Oral Tolerance Characteristics of Allergens Oral allergy syndrome

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 m. L 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 CD 4+ T helper cells • And between the epithelial cells – Mostly CD 8+ 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 (CD 4+) 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 Ig. M and Ig. A 9

Immune Activation in GALT Particulate Antigens (continued) – Ig. A and Ig. M 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 Ig. M (SIg. M) and secretory Ig. A (SIg. A) function as “first line defence” agents in mucous secretions 10

Secretory Ig. A 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 Ig. G 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 Ig. G, but do not trigger the complement cascade – Such antibodies are not associated with allergy – CD 8+ 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 CD 8+ 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 (Tr. I) generate IL-10, which also has an immunosuppressive function • Tolerance to food antigens after early Th 2 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 Antigen- presenting cell T helper ( CD 4+) cells respond Receptor Antigen Th 0 MHC Class II IL-2 IL-3 IL-4 IL-5 Il-13 INF GM-CSF Viruses, Bacteria, Other foreign matter CD 4+CD 25+Treg IL-10 Tr. I Anergy: No immune response Oral Tolerance Ig. G Th 2 Normal Response to Food and Beverages Th 3 Il-2 Il-3 IFN GM-CSF Specific cytokines determine response: Th 1 = protection Th 2 = allergy Allergens T helper cells produce characteristic cytokines White blood cells aid the immune system in recognizing foreign proteins Th 1 Il-3 Il-4 Il-5 Il-13 GM-CSF Development of tolerance following early allergy TGF-β 1 16 Ig. E

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 Ig. E • Attach to Ig. E 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 k. D 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 k. Da – 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 Ig. E 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 Ig. E 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 Ig. E-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 Ig. E mediated allergy • Similar 30 kd proteins in foods tend to trigger the same Ig. E 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 Ig. E 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