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