Food Allergens Atypical IgE-Mediated Conditions Non-IgE-Mediated Conditions

1. § Food AllergensAtypical IgE-Mediated ConditionsNon-IgE-Mediated Conditions § Characteristics and Reaction Mechanisms

2. Types of Allergenic Proteins • Storage proteins, especially in nuts, seeds and cereal grains • Inhibitors of enzymes that may be destructive to storage factors, for example: • Inhibitors of alpha amylases that might break down starches • Anti-trypsin protects against trypsin breakdown of proteins in cereal grains • Structural proteins

3. Types of Allergenic Proteins • Regulatory proteins, such as profilins, that are important in plant fertilization (for example in pollens) • Pathogenesis-related proteins: proteins involved in the defense-related activities of the plant, for example: • Hevamines that are lysozyme-like enzymes that break down fungal cell walls and defend the plant against fungal attack • Lipid transfer proteins (LTP) that are essential in the functioning of a cell

4. Allergenic Proteins in Specific Foods • Each food contains many proteins, some of which are potential allergens, and have different characteristics and degree of allergenicity: for example: • MILK • Contains about 30 potential allergens, some of which are heat stable; some are heat labile: • Caseins (α; β; κ) tend to be heat stable • Whey proteins including alpha-lactalbumin and beta-lactoglobulin tend to be heat labile • Individuals allergic to only heat labile proteins usually can drink heated milk with impunity

5. Allergenic Proteins in Specific Foods: Wheat • Protein makes up ~12% of the dry wheat kernel • Many of the proteins in wheat are allergenic • Wheat proteins are roughly divided into the following four classes • Gliadins • Glutenins • Albumins • Globulins • Gliadins contain as many as 40 to 60 distinct components • Glutenins contain at least 15 • Albumins and Globulins also may be allergenic • Allergy to specific proteins tends to be population-related

6. Egg Allergens • Eggs contain many different proteins that can lead to allergy • An egg-allergic individual is likely to be sensitized to more than one protein • Although egg yolk contains several proteins, egg white (ovalbumin) contains the greatest number of allergens • Up to 24 different antigenic protein fractions have been isolated, although the allergenicity of most of them is unknown • The main allergens are: • Ovalbumin • Ovomucoid • Ovotransferrin • Lysozyme

7. Peanut AllergensThe major allergenic peanut proteins have been characterized and named. The “Ara h” in the name of each protein is derived from the Latin name for peanut, Arachis hypogaea: • Ara h 7 • Ara h 8 • Ara h agglutinin • Ara h LTP • Ara h oleosin • Ara h TI • Ara h 1 • Ara h 2 (5 subtypes) • Ara h 3 • Ara h 4 • Ara h 5 • Ara h 6

8. Relative importance of individual peanut allergens in allergy • Ara h 2 recognized most frequently as the causative allergen in all tests for symptom-triggering allergens and induced a reaction at relatively low concentrations • Ara h 1 and Ara h 3 were recognized less frequently and reacted only at 100-fold higher concentrations than Ara h 2 • Presence of Ara h 2 suggested as marker for peanut allergy Koppelman et al 2004

9. Prevalence of sensitization to all peanut allergens • Population of 40 patients sensitized to peanut: • Ara h 1 (65%) • Ara h 2 (85%) • Ara h 4 (53%) • Ara h 5 (13%) • Ara h 6 (38%) • Ara h 7 (43%) • Although Ara h 6 was considered a minor allergen, the authors found that sensitization to Ara h 6 was associated with more severe clinical symptoms than most of the other allergens Becker et al 2001

10. 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 details of unique proteins of known sequence that are classified as food allergens

11. Classification of Food Allergens[Sampson 1999]: Class 1 food allergens: • Encounter the immune system through the digestive tract • Induce allergic sensitization directly via the intestine • Are resistant to digestive enzymes • Are stable in response to gastric acid • Are heat-stable and are not deactivated by cooking

12. Class 2 food allergens • Do not induce allergic sensitization in the digestive tract • Rapidly dissolve in the oral cavity • Are readily broken down by digestive enzymes • Are susceptible to acid in gastric secretions • Are heat-labile and are generally deactivated by cooking.

13. Class 1 Food Allergens Characteristics • 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)

14. 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

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

16. Major Allergenic Foods:Annex IIIa EU Directive on Labeling of Foods Which Must be Declared • Cereals containing gluten, (i.e. wheat, rye, barley, oats, spelt, kamut or their hybridized strains) and products thereof • Crustaceans and products thereof • Eggs and products thereof • Fish and products thereof • Peanuts and products thereof • Soybeans and products thereof • Milk and products thereof (including lactose)

17. Major Allergenic Foods:Annex IIIa EU Directive on Labeling of Foods Which Must be Declared Continued • Nuts i.e. almonds, hazelnuts, walnuts, cashews, pecan nuts, Brazil nuts, pistachio nuts, macadamia nuts and Queensland nuts and products thereof • Celery and products thereof • Mustard and products thereof • Sesame seeds and products thereof • Sulphur dioxide and sulphites at concentrations of more than 10 mg/kg or 10 mg/litre expressed as SO2. • Lupin and products thereof • Molluscs and products thereof

18. Panallergens • Most allergenic foods contain species-specific proteins • This means that individual sensitisation to a food is specific to that food and none other, even if the foods are zoologically or botanically related • However, recent research is indicating that some proteins with the same function in different food plants or animals may be allergenic • May be: • Lipid transfer proteins • Pathogenesis-related proteins • Profilins

