Food Allergy: Symptoms and Immunological Mechanisms Janice M. Joneja, Ph.D., R.D. 2007

Food Allergy:

Symptoms andImmunological Mechanisms

Janice M. Joneja, Ph.D., R.D.

2007

2

Symptoms of Food Allergy

• Controversy among practitioners because there are no definitive tests for food allergy

• “Allergic diathesis” defined as:– Rhinoconjunctivitis (hayfever)– Asthma– Atopic dermatitis (eczema)

• Other conditions, especially in the digestive tract and nervous system are considered more “subjective” and many practitioners dismiss them as “fictitious” or psychosomatic

3

Examples of Allergic Conditions and Symptoms

• Respiratory Tract– Seasonal or perennial rhinitis (hayfever)

– Rhinorrhea (runny nose)

– Allergic conjunctivitis (itchy, watery, reddened eyes)

– Serous otitis media (earache with effusion) [“gum ear”; “glue ear”]

– Asthma

– Laryngeal oedema (throat tightening due to swelling of tissues)

4

Examples of Allergic Conditions and Symptoms

• Skin and Mucous Membranes– Atopic dermatitis (eczema)

– Urticaria (hives)

– Angioedema (swelling of tissues, especially mouth and face)

– Pruritus (itching)

– Contact dermatitis (rash in contact with allergen)

– Oral allergy syndrome (irritation and swelling of tissues around and inside the mouth)

5

Examples of Allergic Conditions and Symptoms

• Digestive Tract– Diarrhea– Constipation– Nausea and Vomiting– Abdominal bloating and distension– Abdominal pain– Indigestion (heartburn)– Belching

6

Examples of Allergic Conditions and Symptoms

• Nervous System– Migraine

– Other headaches

– Spots before the eyes

– Listlessness

– Hyperactivity

– Lack of concentration

– Tension-fatigue syndrome

– Irritability

– Chilliness

– Dizziness

7

Examples of Allergic Conditions and Symptoms

• Other– Urinary frequency

– Bed-wetting

– Hoarseness

– Muscle aches

– Low-grade fever

– Excessive sweating

– Pallor

– Dark circles around the eyes

8

The Allergic Diathesis

.

Food Allergy

Atopic dermatitis(Eczema)

Allergic rhinoconjunctivitis

(hay fever)

Asthma(cough;wheeze)

Gastrointestinal symptoms

Nervous system: Headaches Irritability

Anaphylaxis

Muscle pain

9

Anaphylaxis

• Severe reaction of rapid onset, involving most organ systems, which results in circulatory collapse and drop in blood pressure

• In the most extreme cases the reaction progresses to anaphylactic shock with cardiovascular collapse

• This can be fatal

10

Anaphylaxis• Usual progress of reaction

– Burning, itching and irritation of mouth and oral tissues and throat

– Nausea, vomiting, abdominal pain, diarrhea– Feeling of malaise, anxiety, generalized itching,

faintness, body feels warm– Nasal irritation and sneezing, irritated eyes– Hives, swelling of facial tissues, reddening– Chest tightness, bronchospasm, hoarseness– Pulse is rapid, weak, irregular, difficult to detect– Loss of consciousness– Death may result from suffocation, cardiac arrhythmia,

or shock

11

Anaphylaxis• Up to a third of cases of anaphylaxis occur in response to

foods• Not all symptoms occur in each case• Symptoms may appear in any order• Severe reactions occur within minutes to up to an hour of

ingestion of allergen• Onset can be delayed for up to two hours• The later the onset of symptoms after eating the food, the

less severe the reaction• In majority of cases of fatal anaphylactic reaction to food,

patient was asthmatic• Potential for anaphylaxis increases when patient is receiving

desensitization injections and is allergic to wasp and bee venom

12

Anaphylaxis• Almost any food can cause anaphylactic reaction• Some foods more common than others:

• Peanut

• Tree nuts

• Shellfish

• Fish

• Egg

– In children under three years• Cow’s milk

• Egg

• Wheat

• Chicken

13

Exercise-induced Anaphylaxis

• Usually occurs within two hours of eating the allergenic food

• Onset during physical activity• Foods known to have induced exercise-induced

anaphylaxis:– Celery

– Shellfish (shrimp; oysters)

– Squid

– Peaches

– Wheat

14

Emergency Treatment for Anaphylactic Reaction

• Injectable adrenalin (epinephrine)

• Fast-acting antihistamine (e.g. Benadryl)

