreign antigen that is
immunologically cross-reactive with a component of self tissues
Figure 4. Skin Allergy Tests
In Vivo Allergy Skin Test Indications
 Documentation of allergic sensitivity to specific allergens in patients
with:
o Asthma
o Rhinitis
o Eczema
o Urticaria
Lorvin, Roms, Deni
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Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics
OS 213
Figure 8. Abnormal Physiologic Responses w/o cell/tissue Injury
(Left) Grave’s Disease- antibodies against the thyroid-stimulating
hormone receptor on thyroid epithelial cells stimulate the cells,
resulting in hyperthyroidism. antibodies overstimulate receptors and
cause excessive production of TSH
 (Right) Myasthenia gravis- antibodies reactive with acetylcholine
receptors in the motor end plates of the skeletal muscles block
neuromuscular transmission and therefore cause muscle weakness.
Antibodies inhibit binding of acetylcholine receptors, causing
myasthenia gravis.
 Autoimmune urticaria- positive to IgG antibodies against these
possible self-antigens:
o IgG
o Alpha subunit of the high affinity IgE
o complex formed by anti-IgE
Leads to degranulation of mast cell and the resultant release of
histamine, Test using the plasma-serum skin test.

Figure 5. Antibody-Mediated Diseases. The antibodies can bind to
tissue antigens and the deposited antibodies can induce inflammation
leading to tissue injury.
B. 3 MECHANISMS OF ANTIBODY-MEDIATED DISEASES
OPSONIZATION AND PHAGOCYTOSIS
 IgG or complement fragments are attached to cell surfaces, making
the cell more attractive to phagocytes, thus increasing the efficiency
of phagocytosis and eventually the cell is engulfed
 Autoimmune Hemolytic Anemia
 Autoimmune Thrombocytopenic Purpura- individuals produce
antibodies against their own blood cell which are then destroyed
 Hemolysis in transfusion reactions- cells from an incompatible
donor react with and are opsonized by preformed antibodies in the
host
 2015: Opsonins are molecules that target antigens for an immune
response (e.g. antibodies like IgG and IgM, components of
complementary system C3b, C4b, mannose-binding lectin).
Opsonization is the process by which bacteria are altered by
opsonins so as to become efficiently engulfed by phagocytes
Figure 9. Autoimmune urticaria. The patient’s serum and plasma
are injected intradermally to the patient’s skin.
IV. TYPE III: IMMUNE COMPLEX MEDIATED

Figure 6. Opsonization and Phagocytosis.
COMPLEMENT
AND
Fc
RECEPTOR-MEDIATED
INFLAMMATION
 Antibodies that are deposited in the tissues recruit neutrophils and
macrophages, which bind to antibodies
 Neutrophils are activated and their products induce acute
inflammation and tissue injury
 Example: Antibody-mediated Glomerulonephritis (also known as
Goodpasture Syndrome)
Figure 7. Complement Fc Receptor Mediated Inflammation.
ABNORMAL
PHYSIOLOGIC
CELL/TISSUE INJURY
RESPONSES
WITHOUT


Antigen-antibody complexes produce tissue damage mainly by
eliciting inflammation at the sites of deposition.
Can be systemic or localized to particular organs.
The disease-causing immune complexes may be composed of
antibodies bound to either self-antigens or foreign antigens,
PHYSIOLOGY
 Antigens injected to the patient put him in the zone of antigen
excess
 As the patient starts to develop antibodies against that antigen,
antigen-antibody complexes are formed, which is the zone of
equivalence
 Later in the immune response, antibody production surpasses
antigen concentration, which leads to the zone of antibody excess
 Antibodies formed at the zone of equivalence are large and
insoluble. These are readily taken up by phagocytosis of cells and
are therefore eliminated by phagocytes.
PATHOLOGY
 The pathology occurs when the antigen continues to be present in
high quantities. the antigen-antibodies complexes are still formed
but they become slightly more soluble and less likely to be taken uo
by the phagocytes. they can trigger inflammatory complexes and
lead to increased vascular permeability and deposition of immune
complexes on tissues, the pathologic sequel of tissue damage
occurs.
 Antigen-antibody complexes cause disease when:
o produced in excessive amounts
o not efficiently cleared
o deposited in tissues
 This can be clinically present as vasculitis, which can occur in skin
and joints. Glomerulonephritis can also occur.
LOCAL IMMUNE COMPLEX DISEASE
1. Arthus Reaction
 Induced by injecting an antigen subcutaneously into a previously
immunized animal
 Localized form of experimental immune complex mediated vasculitis
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Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics
OS 213
A. TYPE IVA





