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