Oral Tolerance

Characteristics of AllergensOral allergy syndrome

Latex allergy

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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

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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

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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

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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

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Peyer’s Patch

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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

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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)

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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 IgM and IgA

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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

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Secretory IgA

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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

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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

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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

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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

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Antigen- presenting cell

Th0

 

Antigen

Th1

Th2

IL-2IL-3IL-4IL-5Il-13INFGM-CSF

 Il-2Il-3IFNGM-CSF

 

Il-3Il-4Il-5Il-13GM-CSF

          

     

 

 

 

Allergens

Viruses, Bacteria,

Other foreign matter

MHC Class II

White blood cells aidthe immune system in recognizing foreignproteins

T helper ( CD4+) cells respond

T helper cells producecharacteristic cytokines

Specific cytokines determine response:Th1 = protectionTh2 = allergy

IgE

IgG

Immunological Pathways to Protection, Allergy, or Oral Tolerance

Receptor

Oral Tolerance

TGF-β1IL-10

Th3

TrI

Anergy: No immune response

CD4+CD25+Treg

Normal Response toFood and Beverages

Development of tolerance following early allergy

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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Incidence of Allergy to Specific Foods

• Increasing incidence of allergy to “exotic foods” such as:

– Kiwi

– Papaya

– Seeds: Sesame; Rape; Poppy

– Grains: Psyllium

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Food Allergen Scale

Joneja2003

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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

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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

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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

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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

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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

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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”

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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

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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

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Oral Allergy SyndromeCross-reacting allergens

• Ragweed pollen with:– Banana– Cantaloupe– Honeydew– Watermelon– Other Melons– Zucchini (Courgette)– Cucumber

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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

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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

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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

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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)

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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

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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

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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

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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