Figure 10. Arthus Reaction. The deposition of immune complezes in
local tissues causes a local inflammatory response known as an Arthus
reaction (Janeway).
B. TYPE IVB


2. Pneumonitis caused by Hypersensitivity
SYSTEMIC IMMUNE COMPLEX DISEASE
 Acute Serum Sickness
 SLE
 Post-streptococcal glomerulonephritis
 Vasculitis- polyarteritis nodosa in chronic hepatitis
NEWER TREATMENT MODALITIES
 Most important: Remove the offending agent
 Anti-inflammatory agents (steroids, NSAIDS)- for serum sickness
 Monoclonal anti-C5 antibody
 Rituximab (anti-CD20 antibody) for antibody suppression)- depletes
B cells
 Intravenous immunoglobulin (IVIG)- competes with FCyR in blocking
platelet destruction in idiopathic thrombocytopenic



Also called cell-mediated hypersensitivity
Four general subtypes: Types IVA, IVB, IVC, and IVD based on T
cell subpopulation involved
T lymphocytes respond against an antigen and usually induce a
chronic inflammatory reaction
o These cells, sensitized after contact with a specific antigen, are
activated by reexposure to the antigen; they damage tissue by
direct toxic effects or through release of cytokines, which
activate eosinophils, monocytes and macrophages, neutrophils,
or killer cells depending on type.
o NOTE: For each subtype, take note of the highlighted cell and
chemical mediators and also the disorders involving these
reactions
Type 2 helper T cell (Th2) and eosinophil-mediated immune
response
TH2-type T cells, upon presentation of antigens, secrete cytokines
(IL-4, IL-13 and IL-5) which promote B cell IgE and IgG4 production,
deactivate macrophages and cause activation of mast cells and
eosinophils
High production of cytokines leads to chronic inflammation, which
eventually leads to tissue injury and fibrosis
Examples:
o chronic allergic rhinitis
o chronic asthma
o chronic atopic dermatitis
o maculopapular exanthema with eosinophilia
C. TYPE IVC


V. TYPE IV: DELAYED-TYPE HYPERSENSITIVITY (DTH)


Type 1 helper T cell (Th1) and monocyte-mediated immune
reactions
Soluble protein antigens processed by macrophages and dendritic
cells, which are then presented to TH1 lymphocytes
TH1 lymphocytes, after multiplying and migrating to the dermis, in
return, will release interferon-γ, TNF-β and IL-2 (proinflammatory
cytokines)
Interferon-γ from TH1 cells will activate surrounding macrophages,
which will then release prostaglandins, leukotrienes, ROS, NO,
cytokines and chemokines – inflammatory response
Examples:
o tuberculin tests
o contact dermatitis to rubber slippers
Cytotoxic CD8+ T cell mediated with cytokines perforin,
granzyme B, and Fas ligand
Examples:
o Contact dermatitis
o Steven-Johnson Syndrome (bullous reaction) and Toxic
Epidermal Necrolysis
o Most drug-induced delayed hypersensitivity reactions
o Macropapular and bullous exanthems
D. TYPE IVD





