1. Characteristics of Allergens Oral allergy syndrome Latex allergy
Oral Tolerance
Characteristics of Allergens
Oral allergy syndrome
Latex allergy

2. 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

3. 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

4. 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

5. 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

6. Peyer’s Patch

7. 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 antibody-presenting cells

8. 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 non-inflamed tissue)
Monocytes
Mast cells (2-3% of lamina propria cells)

9. 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

10. 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

11. Secretory IgA

12. 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 antigen-specific IgG

13. 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

14. 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

15. 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 immuno-suppressive 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

16. IgG IgE CD4+CD25+Treg TGF-β1 IL-10 TrI T helper ( CD4+) cells respond
Immunological Pathways to Protection, Allergy, or Oral Tolerance
Antigen- presenting cell
T helper ( CD4+) cells respond
Th1
Receptor
Il-2
Il-3
IFN
GM-CSF
IgG
Antigen
Viruses, Bacteria,
Other foreign matter
Th0
IL-2
IL-3
IL-4
IL-5
Il-13
INF
GM-CSF
Specific cytokines determine response:
Th1 = protection
Th2 = allergy
MHC Class II
Allergens
T helper cells produce
characteristic cytokines
White blood cells aid
the immune system in
recognizing foreign
proteins
Th2
Il-3
Il-4
Il-5
Il-13
GM-CSF
IgE
Normal Response to
Food and Beverages
Th3
Development of tolerance following early allergy
CD4+CD25+Treg
TGF-β1
IL-10
Anergy:
No immune response
Oral Tolerance
TrI

17. 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

18. 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

19. 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

20. 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

21. Suggested Classification of Food Allergens [Sampson 2003]:
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

22. 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)

23. 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

24. Chemical Structure of Food Allergens
Allergenic proteins from an increasing number of foods have been characterised
The Food Allergy Research Resource Program (Farrp) database ( contains more than 100 unique proteins of known sequence that are classified as food allergens

25. Incidence of Allergy to Specific Foods
In young children: 90% of reactions caused by:
Milk - Soy
Egg - Wheat
Peanut
In adults: 85% of reactions caused by:
Peanut - Tree nuts
Fish
Shellfish

26. Incidence of Allergy to Specific Foods
Increasing incidence of allergy to “exotic foods” such as:
Kiwi
Papaya
Seeds: Sesame; Rape; Poppy
Grains: Psyllium

27. Food Allergen Scale
Joneja
2003

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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”

34. 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

35. 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

36. Oral Allergy Syndrome Cross-reacting allergens
Ragweed pollen with:
Banana
Cantaloupe
Honeydew
Watermelon
Other Melons
Zucchini (Courgette)
Cucumber

37. 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

38. 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

39. 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

40. 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)

41. 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

42. Latex Allergy Related foods
Foods that have been shown to contain a similar 30 kd antigen include:
Avocado Tomato
Banana Celery
Kiwi Fruit Peanut
Fig Tree Nuts
Passion Fruit Chestnut
Citrus Fruits Grapes
Pineapple - Papaya

43. 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

44. 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