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IgE and type I hypersensitivity

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Presentation on theme: "IgE and type I hypersensitivity"— Presentation transcript:

1 IgE and type I hypersensitivity
Kammi Henriksen, MD Department of Pathology

2 Outline Clinical case Immediate (type I) hypersensitivity
Activation of TH2 cells and production of IgE Sensitization and activation of mast cells Mediators of immediate hypersensitivity Late phase reaction Local immediate hypersensitivity reactions Systemic anaphylaxis Development of allergies

3 Case study A 35 year old female with a long-standing history of asthma presents to the ER with acute shortness of breath and audible wheezing Her asthma had been well-controlled until this past year She now has daily symptoms and nightly nocturnal awakenings due to shortness of breath, which is temporarily relieved with bronchodilators She had several exacerbations in the past 6 months requiring hospitalization Symptoms worsen each time she completes a steroid taper Past medical history is significant for seasonal allergies and chronic sinusitis requiring three surgeries Medications include: fluticasone/salmeterol, zileuton, prednisone, montelukast, and albuterol prn which she is currently using 4 times daily Combination of inhaled steroids, leukotriene receptor antagonists, and beta2-adrenergic receptor agonists

4 Case study Physical exam
BP: 150/95 RR: 44/min Oxygen saturation: 92% Pulmonary exam significant for diffuse expiratory wheezes and prolonged expiratory phase Cardiac exam normal CXR was ordered to rule out a superimposed process, such as lobar pneumonia CXR was significant for hyperinflated lungs but was otherwise unremarkable

5 Diagnosis: Severe/refractory asthma
Major Criteria Treatment with continuous or near-continuous oral steroids Treatment with high-dose inhaled corticosteroids  Minor Criteria Additional daily controller medicine Use of short-acting beta-agonist agent on a near-daily basis Persistent airway obstruction FEV<80% Diurnal variation in peak flow >/= 25% At least one urgent care visit per year Three or more steroid bursts per year Prompt deterioration with 25% reduction in steroid dose Episode of near-fatal asthma Patients must have at least one major and two minor criteria

6 Asthma Chronic inflammatory disorder of airways in which many cells and cellular elements play a role, including mast cells and eosinophils Causes episodes of wheezing, breathlessness, chest tightness, and coughing Episodes associated with widespread airflow obstruction that is often reversible, either spontaneously or with treatment Very common, affecting million Americans Causes 3,000 US deaths annually Incidence has steadily increased in the Western hemisphere over the past 40 years

7 Histology: Asthma Inflammatory cells including eosinophils and mast cells Increased mucosal goblet cells and submucosal glands Thickened basement membranes Underlying smooth muscle hypertrophy Normal respiratory mucosa

8 Sputum findings in Asthma
Curschmann’s spirals Spiral-shaped mucous plugs from subepithelial mucous gland ducts or bronchioles Charcot-Leyden crystals Microscopic crystals in people with allergic disease or parasitic infection Composed of lysophospholipase, released by breakdown of eosinophils

9

10 Immediate (Type I) Hypersensitivity
Allergic reactions, or “allergies” Induced by environmental antigens (allergens) that stimulate strong TH2 responses and IgE production in genetically susceptible individuals Rapid immunologic reaction occurring in a previously sensitized individual Triggered by the binding of an antigen/allergen to IgE antibody on the surface of mast cells Caused by excessive TH2 response, resulting in IgE production and inflammation

11 Allergens Many allergies are induced by small proteins that reproducibly elicit an IgE response in susceptible individuals Most allergens are small and highly soluble Many are enzymes, especially proteases Allergens are carried on dry particles (e.g. pollen, cat dander) and upon contact with the mucosa they elute from the particle and diffuse into the mucosa Typically presented to the immune system at very low doses (e.g. allergens in ragweed at ~ 1 ug/yr)

