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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

Oral Tolerance

Characteristics of Allergens

Oral allergy syndrome

Latex allergy

development of tolerance
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
tolerance continued
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
immune system of the gut
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
immune system of the gut1
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
immune processing in the gut
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
immune system of the gut2
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)
immune activation in galt particulate antigens
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
immune activation in galt particulate antigens continued
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
development of tolerance in galt soluble protein
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
development of tolerance1
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
development of tolerance2
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
development of tolerance continued
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
slide16

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

development of tolerance3
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
development of tolerance continued1
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
food allergy
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
food allergy continued
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
suggested classification of food allergens sampson 2003
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
characteristics of food allergens
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)
lipid transfer proteins
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
chemical structure of food allergens
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
incidence of allergy to specific foods
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
incidence of allergy to specific foods1
Incidence of Allergy to Specific Foods
  • Increasing incidence of allergy to “exotic foods” such as:
    • Kiwi
    • Papaya
    • Seeds: Sesame; Rape; Poppy
    • Grains: Psyllium
oral allergy syndrome oas
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
oral allergy syndrome characteristics
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
oral allergy syndrome allergens
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
oral allergy syndrome allergens1
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
oral allergy syndrome cross reactivity
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
oral allergy syndrome associated foods
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”
oral allergy syndrome characteristics of associated foods
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
oral allergy syndrome cross reacting allergens
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
oral allergy syndrome cross reacting allergens1
Oral Allergy SyndromeCross-reacting allergens
  • Ragweed pollen with:
    • Banana
    • Cantaloupe
    • Honeydew
    • Watermelon
    • Other Melons
    • Zucchini (Courgette)
    • Cucumber
oral allergy syndrome diagnosis
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

expression of oas symptoms
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
identification of foods responsible for oas symptoms
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
latex allergy
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)
latex allergy cross reacting allergens
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
latex allergy related foods
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
common allergens in unrelated plant materials summary
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
common allergens in unrelated plant materials summary1
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