Characteristics of Allergens
Allergenic relatedness
Oral allergy syndrome
Latex allergy
Oral tolerance
Characteristics of Food Allergens
• Physicochemical properties that confer
allergenicity are relatively unknown
• Usual characteristics of allergenic fraction of food:
– Protein or glycoprotein
– Molecular size 10 to 70 kDa
– Heat stable
– Water soluble
– Relatively resistant to acid hydrolysis
– Relatively resistant to proteases (especially
digestive enzymes)
2
Lipid Transfer Proteins
• Recently identified as food allergens
• Induce specific IgE antibodies
• LTPs are generally resistant to proteolytic
enzymes, gastric acid, and heat
• Tend to be stable after food processing
• Reach the gastrointestinal immune system
and induce IgE directly
3
Chemical Structure of Food Allergens
• Allergenic proteins from an increasing
number of foods have been characterised
• The Food Allergy Research Resource
Program (Farrp) database
(http://www.allergenonline.com) contains
more than 100 unique proteins of known
sequence that are classified as food
allergens
4
Incidence of Allergy to Specific Foods
• In young children: 90% of reactions caused by:
– Milk
– Egg
– Peanut
- Soy
- Wheat
• In adults: 85% of reactions caused by:
– Peanut
– Fish
– Shellfish
- Tree nuts
5
Incidence of Allergy to Specific Foods
• Increasing incidence of allergy to “exotic
foods” such as:
– Kiwi
– Papaya
– Seeds: Sesame; Rape; Poppy
– Grains: Psyllium
6
Food
Allergen
Scale
Joneja
2003
7
Oral Allergy Syndrome
(OAS)
• OAS refers to clinical symptoms in the mucosa of
the mouth and throat that:
• Result from direct contact with a food allergen
• In an individual who also exhibits allergy to
inhaled allergens.
• Usually pollens (pollinosis) are the primary
allergens
• Pollens usually trigger rhinitis or asthma in these
subjects
8
Oral Allergy Syndrome
Characteristics
• Inhaled pollen allergens sensitise tissues of the
upper respiratory tract
• Tissues of the respiratory tract are adjacent to oral
tissues, and the mucosa is continuous
• sensitisation of one leads to sensitisation of the
other
• First described in 1942 in patients allergic to birch
pollens who experience oral symptoms when
eating apple and hazelnut
• OAS symptoms are mild in contrast to primary
food allergens and occur only in oral tissues
9
Oral Allergy Syndrome
Allergens
• Pollens and foods that cause OAS are
usually botanically unrelated
• Several types of plant proteins with specific
functions have been identified as being
responsible for OAS:
– Profilins
– Pathogenesis-related proteins
– Hevamines
10
Oral Allergy Syndrome
Allergens
• Profilins are associated with reproductive
functions
• Pathogenesis-related proteins tend to be
expressed when the tree is under “stress”
(e.g. growing in a polluted area)
• Hevamines are hydrolytic enzymes with
lysozyme activity
11
Oral Allergy Syndrome
Cross-Reactivity
• Occurs most frequently in persons allergic
to birch and alder pollens
• Also occurs with allergy to:
– Ragweed pollen
– Mugwort pollen
– Grass pollens
12
Oral Allergy Syndrome
Associated foods
• Foods most frequently associated with OAS are
mainly fruits, a few vegetables, and nuts
• The foods cause symptoms in the oral cavity and
local tissues immediately on contact:
–
–
–
–
–
Swelling
Throat tightening
Tingling
Itching
“Blistering”
13
Oral Allergy Syndrome
Characteristics of Associated foods
• The associated foods usually cause a reaction
when they are eaten raw
• Foods tend to lose their reactivity when cooked
• This suggests that the allergens responsible are
heat labile
• Allergic persons can usually eat cooked fruits,
vegetables, nuts, but must avoid them in the raw
state
14
Oral Allergy Syndrome
Cross-reacting allergens
• Birch pollen (also: mugwort, and grass pollens)
with:
–
–
–
–
–
–
–
–
Apple
Stone Fruits (Apricot, Peach, Nectarine, Plum, Cherry)
Kiwi Fruit
Orange
- Peanut
Melon
- Hazelnut
Watermelon
- Carrot
Potato
- Celery
Tomato
- Fennel
