Oral Tolerance
Characteristics of Allergens
Oral allergy syndrome
Latex allergy
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?
• At the same time potential pathogens taken
in with the food are excluded
2
Tolerance (continued)
• In addition, micro-organisms of the resident
microflora are tolerated:
– Estimated 1012 – 1014 microorganisms per mL
in the bowel of the healthy human
– Essential for:
• Exclusion of potential pathogens
• Synthesis of essential vitamins (Vitamin K; some B
vitamins)
• Interaction with mucosal epithelium to maintain
health
3
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
4
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
5
Peyer’s Patch
6
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
7
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)
8
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
9
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
10
Secretory IgA
11
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
12
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
13
Development of Tolerance
• Normal tolerance to dietary proteins is partly 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
14
Development of Tolerance (continued)
• In addition, regulatory T cells (Treg) in the thymus
stop further action
– Probably mediated by TGF-
• Possibly regulatory T cells named inducible T reg
(TrI) generate IL-10, which also has an immunosuppressive function
• Tolerance to food antigens after early Th2
response may be due to the same process:
– Children “outgrow” their early food allergies usually
between 2 and 7 years of age
15
Immunological Pathways to Protection, Allergy, or Oral Tolerance
Antigenpresenting cell
T helper ( CD4+) cells respond
Th1
Receptor
Antigen
Th0
MHC
Class II
IL-2
IL-3
IL-4
IL-5
Il-13
INF
GM-CSF
Il-2
Il-3
IFN
GM-CSF
Viruses,
Bacteria,
Other
foreign
matter
Specific cytokines
determine response:
Th1 = protection
Th2 = allergy
Allergens
T helper cells produce
characteristic cytokines
White blood cells aid
the immune system in
recognizing foreign
proteins
Th2
Normal Response to
Food and Beverages
Th3
CD4+CD25+Treg
IL-10
TrI
Anergy:
No immune response
Oral Tolerance
IgG
Il-3
Il-4
Il-5
Il-13
GM-CSF
Development of
tolerance following early
allergy
TGF-β1
16
IgE
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
17
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
18
Food Allergy
• Food allergens reach the intestinal mucosa
intact
• 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
19
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
20
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
21
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)
22
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
23
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
24
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
25
Incidence of Allergy to Specific Foods
• Increasing incidence of allergy to “exotic
foods” such as:
– Kiwi
– Papaya
– Seeds: Sesame; Rape; Poppy
– Grains: Psyllium
26
Food
Allergen
Scale
Joneja
2003
27
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
28
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
29
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
30
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
31
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
32
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”
33
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
34
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
35
Oral Allergy Syndrome
Cross-reacting allergens
• Ragweed pollen with:
–
–
–
–
–
–
–
Banana
Cantaloupe
Honeydew
Watermelon
Other Melons
Zucchini (Courgette)
Cucumber
36
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
37
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
38
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
39
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)
40
Latex Allergy
Cross-reacting allergens
• As antigen comes into contact with immune
cells, repeated exposure seems to lead to
IgE mediated allergy
• Similar 30 kd proteins in foods tend to
trigger the same IgE response
• In extreme cases can cause anaphylactic
reaction
41
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
42
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
43
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
44