12 Immediate (Type I) Hypersensitivity
Systemic disorder - Anaphylaxis Injection (bee sting) Ingestion (peanut allergens) Local reaction Skin (rash, blister, hives) Nasal and conjunctival discharge (allergic rhinitis and conjunctivitis) Bronchial asthma Allergic gastroenteritis

13 Immediate hypersensitivity: 2 phases
Immediate reaction (within minutes): vasodilation and vascular leakage (edema), smooth muscle spasm, glandular secretions Subsides within hours Late-phase reaction (2-24 hours): infiltration of tissues by eosinophils, basophils, monocytes, and CD4+ T cells, accompanied by mucosal/epithelial damage May last for several days

14 Early stages: Activation of TH2 cells and production of IgE
Dendritic cells capture antigen/allergen at site of entry and present to naïve CD4+ helper T cells In response to antigen/allergen and other stimuli (IL-4 produced at local site), they differentiate into TH2 cells Some environmental antigens (allergens) elicit strong TH2 responses – mechanism is poorly understood Defense system against parasites is anatomically distributed to their sites of entry (skin, respiratory mucosa, GI-associated lymphoid tissue) CD4+ cells at these sites are programmed to secrete cytokines that drive the TH2 response New TH2 cells produce cytokines (IL-4, IL-5, IL-13), inducing B cells to class switch to IgE IL-4 promotes development of additional TH2 cells IL-5 activates eosinophils IL-13 enhances IgE production and induces epithelial cells to stimulate mucus secretion TH2 cells and mast cells produce chemokines to attract more TH2 cells and other leukocytes to site

15 IL-4, IL-13 IgE-coated mast cells are “sensitized”

16 Mast cells Bone marrow-derived cells
Circulating counterpart - basophils Abundant near blood vessels and nerves, and in subepithelial tissues Cytoplasmic membrane-bound granules containing biologically active mediators Acidic proteoglycans

17 Mast cells Degranulation of mast cells, e.g., in response to allergens

18 Mast cell activation Cross-linking of high-affinity IgE Fc receptors (FceRI) IgE-coated mast cells are “sensitized” – sensitive to subsequent encounter with specific antigen Also triggered by other stimuli: Complement components C5a and C3a (“anaphylatoxins”) Chemokines (IL-8) Drugs (codeine and morphine) Melittin (present in bee venom) Physical stimuli (cold, heat, sunlight)

19 Sensitization and Activation of Mast Cells
Repeat exposure to antigen/allergen Binds to IgE antibodies previously attached to mast cells Multivalent antigens bind to and cross-link adjacent IgE antibodies previously attached to mast cells – activate signal transduction pathways Production of mediators responsible for immediate hypersensitivity

20 Mast cell activation and degranulation
Histamine receptors: H1 on bronchial smooth muscle -> constriction H2 on vascular smooth muscle -> vasodilation

21 Mast cell mediators

22 Mast cell mediators of immediate hypersensitivity
Preformed (primary) mediators Vasoactive amines: histamine Bronchial smooth muscle contraction Vasodilation and increased vascular permeability Increased mucus secretion by nasal, bronchial, and gastric glands Enzymes: neutral proteases (chymase, tryptase) and acid hydrolases Cause tissue damage and lead to generation of kinins and activated complement components (C3a) Proteoglycans: heparin (anticoagulant) and chondroitin sulfate Secondary mediators

23 Mast cell mediators of immediate hypersensitivity
Preformed (primary mediators) Secondary mediators Lipid mediators: arachidonic acid-derived products (derived from activation of phospholipase A2) Leukotrienes C4 and D4: the most potent vasoactive and spasmogenic agents known; increase vascular permeability and induce bronchial smooth muscle contraction Leukotriene B4: highly chemotactic for neutrophils, eosinophils, and monocytes Prostaglandin D2: bronchospasm and increased mucus secretion Platelet-activating factor (PAF): causes platelet aggregation, release of histamine, bronchospasm, increased vascular permeability, and vasodilation Cytokines 5-lipoxygenase pathway produces leukotrienes Cyclooxygenase pathway produces prostaglandins

