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Food Allergy:
Symptoms and
Immunological Mechanisms
Janice M. Joneja, Ph.D., R.D.
2007
Symptoms of Food Allergy
• Controversy among practitioners because there are
no definitive tests for food allergy
• “Allergic diathesis” defined as:
– Rhinoconjunctivitis (hayfever)
– Asthma
– Atopic dermatitis (eczema)
• Other conditions, especially in the digestive tract
and nervous system are considered more
“subjective” and many practitioners dismiss them
as “fictitious” or psychosomatic
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Examples of Allergic Conditions
and Symptoms
• Respiratory Tract
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–
–
–
Seasonal or perennial rhinitis (hayfever)
Rhinorrhea (runny nose)
Allergic conjunctivitis (itchy, watery, reddened eyes)
Serous otitis media (earache with effusion) [“gum ear”;
“glue ear”]
– Asthma
– Laryngeal oedema (throat tightening due to swelling of
tissues)
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Examples of Allergic Conditions
and Symptoms
• Skin and Mucous Membranes
– Atopic dermatitis (eczema)
– Urticaria (hives)
– Angioedema (swelling of tissues, especially mouth
and face)
– Pruritus (itching)
– Contact dermatitis (rash in contact with allergen)
– Oral allergy syndrome (irritation and swelling of
tissues around and inside the mouth)
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Examples of Allergic Conditions
and Symptoms
• Digestive Tract
–
–
–
–
–
–
–
Diarrhea
Constipation
Nausea and Vomiting
Abdominal bloating and distension
Abdominal pain
Indigestion (heartburn)
Belching
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Examples of Allergic Conditions
and Symptoms
• Nervous System
–
–
–
–
–
–
–
–
–
–
Migraine
Other headaches
Spots before the eyes
Listlessness
Hyperactivity
Lack of concentration
Tension-fatigue syndrome
Irritability
Chilliness
Dizziness
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Examples of Allergic Conditions
and Symptoms
• Other
–
–
–
–
–
–
–
–
Urinary frequency
Bed-wetting
Hoarseness
Muscle aches
Low-grade fever
Excessive sweating
Pallor
Dark circles around the eyes
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The Allergic Diathesis
Atopic dermatitis
(Eczema)
.
Gastrointestinal
symptoms
Nervous system:
Headaches
Irritability
Food Allergy
Asthma
(cough;
wheeze)
Muscle pain
Allergic
rhinoconjunctivitis
(hay fever)
Anaphylaxis
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Anaphylaxis
• Severe reaction of rapid onset, involving
most organ systems, which results in
circulatory collapse and drop in blood
pressure
• In the most extreme cases the reaction
progresses to anaphylactic shock with
cardiovascular collapse
• This can be fatal
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Anaphylaxis
• Usual progress of reaction
– Burning, itching and irritation of mouth and oral tissues
and throat
– Nausea, vomiting, abdominal pain, diarrhea
– Feeling of malaise, anxiety, generalized itching,
faintness, body feels warm
– Nasal irritation and sneezing, irritated eyes
– Hives, swelling of facial tissues, reddening
– Chest tightness, bronchospasm, hoarseness
– Pulse is rapid, weak, irregular, difficult to detect
– Loss of consciousness
– Death may result from suffocation, cardiac arrhythmia,
or shock
10
Anaphylaxis
• Up to a third of cases of anaphylaxis occur in response to
foods
• Not all symptoms occur in each case
• Symptoms may appear in any order
• Severe reactions occur within minutes to up to an hour of
ingestion of allergen
• Onset can be delayed for up to two hours
• The later the onset of symptoms after eating the food, the
less severe the reaction
• In majority of cases of fatal anaphylactic reaction to food,
patient was asthmatic
• Potential for anaphylaxis increases when patient is
receiving desensitization injections and is allergic to wasp
and bee venom
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Anaphylaxis
• Almost any food can cause anaphylactic reaction
• Some foods more common than others:
•
•
•
•
•
Peanut
Tree nuts
Shellfish
Fish
Egg
– In children under three years
•
•
•
•
Cow’s milk
Egg
Wheat
Chicken
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Exercise-induced Anaphylaxis
• Usually occurs within two hours of eating the
allergenic food
• Onset during physical activity
• Foods known to have induced exercise-induced
anaphylaxis:
–
–
–
–
–
Celery
Shellfish (shrimp; oysters)
Squid
Peaches
Wheat
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Emergency Treatment for
Anaphylactic Reaction
•
•
•
•
•
Injectable adrenalin (epinephrine)
Fast-acting antihistamine (e.g. Benadryl)
Usually in form of Anakit® or Epipen®
Transport to hospital immediately
Second phase of reaction is sometimes fatal,
especially in an asthmatic
– Patient may appear to be recovering, but 2-4 hours
later symptoms increase in severity and reaction
progresses rapidly
14
Definition of Terms
European Academy of Allergy and Clinical Immunology
2001
• Allergy is a hypersensitivity reaction initiated by
immunologic mechanisms
• An adverse reaction to food should be called food
hypersensitivity
– When immunologic mechanisms have been
demonstrated, the appropriate term is food allergy
– If the role of IgE is highlighted, the correct term is IgEmediated food allergy
– All other reactions, previously sometimes referred to as
“food intolerance”, should be referred to as nonallergic
food hypersensitivity
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Definition of Terms
(continued) European Academy of Allergy and Clinical Immunology
2001
• Severe, generalized allergic reactions to food can
be classified as anaphylaxis
• Anaphylaxis is a severe, life-threatening,
generalized or systemic hypersensitivity reaction.