• Usually in form of Anakit® or Epipen®

• Transport to hospital immediately

• Second phase of reaction is sometimes fatal, especially in an asthmatic– Patient may appear to be recovering, but 2-4 hours

later symptoms increase in severity and reaction progresses rapidly

15

Definition of TermsEuropean Academy of Allergy and Clinical Immunology

2001 • Allergy is a hypersensitivity reaction initiated by

immunologic mechanisms• An adverse reaction to food should be called food

hypersensitivity– When immunologic mechanisms have been

demonstrated, the appropriate term is food allergy– If the role of IgE is highlighted, the correct term is IgE-

mediated food allergy – All other reactions, previously sometimes referred to as

“food intolerance”, should be referred to as nonallergic food hypersensitivity

16

Definition of Terms

(continued) European Academy of Allergy and Clinical Immunology

2001

• Severe, generalized allergic reactions to food can be classified as anaphylaxis

• Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction.

• Atopy is a personal or familial tendency:– to produce IgE antibodies in response to low doses of

allergens, usually proteins

– and to develop typical symptoms such as asthma, rhiniconjunctivitis (hay fever) or eczema/dermatitis

17

Food Allergy & Food Intolerance DEFINITIONS: American Academy of Allergy and Immunology Committee on Adverse

Reactions to Foods, 1984

Food Allergy

“An immunologic

reaction resulting

from the ingestion

of a food or

food additive”

Food Intolerance

“A generic term

describing an abnormal

physiological response

to an ingested food or

food additive which is

not immunogenic”

18

T- Cell Lymphocytes

• T cell lymphocytes are the “controllers” of the immune response

• There are two major classes of T cells, differentiated on the basis of their cell surface receptors:– Helper T cells (Th)

• Express CD4 receptor (CD4+)• Act in conjunction with MHC class II molecules

– Cytotoxic (Tc) and Suppressor (Ts) T cells• Express CD8 receptor (CD8+)• Act in conjunction with MHC class I molecules

19

Immune Response in AllergyThe Hypersensitivity Reactions:

Antigen Recognition

• The first stage of an immune response is recognition of a “foreign antigen”

• T helper cells (CD4+ subclass) identify the foreign protein as a “potential threat”

• Cytokines are released

• The types of cytokines produced control the resulting immune response

20

T-helper Cell Subclasses

• There are two subclasses of T-helper cells, differentiated according to the cytokines they release:

– Th1– Th2

– Each subclass produces a different set of cytokines

21

Significant Cytokines of the T-Cell Subclasses

• Th1 subclass produces:

» Interferon-gamma (IFN-)

» Interleukin-2 (IL-2)

» Tumor necrosis factor alpha (TNF)

» IL-12

• Th2 subclass produces:

» Interleukin-4 (IL-4)

» Interleukin-5 (IL-5)

» Interleukin-6 (IL-6)

» Interleukin-8 (IL-8)

» Interleukin-10 (IL-10)

» Interleukin-13 (IL-13)

22

T-helper cell subtypes

• Th1 triggers the protective response to a pathogen such as a virus or bacterium– IgM, IgG, IgA antibodies are produced

• Th2 is responsible for the Type I hypersensitivity reaction (allergy)– IgE antibodies are produced

23

TH1 TH2 InteractionsFactors promoting:

Th1- Bacterial and viral infections - Maturation of the immune system - Antigen tolerance

Th2- Parasite infestations- Immature immune system- Sensitization to antigen

24

TH1 TH2 InteractionsFactors promoting:

Th1- Bacterial and viral infections - Maturation of the immune system - Antigen tolerance

Th2- Parasite infestations- Immature immune system- Sensitization to antigen

Predisposing factors:- Genetic inheritance- Early exposure to allergen- Increased antigen uptake

25

T-Cells in the Immune and Allergic Response

Stage 1: Protein enters• Antigen (protein molecule) enters body• It is taken up by an antigen-presenting cell (APC)

– Examples of APCs:• Dendritic cells

• Monocytes and macrophages

• B cell lymphocytes

• Partial activation of the T-cell occurs

26

T-Cells in the Immune and Allergic Response continued

Stage 2: To respond or not?