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Oral Allergy Syndrome
Cross-reacting allergens
• Ragweed pollen with:
–
–
–
–
–
–
–
Banana
Cantaloupe
Honeydew
Watermelon
Other Melons
Zucchini (Courgette)
Cucumber
16
Oral Allergy Syndrome Diagnosis
• Syndrome seen most often in persons with birch pollen
allergy compared to those with allergy to other pollens
• Seen in adults much more frequently than children
• Reactions to raw fruits and vegetables are the most
frequent food allergies with onset in persons over the
age of 10 years
• Has also been described in persons with IgE-mediated
allergy to shrimp and egg
 This may not be true OAS; allergy may be
expressed as symptoms in the mouth in conditions
distinct from OAS
17
Expression of OAS Symptoms
• Oral reactivity to the food significantly decreases when
food is cooked
• Reactivity of the antigen depends on ripeness
– Antigen becomes more potent as the plant material ages
• People differ in the foods which trigger OAS, even when
they are allergic to the cross-reacting pollens
– Foods express the same antigen as the allergenic pollen, but
not all people will develop OAS to all foods expressing that
antigen
18
Identification of Foods Responsible
for OAS Symptoms
• Skin tests will identify the allergenic plant pollen
• Skin testing has not been successful in identifying
persons who react to cross-reacting food antigens
– Plant antigens are unstable and do not survive the
process of antigen preparation
– Crushing plant material leads to release of phenols and
degradative enzymes
• Prick + prick technique are more reliable than
standard skin tests
– Lancet is inserted in raw fruit or vegetable, withdrawn
and then used to prick the person’s skin
19
Suggested Classification of Food
Allergens [Sampson 2003]:
• Class 1:
– Direct sensitisation via the gastrointestinal tract after
ingestion
– Water-soluble glycoproteins or proteins
– Stable to heat, proteases, and acid
– 10 – 70 kD in size
• Class 2:
– Sensitisation by inhalation of air-borne allergen
– Cross-reaction to foods containing structurally identical
proteins
– Heat labile
20
Latex Allergy
• Allergy to latex is thought to start as a Type
IV (contact) hypersensitivity reaction
• Contact is with a 30 kd protein, usually
through:
– Abraded (non-intact) skin
– Mucous membrane
– Exposed tissue (e.g. during surgery)
21
Latex Allergy
Cross-reacting allergens
• As antigen comes into contact with immune
cells, repeated exposure seems to lead to
Type I hypersensitivity (IgE mediated
allergy)
• Similar 30 kd proteins in foods tend to
trigger the same IgE response
• In extreme cases can cause anaphylactic
reaction
22
Latex Allergy
Related foods
• Foods that have been shown to contain a similar
30 kd antigen include:
–
–
–
–
–
–
–
Avocado
Banana
Kiwi Fruit
Fig
Passion Fruit
Citrus Fruits
Pineapple
- Tomato
- Celery
- Peanut
- Tree Nuts
- Chestnut
- Grapes
- Papaya
23
Common allergens in unrelated plant
materials: Summary
• OAS and latex allergy are examples of conditions
in which common antigens, expressed in
botanically unrelated plants, are capable of
eliciting a hypersensitivity reaction
• Previous assumptions that plant foods in the same
botanic family are likely to elicit the production of
the same antigen- specific IgE are thus
questionable
24
Common allergens in unrelated plant
materials: Summary
• In practice, when a specific plant food elicits an
allergic response, foods in the same botanic family
rarely elicit allergy
• It is important to recognize the allergenic potential
of antigens common to certain botanically
unrelated plant species, and take appropriate
measures to avoid exposure of the allergic
individual to them
25
Development of Tolerance
• Food comprises material from a huge
variety of plants and animals, all “foreign”
to the human body
• This material is intimately integrated as
structural and functional elements in the
body
• How does the body by-pass the natural
barrier to “non-self” material?