• Atopy is a personal or familial tendency:
– to produce IgE antibodies in response to low doses of
allergens, usually proteins
– and to develop typical symptoms such as asthma,
rhiniconjunctivitis (hay fever) or eczema/dermatitis
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Food Allergy & Food Intolerance
DEFINITIONS: American Academy of Allergy and Immunology Committee on Adverse
Reactions to Foods, 1984
Food Allergy
Food Intolerance
“A generic term
“An immunologic
describing an abnormal
reaction resulting
physiological response
from the ingestion
to an ingested food or
of a food or
food additive which is
food additive”
not immunogenic”
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T- Cell Lymphocytes
• T cell lymphocytes are the “controllers”
of the immune response
• There are two major classes of T cells,
differentiated on the basis of their cell
surface receptors:
– Helper T cells (Th)
• Express CD4 receptor (CD4+)
• Act in conjunction with MHC class II molecules
– Cytotoxic (Tc) and Suppressor (Ts) T cells
• Express CD8 receptor (CD8+)
• Act in conjunction with MHC class I molecules
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Immune Response in Allergy
The Hypersensitivity Reactions:
Antigen Recognition
• The first stage of an immune response is
recognition of a “foreign antigen”
• T helper cells (CD4+ subclass) identify the
foreign protein as a “potential threat”
• Cytokines are released
• The types of cytokines produced control the
resulting immune response
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T-helper Cell Subclasses
• There are two subclasses of T-helper cells,
differentiated according to the cytokines they
release:
– Th1
– Th2
– Each subclass produces a different set of
cytokines
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Significant Cytokines of the T-Cell Subclasses
• Th1 subclass produces:
» Interferon-gamma (IFN-)
» Interleukin-2 (IL-2)
» Tumor necrosis factor alpha (TNF)
» IL-12
• Th2 subclass produces:
» Interleukin-4 (IL-4)
» Interleukin-5 (IL-5)
» Interleukin-6 (IL-6)
» Interleukin-8 (IL-8)
» Interleukin-10 (IL-10)
» Interleukin-13 (IL-13)
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T-helper cell subtypes
• Th1 triggers the protective response to a
pathogen such as a virus or bacterium
– IgM, IgG, IgA antibodies are produced
• Th2 is responsible for the Type I
hypersensitivity reaction (allergy)
– IgE antibodies are produced
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TH1
TH2 Interactions
Factors promoting:
Th1
- Bacterial and viral infections
- Maturation of the immune system
- Antigen tolerance
Th2
- Parasite infestations
- Immature immune system
- Sensitization to antigen
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TH1
TH2 Interactions
Factors promoting:
Th1
- Bacterial and viral infections
- Maturation of the immune system
- Antigen tolerance
Th2
- Parasite infestations
- Immature immune system
- Sensitization to antigen
Predisposing factors:
- Genetic inheritance
- Early exposure to allergen
- Increased antigen uptake
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T-Cells in the Immune and
Allergic Response
Stage 1: Protein enters
• Antigen (protein molecule) enters body
• It is taken up by an antigen-presenting cell (APC)
– Examples of APCs:
• Dendritic cells
• Monocytes and macrophages
• B cell lymphocytes
• Partial activation of the T-cell occurs
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T-Cells in the Immune and Allergic
Response continued
Stage 2: To respond or not?
