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Oral Tolerance

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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 ... – PowerPoint PPT presentation

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Title: Oral Tolerance


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 Peyers 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
Peyers Patch
7
Immune Processing in the Gut
  • Antigen-presenting cells are found predominantly
    in Peyers patches
  • Also as scattered cells in lamina propria
  • Most efficient sampling occurs in the flattened
    epithelial cells overlying Peyers 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 Peyers 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 GALTSoluble 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
Th2
White blood cells aid the immune system in
recognizing foreign proteins
Il-3 Il-4 Il-5 Il-13 GM-CSF
IgE
Normal Response to Food and Beverages
Th3
Development of tolerance following early allergy
CD4CD25Treg
TGF-ß1
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
  • Individuals 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 persons 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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