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Transcript
Food Allergy: Symptoms and Immunological Mechanisms Janice M. Joneja, Ph.D., R.D. 2007 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 2 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) 3 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) 4 Examples of Allergic Conditions and Symptoms • Digestive Tract – – – – – – – Diarrhea Constipation Nausea and Vomiting Abdominal bloating and distension Abdominal pain Indigestion (heartburn) Belching 5 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 6 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 7 The Allergic Diathesis Atopic dermatitis (Eczema) . Gastrointestinal symptoms Nervous system: Headaches Irritability Food Allergy Asthma (cough; wheeze) Muscle pain Allergic rhinoconjunctivitis (hay fever) Anaphylaxis 8 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 9 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 10 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 11 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 12 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 13 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 14 Definition of Terms European 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 IgEmediated food allergy – All other reactions, previously sometimes referred to as “food intolerance”, should be referred to as nonallergic food hypersensitivity 15 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 16 Food Allergy & Food Intolerance DEFINITIONS: American Academy of Allergy and Immunology Committee on Adverse Reactions to Foods, 1984 Food Allergy Food Intolerance “A generic term “An immunologic describing an abnormal reaction resulting physiological response from the ingestion to an ingested food or of a food or food additive which is food additive” not immunogenic” 17 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 18 Immune Response in Allergy The 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 19 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 20 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) 21 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 22 TH1 TH2 Interactions Factors promoting: Th1 - Bacterial and viral infections - Maturation of the immune system - Antigen tolerance Th2 - Parasite infestations - Immature immune system - Sensitization to antigen 23 TH1 TH2 Interactions Factors 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 24 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 25 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 RESPONSE accompanied by cytokine and antibody production • If “self”, no second signal is conveyed and the Tcells assume a temporary state of unresponsiveness 26 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 27 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 28 maternal-foetal interface 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 immunedeviating signals during T cell activation • This deficit is more pronounced in atopic individuals 29 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 30 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 31 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 32 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 33 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) 34 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 35 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 36 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: Histamine Proteases Eicosanoids (prostaglandins; leukotrienes) Cytokines 37 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” 38 IgE-mediated hypersensitivity Intracellular Granules are Released 39 Mediator Release ALLERGEN + IgE MAST CELL CHANGE IN CELL ENERGY ADENYLATE CYCLASE-cAMP CALCIUM ENTERS CELL DEGRANULATION Release of Inflammatory Mediators Pre-formed Mediators HISTAMINE HEPARIN CHEMOTAXINS ENZYMES : - PHOPHOLIPASE A2 Arachidonic Acid Secondary Mediators: PROSTAGLANDINS: PG-2 LEUKOTRIENES: LT-4 40 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) Antidote: Antihistamines • Flushing Block histamine receptors (H1; H2) • Reddening on reactive cells 41 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 42 Secondary Mediator Release Arachidonic acid Cyclo-oxygenase Lipoxygenase PROSTAGLANDINS LEUKOTRIENES (PG2) LTA4 PROSTACYCLIN (PGI2) LTC4 LTD4 THROMBOXANE LTE4 (TX) LTB4 43 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 44 Prostaglandins • • • • • Chemoattractant : PGD2 Smooth muscle contraction and relaxation Dilation and constriction of blood vessels Increase vascular permeability Responsible for pain 45 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 46 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 47 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 48 IgG-mediated Hypersensitivity Continued • 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 49 Sequence of Reactions in the Complement Cascade Antigen A C1q C1r +Ca++ C1s Antibody (IgG or IgM) S Antigen - Antibody Complex AS “Recognition Complex” AS, C1qrs C4 C4a Mg++ C2 Alternative pathway enters here C3 AS, C1qrs, C4b, 2a AS, C1qrs, C4b, 2a, 3b C5 C6 AS, C1qrs, C4b, 2a, 3b, C5b C7 AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7 C8 C9 AS, C1qrs, C4b, 2a, 3b, C5b, 6, 7, 8, 9 Membrane damaged cell LYSIS C2b C3a Anaphylatoxin (degranulation) C5a Chemotaxin Anaphylatoxin (degranulation) IgG-mediated Hypersensitivity Continued • 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: – in kidneys: – in joints: urticaria angioedema albuminuria arthritis 51 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 52