• The new antigen is recognized by T-helper cells (CD4+)
• The antigen is compared to “self-antigens” and is identified
as “self” or “foreign”
• If “foreign”, a second signal is supplied by the T-cells via the
CD28/CD8 or CD40/CD40 receptor-ligand complex which
leads to:
ACTIVATION OF THE IMMUNE RESPONSE
accompanied by cytokine and antibody production
• If “self”, no second signal is conveyed and the Tcells assume a temporary state of unresponsiveness
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Role of T-cell Lymphocytes
When conditions interfere with the process of tolerance, T-cells
are activated:
• A Th1 response (IgM and IgG with activation of the
complement cascade) is likely to induce damage to the mucosa
– in response to food this may be a
PROTEIN-SENSITIVE ENTEROPATHY
• A Th2 response leads to an IgE-mediated hypersensitivity
reaction
– in response to food this may be
IMMEDIATE-TYPE ALLERGY or anaphylaxis
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T cells in Foetal Life
• Neonates with and without a family history of
atopy display Th2 activity
– various combinations of IL-4; IL-5; IL-9 are detectable
– IFN below level of detection
Rationale:
• In a successful pregnancy the foetus is embedded
in a Th2 cocktail:
• A Th1 environment may predispose to foetal
rejection
• High levels of IL-4, IL-10, PGE2 and progesterone
maintains a barrier to Th1 response at the
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maternal-foetal interface
Maturing of the Immune System
• Postnatally, Th1 response progressively increases
with age
• However, remains “deficient” relative to adult
levels for varying periods during childhood
• Deficit seems to be at the level of APCs,
especially dendritic cells
• APC fails to provide appropriate immunedeviating signals during T cell activation
• This deficit is more pronounced in atopic
individuals
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The Th2 Response in Allergy
Synthesis of IgE
• Naïve B cells are activated by cytokines
• IgM is formed first
• Specific antibodies are then produced in a
process of class switching, driven by
exposure to specific antigens
• The immature B cell matures into a “virgin”
B cell that expresses both IgM and IgD
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B cell Maturation and Production of
Antibody
• In the presence of antigen, B cells expressing
specific antibodies are selected
• Others are eliminated by apoptosis
• Class switching occurs at this stage
• The direction of switching is regulated by
cytokines secreted by the Th cells
– IL-4, and to a lesser extent IL-13 from Th2 cells
causes switching to IgE
– IFN produced by Th1 cells inhibits switch to IgE
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Control of IgE Production
• Overproduction of IgE leads to
hypersensitivity
• IgE mediates the release of inflammatory
mediators from a variety of granulocytes,
including:
– Mast cells
– Basophils
– Eosinophils
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Conditions that may Induce T-cell
Response in Food Allergy
• Inherited allergic potential
• Immaturity of the immune system (the TH2
response predominates in the neonate)
• Inflammatory conditions in the gut that interfere
with the normal antigen processing pathway
• Immaturity of the digestive mucosa leading to
hyperpermeability
• Increased uptake of antigens
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Immune Response in Allergy:
Early Response
• Allergic responses are biphasic
– Cytokines regulate each stage of the immune
response
• Early Response
– IgE-mediated activation of granulocytes (mast
cells; basophils)
– Release of inflammatory mediators (histamine;
prostaglandins; leukotrienes)
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Immune Response in Allergy:
Early Response continued
• Clinical manifestations:
– Upper airways:
sneezing, itching, rhinorrhoea, nasal
congestion
– Lower airways:
bronchoconstriction, dyspnoea, wheezing,
cough
– Skin:
wheal, flare, itching, reddening
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Immune Response in Allergy:
Late Response
• Late Response
– Mediated by chemotactic factors (chemokines;
LTB4; PGD2) from early phase
– Move lymphocytes, monocytes, neutrophils,
basophils, eosinophils to reactive tissues
– These new granulocytes release their own
battery of inflammatory mediators
– The allergic response is augmented
– This can be the life-threatening stage of an
anaphylactic reaction or an asthma attack
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Mast Cells
 Central to inflammation and the allergic response
 Release of mast cell mediators by allergen is the
initiating step of the early phase response
 Initiation and control of allergic inflammation is
effected by mast cell generation of:
 Histamine
 Proteases
 Eicosanoids (prostaglandins; leukotrienes)
 Cytokines
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Mast Cells