• The dominant response in the gut-associated
lymphoid tissue (GALT) is immune
suppression (tolerance)
26
Immune System of the Gut
• GALT is located mainly in the lamina
propria
• It is present in the small intestine:
– Diffusely (distributed throughout the
tissue)
– Solitary nodules
– Aggregated nodules: Peyer’s patches
27
Immune System of the Gut
• Lymphocytes are found both in the lamina
propria
– Mostly CD4+ T helper cells
• And between the epithelial cells
– Mostly CD8+ T suppressor cells
• T cells migrate out of the epithelium to
mesenteric lymph nodes, proliferate, and
enter the systemic circulation
• Return to mucosa as memory T cells
28
Peyer’s Patch
29
Immune Processing in the Gut
• Antigen-presenting cells are found
predominantly in Peyer’s patches
• Also as scattered cells in lamina propria
• Most efficient sampling occurs in the
flattened epithelial cells overlying Peyer’s
patches
• Lymphoid tissues contains both T cells and
B cells
• Activated T cells (CD4+) aid in
differentiation of B cells to antibodypresenting cells
30
Immune System of the Gut
• Other haematopoietic cells in the GI tissue
include:
– Eosinophilic granulocytes (4-6% of
lamina propria cells)
– Neutrophilic granulocytes (rare in noninflamed tissue)
– Monocytes
– Mast cells (2-3% of lamina propria cells)
31
Immune Activation in GALT
Particulate Antigens
• Particulate antigens, such as intact bacteria,
viruses, parasites are processed through M
(microfold) cells, specialised epithelial cells that
overlie Peyer’s patches
• Sequence of Events:
– M cell endocytoses macromolecule at the apical end of
the cell
– Transports it across cell to the basolateral surface
– Antigen encounters intra-epithelial lymphocytes
– Lymphocytes (T and B cells) are activated to generate
antigen-specific IgM and IgA
32
Immune Activation in GALT
Particulate Antigens (continued)
– IgA and IgM molecules pass through mucosal
epithelial cell and link to receptor on cell
surface
– Expelled into the gut lumen, together with
receptor
– Receptor forms the secretory component that
protects the antibody from digestion by
enzymes in the gut lumen
– Secretory IgM (SIgM) and secretory IgA
(SIgA) function as “first line defence” agents in
mucous secretions
33
Development of Tolerance in GALT:
Soluble Protein
• Intestinal epithelial cells (IEC) appear to be the
major antigen presenting cells involved in
immunosuppression in the GALT
• Events leading to tolerance:
–
–
–
–
IEC express MHC class II molecules
Take up soluble protein
Transport it through the cell
T and B cell lymphocytes at the basolateral interface
may be activated
– May result in generation of low levels of antigenspecific IgG
34
Development of Tolerance
– Antibody production against foods is a
universal phenomenon in adults and children
– Most antibodies to foods in non-reactive
humans are IgG, but do not trigger the
complement cascade
– Such antibodies are not associated with allergy
– CD8+ suppressor cells at basolateral surface
are activated
– In conjunction with MHC class I molecules
– Suppressor cytokines generated (e.g. TGF-)
– Results in lymphocyte anergy or deletion
35
Development of Tolerance
• Thus: Normal tolerance to dietary proteins is due
to generation of CD8+ T suppressor cells
• These are at first located in the GALT, and after
prolonged exposure to the same antigen can be
detected in the spleen
• Activation depends on several factors including:
– antigen characteristics
– dose
– frequency of exposure
36
Development of Tolerance
• Evidence indicates that “low dose,
continuous exposure” to antigen is
important in T cell tolerance
• Large dose, infrequent exposure seems to
promote sensitisation
37
Development of Tolerance
continued
• Other factors that might influence tolerance
include:
– Individual’s age
– Nature of intestinal microflora
• Microbial lipopolysaccharide from
Gram-negative Enterobacteria in the
colon might act as an immunological
adjuvant
38
Food Allergy
• True food allergens in contrast to those associated
with OAS reach the intestinal mucosa intact
• Tend to be LTPs
• Suggested to by-pass gut immune processing by
moving through weakened “tight junction”
between epithelial cells
• Tight junction weakened by:
– Immaturity (in infants)
– Alcohol ingestion
– Inflammation in the gut epithelium and associated
tissues
39
Food Allergy continued
• Absorption of proteins more efficient
through the gut epithelium than through the
oral mucosa
• Induce production of IgE
• Attach to IgE on the surface of mast cells in
the vicinity of the gut epithelium to cause
local symptoms
• Cause allergy symptoms in distant organ
systems after absorption
40
From;
Allergy
Holgate,
Church and
Lichtenstein
2001
Page 132
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