• The new antigen is recognized by T-helper cells (CD4+)• The antigen is compared to “self-antigens” and is identified

as “self” or “foreign”• If “foreign”, a second signal is supplied by the T-cells via the

CD28/CD8 or CD40/CD40 receptor-ligand complex which leads to:

ACTIVATION OF THE IMMUNE RESPONSEaccompanied by cytokine and antibody production

• If “self”, no second signal is conveyed and the T-cells assume a temporary state of unresponsiveness

27

Role of T-cell Lymphocytes

When conditions interfere with the process of tolerance, T-cells are activated:

• A Th1 response (IgM and IgG with activation of the complement cascade) is likely to induce damage to the mucosa– in response to food this may be a

PROTEIN-SENSITIVE ENTEROPATHY

• A Th2 response leads to an IgE-mediated hypersensitivity reaction– in response to food this may be

IMMEDIATE-TYPE ALLERGY or anaphylaxis

28

T cells in Foetal Life

• Neonates with and without a family history of atopy display Th2 activity– various combinations of IL-4; IL-5; IL-9 are detectable– IFN below level of detection

Rationale:• In a successful pregnancy the foetus is embedded in

a Th2 cocktail: • A Th1 environment may predispose to foetal

rejection• High levels of IL-4, IL-10, PGE2 and progesterone

maintains a barrier to Th1 response at the maternal-foetal interface

29

Maturing of the Immune System

• Postnatally, Th1 response progressively increases with age

• However, remains “deficient” relative to adult levels for varying periods during childhood

• Deficit seems to be at the level of APCs, especially dendritic cells

• APC fails to provide appropriate immune-deviating signals during T cell activation

• This deficit is more pronounced in atopic individuals

30

The Th2 Response in Allergy

Synthesis of IgE• Naïve B cells are activated by cytokines• IgM is formed first• Specific antibodies are then produced in a

process of class switching, driven by exposure to specific antigens

• The immature B cell matures into a “virgin” B cell that expresses both IgM and IgD

31

B cell Maturation and Production of Antibody

• In the presence of antigen, B cells expressing specific antibodies are selected

• Others are eliminated by apoptosis• Class switching occurs at this stage• The direction of switching is regulated by

cytokines secreted by the Th cells– IL-4, and to a lesser extent IL-13 from Th2 cells

causes switching to IgE– IFN produced by Th1 cells inhibits switch to IgE

32

Control of IgE Production

• Overproduction of IgE leads to hypersensitivity

• IgE mediates the release of inflammatory mediators from a variety of granulocytes, including:

– Mast cells

– Basophils

– Eosinophils

33

Conditions that may Induce T-cell Response in Food Allergy

• Inherited allergic potential• Immaturity of the immune system (the TH2

response predominates in the neonate)• Inflammatory conditions in the gut that interfere

with the normal antigen processing pathway• Immaturity of the digestive mucosa leading to

hyperpermeability• Increased uptake of antigens

34

Immune Response in Allergy: Early Response

• Allergic responses are biphasic– Cytokines regulate each stage of the immune

response• Early Response

– IgE-mediated activation of granulocytes (mast cells; basophils)

– Release of inflammatory mediators (histamine; prostaglandins; leukotrienes)

35

Immune Response in Allergy: Early Response continued

• Clinical manifestations:– Upper airways:

sneezing, itching, rhinorrhoea, nasal congestion

– Lower airways: bronchoconstriction, dyspnoea, wheezing, cough

– Skin: wheal, flare, itching, reddening

36

Immune Response in Allergy: Late Response

• Late Response– Mediated by chemotactic factors (chemokines;

LTB4; PGD2) from early phase– Move lymphocytes, monocytes, neutrophils,

basophils, eosinophils to reactive tissues– These new granulocytes release their own

battery of inflammatory mediators– The allergic response is augmented– This can be the life-threatening stage of an

anaphylactic reaction or an asthma attack

37

Mast Cells

Central to inflammation and the allergic response Release of mast cell mediators by allergen is the

initiating step of the early phase response Initiation and control of allergic inflammation is

effected by mast cell generation of:HistamineProteasesEicosanoids (prostaglandins; leukotrienes)Cytokines

38

Mast Cells

• Filled with granules containing preformed inflammatory mediators in proteoglycan (mostly heparin) matrix

• When mast cell is activated:– Granules swell– Contents become solubilised– Individual mediators are expelled into the local

extracellular environment– Process known as “degranulation”

39

IgE-mediated hypersensitivity Intracellular Granules are Released

40

Mediator ReleaseALLERGEN + IgE

MAST CELL

CHANGE IN CELL ENERGY

ADENYLATE CYCLASE-cAMP

CALCIUM ENTERS CELL

DEGRANULATION

Pre-formed Mediators

HISTAMINE

HEPARIN

CHEMOTAXINS

ENZYMES :