CD4+ and CD8+ T cell and neutrophil-mediated with cytokines IL8 and GM-CSF
TH17 T-cells act as effector cells
Emigrate to tissues and can kill tissue cells (ex. hepatocytes,
keratinocytes)
TH17 cells release IL-17, which then induce cytokine production in
other surrounding cell types (ex. fibroblasts) and neutrophil
migration
Examples:
o Psoriasis
o Behcet’s disease
o Acute generalized exanthematous pustulosis (AGEP)
E. DIAGNOSTICS FOR TYPE IV HYPERSENSITIVITY
PATCH TESTING
 Measure of delayed hypersensitivity reaction
 Artificially attempts to reproduce the clinical symptoms of the patient
 Helps to determine provocative antigens
 Sensitivity and specificity of 70%
VI. ALLERGIC HISTORY AND PHYSICAL EXAMINATION
A. HISTORY


Figure 11 . DTH Subtypes. Please refer to this figure as you go through
DTH. This concisely covers the four DTH subtypes. But if you want more
details (higher learning!), please see the low quality pictures in the
handout in UVLE.
Lorvin, Roms, Deni
Single most important in diagnosing allergic disorders
Focused allergic history consists of:
o Symptoms
o Alleviating/exacerbating factors
o Family History
o Environmental History
o Psychosocial Issues (stress may aggravate allergies)
SYMPTOMS
 Age of onset
 Duration of illness
 Time of occurrence (morning, afternoon, evening, dawn)
o Urticaria usually occurs in the afternoon or evening
o Nocturnal cough in asthma
 Pattern of occurrence (perennial, episodic, seasonal)
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Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics
o Episodic – dust mite or cockroach
o Seasonal - pollens
Ocular Symptoms (can be a
accompanied
by
allergic
conjunctivitis)
 Pruritus
 Photophobia
 Lacrimation
 Angioedema (e.g. NSAID
allergy)
 Congestion
Throat Symptoms
 Throat pruritus
 Post-nasal drip
 Cough
 Palatal Itch
 Throat clearing
 Soreness
 Hoarseness
Lung Symptoms
 Dyspnea
 Chest tightness
 Wheezing
 Expectoration
 Gurgly chest (halak)
Ear Symptoms
 Pruritus
 Angioedema
 Discharge
 Fullness
 Otitis media (complication of
allergic rhinitis)
Nasal Symptoms
 Sneezing
 Pruritus
 Rhinorrhea
 Congestion
 Sniffing
 Anosmia
Skin Symptoms
 Pruritus
 Wheal
 Macule/patch
 Papule/plaque
 Vesicle/bulla
 Hyper- or hypopigmentation
PRECIPITATING/EXACERBATING FACTORS






Dust
Strong odors
o Exhaust fumes
o Perfumes
o Cigarette smoke
Changes in temperature
Changes in weather
Sweat
Bath – hot or cold







Exercise
Respiratory infections
Emotions
Stress
Hormonal changes
o Pregnancy
o Menstruation/menopause
Food
Medications
ASSOCIATED SYMPTOMS
 Headache
 Paranasal pain
 Maxillary fullness
 Nausea
 Vomiting



OS 213
Dizziness
Abdominal pain
Joint pain (may indicate an
autoimmune disease)
Orthopnea
Jaundice (can be due to drug
allergy)


