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Oral Tolerance

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

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Oral Tolerance

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  1. 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 GALTParticulate 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 GALTParticulate 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. 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]: • 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

  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 (http://www.allergenonline.com) 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 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

  30. 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 • Hevamines

  31. 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) • Hevamines are hydrolytic enzymes with lysozyme activity

  32. 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

  33. 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”

  34. 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

  35. Oral Allergy SyndromeCross-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 SyndromeCross-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 AllergyCross-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 AllergyRelated 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

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