- PHOPHOLIPASE A2

Release of Inflammatory Mediators

Secondary Mediators:PROSTAGLANDINS: PG-2LEUKOTRIENES: LT-4

ArachidonicAcid

41

Action of Inflammatory Mediators on Tissues:

Histamine • Vasodilation• Swelling of tissues• Increased vascular permeability

– angioedema (swelling)– rhinitis (stuffy nose)– rhinorrhea (runny nose)– urticaria (hives)– otitis media (earache)

• Pruritus (itching)• Flushing• Reddening

Antidote:Antidote: AntihistaminesAntihistaminesBlock histamine receptors (HBlock histamine receptors (H11;; HH22) ) on reactive cellson reactive cells

42

Inflammatory Mediators

Enzymes• Tryptase; chymase; carboxypeptidase; cathepsin

G: – Act directly on tissues and cause damage

Phospholipase A2• Acts on cell membrane and releases arachidonic

acid• Leads to production of secondary inflammatory

mediators by two enzyme pathways:– Cyclo-oxygenase to prostaglandins– Lipoxygenase to leukotrienes

43

Secondary Mediator Release

Arachidonic acid

Lipoxygenase

LEUKOTRIENES

LTA4

LTB4LTC4

LTD4

LTE4

Cyclo-oxygenase

PROSTAGLANDINS

(PG2)

PROSTACYCLIN

(PGI2)

THROMBOXANE

(TX)

44

Action of inflammatory mediators: Leukotrienes

• LTB4 : Chemotaxin:

– Attracts more leukocytes to reaction site

– Augments allergic reaction

• LTC4; LTD4; LTE4:

– Smooth muscle contraction

– Responsible for bronchospasm of asthma

– Involved in inflammatory process in eczema

45

Prostaglandins

• Chemoattractant : PGD2

• Smooth muscle contraction and relaxation

• Dilation and constriction of blood vessels

• Increase vascular permeability

• Responsible for pain

46

Summary: IgE-mediated Hypersensitivity

• Food allergen cross-links two IgE antibodies

attached to FcRI receptors on mast cell• Mast cells are degranulated and release preformed

inflammatory mediators • Secondary cells of inflammation (eosinophils,

neutrophils, basophils, lymphocytes) are recruited by chemotactic factors including chemokines

47

Summary: IgE-mediated Hypersensitivity

• Results in local symptoms in the gut (abdominal pain; diarrhoea)

• Allows increased absorption of the same and other antigens through the gut epithelium

• Leads to systemic effects such as mast cell activation in– lungs: asthma

– skin: urticaria, angioedema, eczema

– multiple organ systems: anaphylaxis

48

Immune complex-mediated reactions

IgM and IgG antibodies are frequently formed against food antigens

• IgG4 subclass is a high-affinity antibody for food antigens

When food antigens pass into circulation they complex with their homologous antibodies

• The immune complexes are usually rapidly cleared from circulation and do not cause

any pathology

49

IgG-mediated HypersensitivityContinued

• Tissue damage may result if there are high concentrations of complexes

• High concentrations of complexes triggers the complement cascade

• Anaphylatoxins formed by the complement pathway induce release of inflammatory mediators

Sequence of Reactions in the Complement Cascade

Antigen Antibody

A (IgG or IgM)

S

Antigen - Antibody

Complex

AS

AS, C1qrs

AS, C1qrs, C4b, 2a

AS, C1qrs, C4b, 2a, 3b

AS, C1qrs, C4b, 2a, 3b, C5b

AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7

AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7, 8, 9

Membrane damaged cell

LYSIS

C1q

C1r +Ca++

C1s

C4

C2 Mg++

C4a

C2b

“Recognition Complex”

Alternative pathway enters here C3

C3a Anaphylatoxin (degranulation)

C5 C5a

Chemotaxin Anaphylatoxin (degranulation)

C6

C7

C8

C9

51

IgG-mediated HypersensitivityContinued

• If antigen is present in excess, the immune complexes may be deposited in vessel walls where an inflammatory reaction with fever is provoked:– in skin: urticaria

angioedema– in kidneys: albuminuria– in joints: arthritis

52

Food Specific IgG and Tolerance

• Clinical evidence suggests that specific IgG to a food that previously triggered production of IgE is a sign of tolerance

• Theoretically:– Food antigen now elicits Th1 response rather

than Th2– Low level of IgG does not trigger complement

cascade– Food antigen-IgG complex is removed in

normal process of phagocytosis