PAST MEDICAL HISTORY
 Previous consults, work-up, surgeries and procedures
 Previous and current medications, dose, and frequency, duration
and response to treatment
 Other medical problems
FAMILY MEDICAL HISTORY
 Allergies have a strong hereditary link
 One parent: 40% risk
 Both parents: 60-80% risk
ENVIRONMENTAL HISTORY
 Manner of cleaning (broom, moist rag, vacuum cleaner)
 Dust-collecting fixtures (curtains, drapes, carpet, books, clothing,
stuffed toys, screens, upholstery)
 Beddings
o Pillow material (kapok, down feathers, cotton, foam)
o Blanket material (Wool, cotton, flannel)
 Ventilation (air conditioning, electric fan, open windows) and
humidity (damp, dry or dusty)
 Presence of pests/pets
 Yard and vicinity (trees, vacant lots, busy streets, factory fumes and
smoke)
 School or workplace (dusty books or papers, chemical fumes, chalk
dust, ventilation and humidity)
 Activities (indoor deskwork, field work, manual labor, prolonged sun
exposure, sports and exercise)
 Psychosocial issues – stress may aggravate allergies
B. PHYSICAL EXAMINATION
ANTHROPOMETRICS AND VITAL SIGNS
 Weight and height
 Stunting or muscle wasting
 Vital signs: BP, HR, RR, temperature
HAIR AND SCALP
 Alopecia
 Cradle cap - infantile or neonatal seborrhoeic dermatitis
Figure 12 . The Atopic March. It refers to natural history of atopic
manifestations, which is characterized by a typical sequence of
immunoglobulin E (IgE) antibody responses and clinical symptoms that
appear early in life, persist over years or decades, and often remit
spontaneously with age.
SKIN
 Xerosis (abnormal dryness)
 Keratosis pilaris (“chicken
skin”)
 Macules, papules, nodules,
and wheals
 Excoriations, lichenifications
 Mucosal involvement (i.e.
Stevens-Johnson Syndrome)





Pityriasis alba (dry, finescaled, pale patches on the
face)
Ichthyosis
Patches, plaques, tumors, and
urticarial
Hyper– and hypopigmentation
Nikolsky sign (for pemphigus
vulgaris) – the epidermis
detaches when you stroke the
skin
EYES
 Conjunctival injection
 Icteric sclerae
 Allergic shiners (in allergic rhinitis)
 Cobblestoning
 Tearing
 Dennie-Morgan fold (fold or line in the skin
lower eyelid caused by edema in atopic dermatitis)
below
the
EARS
 Check pinnae, ear canal, tympanic membrane
 Check for discharge
Figure 13 . Drug allergy. The most recently introduced drug is usually
the culprit. In this case, it is cotrimoxazole.
Lorvin, Roms, Deni
NOSE
 Allergic salute – the gesture of wiping of the nose in an upward
movement using the palm, the back of the hand or the fingers
 Nasal crease – formed along the border between the cartilaginous
and bony parts of the nasal bridge, due to the constant wiping of the
nose, especially when the patient has a habit of doing the allergic
salute
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Lec 02: Hypersensitivity and Allergic History, Physical Examination and Diagnostics


Bunny red nose
Alar flaring
NASAL TURBINATES
 Pink/pale
 Congested
 Boggy
 Polypoid
 Check if the left, right, or both turbinates have the same
characteristics
NASAL DISCHARGE
 Check whether it is watery, mucoid, purulent, or bloody
THROAT
 Cobblestoning (in chronic post-nasal drip)
 Hyperemia
 Tonsillar hypertrophy
 Post-nasal drip
ORAL CAVITY
 Cheilitis – inflammation of the lips
NECK AND THYROID
 Thyromegaly (thyroiditis from urticaria)
CHEST AND LUNGS
 Use of accessory muscles
 Breath sounds (decreased, hyperresonant)
 Adventitious sounds (rales, wheezing, rhonchi)
APPENDIX A: TYPES OF HYPERSENSITIVITY REACTIONS
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HEART
 Check for presence of irregular rhythms or murmurs
ABDOMEN
 Check for hepatomegaly, splenomegaly, or both
EXTREMITIES
 Palmar hyperlinearity, edema, joint swelling, dry palms
OTHERS
 Lymphadenopathies
 Headlight sign
o For atopic dermatitis patients, the nose is spared from the
spread of itch making it appear to have lighter color than the
surrounding skin
END OF TRANSCRIPTION
Greetings!
LORVIN: Hello!
ROMS: Hi!
DENI: Hi! AFTG!
Types 1, 2, 3 = antibody-mediated
Type 4 = T-cell mediated
Lorvin, Roms, Deni
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