19. Panallergens continued • A person sensitised to such a protein may then be sensitive to the same protein where it occurs in different species • The proteins tend to be weakly allergenic • Such allergens have been designated “Panallergens” • Examples include: • Parvalbumins in fish • Proteins responsible for oral allergy syndrome and latex allergy

20. 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

21. Oral Allergy SyndromeCharacteristics • 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

22. Oral Allergy SyndromeAllergens • 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

23. Oral Allergy SyndromeAllergens • 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; exposed to potential pathogens) • May be hevamines

24. Oral Allergy SyndromeCross-Reactivity • Occurs most frequently in persons allergic to birch and alder pollens • Also occurs with allergy to: • Ragweed pollen • Mugwort pollen • Grass pollens

25. Oral Allergy SyndromeAssociated 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”

26. Oral Allergy SyndromeCharacteristics 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

27. Oral Allergy Syndrome (OAS):Cross-reacting Foods and Pollens

28. Oral Allergy SyndromeCross-reacting allergens • Ragweed pollen with: • Banana • Cantaloupe • Honeydew • Watermelon • Other Melons • Courgette • Cucumber

29. 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

30. 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

31. 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

32. Latex Allergy • Allergy to latex frequently starts as a Type IV (contact) hypersensitivity reaction • Contact is with an allergenic protein usually through: • Abraded (non-intact) skin • Mucous membrane by inhalation • Exposed tissue (e.g. during surgery)

33. Latex AllergyCross-reacting allergens • As antigen comes into contact with immune cells, repeated exposure seems to lead to IgE mediated allergy • Reaction becomes systemic • Similar proteins in foods tend to trigger the same IgE response • In extreme cases can cause anaphylactic reaction

34. Foods with Allergens Similar to Latex

35. 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

36. 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

37. Non-IgE-Mediated Allergies Eosinophilic Gastrointestinal Diseases Food Protein Induced Enteropathies

38. Eosinophilic Gastrointestinal Diseases (EGID) • Expanded definition of food allergy now encompasses any immunological response to food components that results in symptoms when the food is consumed • Example is group of conditions in the digestive tract in which infiltration of eosinophils is diagnostic • Collectively these diseases are becoming known as eosinophilic gastrointestinal diseases (EGID).

39. Characteristics of EGID • Inflammatory mediators are released from the eosinophils, and act on local tissues in the oesophagus and gastrointestinal tract, causing inflammation • In eosinophilic digestive diseases there is no evidence of IgE, therefore tests for IgE-mediated allergy are usually negative • Unless there is a concomitant IgE-mediated reaction to food

40. Characteristics of EGID • Eosinophils are also found in abundance in the intestinal canal in diseases such as: • inflammatory bowel disease • infections caused by parasites such as helminths and nematode worms • These need to be ruled out before EGID is diagnosed

41. Eosinophilic Oesophagitis • Symptoms most frequently associated with EO and considered to be typical of the disease include: • Vomiting • Regurgitation of food • Difficulty in swallowing: foods are said to be sticking on the way down • Choking on food • Heartburn and chest pain • Water brash (regurgitation of a watery fluid not containing food material) • Poor eating • Failure to thrive (poor or no weight gain, or weight loss)

42. Eosinophilic Oesophagitis • Although the symptoms resemble gastro-oesophageal reflux disease (GORD), the reflux of EO dose not respond to the medications used to suppress the gastric acid and control regurgitation (antireflux therapy) in GORD • There is emerging data to suggest that use of acid-suppressing medications may predispose patients to the development of EO

43. Diagnosis of EO Three criteria must be met: • Clinical symptoms of oesophageal dysfunction • Oesophageal biopsy with an eosinophil count of at least 15 eosinophils per high-power (x400 mag) microscopy field • Exclusion of other possible causes of the condition Dellon ES 2013

44. Eosinophilic OesophagitisFoods most frequently implicatedin Children

45. Six-Food Elimination Diet and EoEAdult study 2013 • Foods eliminated: • Cereals • Wheat • Rice • Corn • Milk and milk products • Eggs • Fish and seafood • Legumes including peanuts • Soy Lucendo et al 2013

46. Six-Food Elimination Diet and EoE • Indicators of positive outcome: • Biopsy eosinophil count (< 15/hpf) • Negative gastro-oesophageal reflux • Reduced eosinophil count: 73.1% of subjects • Maintained remission for 3 years • Incidence of single triggering factors: • Cow’s milk 61.9% • Wheat 28.6% • Eggs 26.2% • Legumes 23.8% • No correlation with allergy tests

47. Eosinophilic Gastroenteritis:Diagnosis by biopsy:Abnormal number of eosinophils in the stomach and small intestineFoods most frequently implicated

48. Eosinophilic ProctocolitisDiagnosis by biopsy:Abnormal number of Eosinophils confined to the colonFoods most frequently implicated • Cow’s milk • Soy proteins Most frequently develops within the first 60 days of life Is a non-IgE-mediated condition

49. Food Protein Enteropathies • Increasing recognition of a group of non-IgE-mediated food-related gastrointestinal problems associated with delayed or chronic reactions • Conditions include: • Food protein induced enterocolitis syndrome (FPIES) • Food protein induced proctocolitis (FPIP) • These digestive disorders tend to: • Appear in the first months of life • Be generally self-limiting • Typically resolve at about two years of age

50. Food Protein Induced Enterocolitis Syndrome:Symptoms Symptoms in infants typically include: • Profuse vomiting • Diarrhoea, which can progress to dehydration and shock in severe cases • Increased intestinal permeability • Malabsorption • Dysmotility • Abdominal pain • Failure to thrive (typically weight gain less than 10 g/day) • In severe episodes the child may be hypothermic (<36 degrees C)