• Filled with granules containing preformed
inflammatory mediators in proteoglycan
(mostly heparin) matrix
• When mast cell is activated:
– Granules swell
– Contents become solubilised
– Individual mediators are expelled into the local
extracellular environment
– Process known as “degranulation”
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IgE-mediated hypersensitivity
Intracellular Granules are Released
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Mediator Release
ALLERGEN + IgE
MAST CELL
CHANGE IN CELL ENERGY
ADENYLATE CYCLASE-cAMP
CALCIUM ENTERS CELL
DEGRANULATION
Release of Inflammatory Mediators
Pre-formed Mediators
HISTAMINE
HEPARIN
CHEMOTAXINS
ENZYMES :
- PHOPHOLIPASE A2
Arachidonic
Acid
Secondary Mediators:
PROSTAGLANDINS:
PG-2
LEUKOTRIENES:
LT-4
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Action of Inflammatory Mediators on Tissues:
 Histamine 
• Vasodilation
• Swelling of tissues
• Increased vascular permeability
– angioedema (swelling)
– rhinitis (stuffy nose)
– rhinorrhea (runny nose)
– urticaria (hives)
– otitis media (earache)
• Pruritus (itching)
Antidote: Antihistamines
• Flushing
Block histamine receptors (H1; H2)
• Reddening
on reactive cells
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Inflammatory Mediators
Enzymes
• Tryptase; chymase; carboxypeptidase; cathepsin
G:
– Act directly on tissues and cause damage
Phospholipase A2
• Acts on cell membrane and releases arachidonic
acid
• Leads to production of secondary inflammatory
mediators by two enzyme pathways:
– Cyclo-oxygenase to prostaglandins
– Lipoxygenase to leukotrienes
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Secondary Mediator Release
Arachidonic acid
Cyclo-oxygenase
Lipoxygenase
PROSTAGLANDINS
LEUKOTRIENES
(PG2)
LTA4
PROSTACYCLIN
(PGI2)
LTC4
LTD4
THROMBOXANE
LTE4
(TX)
LTB4
43
Action of inflammatory mediators:
 Leukotrienes 
• LTB4 : Chemotaxin:
– Attracts more leukocytes to reaction site
– Augments allergic reaction
• LTC4; LTD4; LTE4:
– Smooth muscle contraction
– Responsible for bronchospasm of asthma
– Involved in inflammatory process in eczema
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Prostaglandins
•
•
•
•
•
Chemoattractant : PGD2
Smooth muscle contraction and relaxation
Dilation and constriction of blood vessels
Increase vascular permeability
Responsible for pain
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Summary:
IgE-mediated Hypersensitivity
• Food allergen cross-links two IgE antibodies
attached to FcRI receptors on mast cell
• Mast cells are degranulated and release preformed
inflammatory mediators
• Secondary cells of inflammation (eosinophils,
neutrophils, basophils, lymphocytes) are recruited by
chemotactic factors including chemokines
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Summary:
IgE-mediated Hypersensitivity
• Results in local symptoms in the gut (abdominal
pain; diarrhoea)
• Allows increased absorption of the same and other
antigens through the gut epithelium
• Leads to systemic effects such as mast cell
activation in
– lungs: asthma
– skin: urticaria, angioedema, eczema
– multiple organ systems: anaphylaxis
47
Immune complex-mediated reactions
IgM and IgG antibodies are frequently formed
against food antigens
• IgG4 subclass is a high-affinity antibody for food
antigens
When food antigens pass into circulation they
complex with their homologous antibodies
• The immune complexes are usually rapidly
cleared from circulation and do not cause
any pathology
48
IgG-mediated Hypersensitivity
Continued
• Tissue damage may result if there are high
concentrations of complexes
• High concentrations of complexes triggers
the complement cascade
• Anaphylatoxins formed by the complement
pathway induce release of inflammatory
mediators
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Sequence of Reactions in
the Complement Cascade
Antigen
A
C1q
C1r
+Ca++
C1s
Antibody
(IgG or IgM)
S
Antigen - Antibody
Complex
AS
“Recognition Complex”
AS, C1qrs
C4
C4a
Mg++
C2
Alternative pathway enters here
C3
AS, C1qrs, C4b, 2a
AS, C1qrs, C4b, 2a, 3b
C5
C6
AS, C1qrs, C4b, 2a, 3b, C5b
C7
AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7
C8
C9
AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7, 8, 9
Membrane damaged cell
LYSIS
C2b
C3a Anaphylatoxin
(degranulation)
C5a
Chemotaxin
Anaphylatoxin
(degranulation)
IgG-mediated Hypersensitivity
Continued
• If antigen is present in excess, the immune
complexes may be deposited in vessel walls
where an inflammatory reaction with fever
is provoked:
– in skin:
– in kidneys:
– in joints:
urticaria
angioedema
albuminuria
arthritis
51
Food Specific IgG and Tolerance
• Clinical evidence suggests that specific IgG to a
food that previously triggered production of IgE is
a sign of tolerance
• Theoretically:
– Food antigen now elicits Th1 response rather
than Th2
– Low level of IgG does not trigger complement
cascade
– Food antigen-IgG complex is removed in
normal process of phagocytosis
52