24 Mast cell mediators of immediate hypersensitivity
Preformed (primary mediators) Secondary mediators Lipid mediators Cytokines TNF, IL-1, and chemokines: promote leukocyte recruitment (late-phase reaction) IL-4: amplifies TH2 response Recruited inflammatory cells produce additional cytokines and cause epithelial cell damage

25 Late phase reaction Leukocytes are recruited to amplify and sustain the inflammatory response (without additional exposure to triggering antigen) Major cause of symptoms in some type I disorders, such as allergic asthma Therefore, treatment requires broad-spectrum anti-inflammatory drugs (steroids) rather than just anti-histamines Eosinophils are abundant Recruited by chemokines (eotaxin) and other products of epithelial cells, mast cells, and TH2 cells Activated by IL-5 Liberate proteolytic enzymes, major basic protein, and eosinophil cationic protein, which damage tissues

26 Eosinophil mediators

27 Actions of mast cells and eosinophils

28 Immediate Hypersensitivity: Clinical Manifestations
Clinical Syndrome Clinical and Pathologic Manifestations Anaphylaxis (drugs, bee sting, food) Fall in blood pressure (shock) caused by vascular dilation; airway obstruction due to laryngeal edema Bronchial asthma Airway obstruction caused by bronchial smooth muscle hyperactivity; inflammation and tissue injury caused by late phase reaction Allergic rhinitis, sinusitis (hay fever) Increased mucus secretion; inflammation of upper airways and sinuses Food allergies Increased peristalsis due to contraction of intestinal muscles

29 Local Immediate Hypersensitivity Reactions
10-20% of the population suffers from allergies involving localized reactions to common environmental allergens Pollen, animal dander, house dust, foods, etc Specific diseases: urticaria (hives), allergic rhinitis (hay fever), bronchial asthma, and food allergies

30 Urticaria: “Wheal and flare” reaction
Distinctive response utilized in allergy testing In response to release of mast cell mediators, local blood vessels dilated and become leaky Produces redness and local swelling (wheal) – black arrow Subsequent dilation of vessels at edge of swelling appears like a red rim (flare) – blue arrow

31 Systemic Anaphylaxis Most severe form of immediate hypersensitivity
Systemic reaction characterized by edema in many tissues (including the larynx) and vascular shock (sudden fall in blood pressure) Life threatening due to airway obstruction and shock Triggers: bee venom, injected or ingested penicillin-family antibiotics, and ingested food allergens (nuts, shellfish) Extremely small doses of antigen may trigger anaphylaxis

32 Signs and symptoms of systemic anaphylaxis

33 Natural history of systemic anaphylaxis
Within minutes: itching, hives, skin erythema Striking contraction of respiratory bronchioles and respiratory distress Laryngeal edema results in hoarseness and further compromises breathing Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction Patient may go into shock and die within an hour of onset

34 Treatment of Systemic Anaphylaxis
Epinephrine: a 2-adrenergic agonist - Binds to receptors on vascular and bronchial smooth muscle cells - Constricts the blood vessels, stopping vascular leak and raising BP - Dilates bronchi and relieves wheezing and other respiratory symptoms

35 Immediate Hypersensitivity: Therapy
Aimed at inhibiting mast cell degranulation, antagonizing the effects of mast cell mediators, and reducing inflammation

36 Development of Allergies
Genetic susceptibility “Atopy” = increased propensity to develop immediate hypersensitivity reactions Triad: eczema, allergic rhinitis, and asthma Atopic individuals have higher serum IgE levels and more IL-4-producing TH2 cells than the general population Positive family history of allergy in 50% of atopic individuals Studies in patients with asthma reveal linkage to polymorphisms in several genes (5q31) including IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF Linkage has also been noted to 6p, close to the HLA complex Environmental factors

37 Genetic susceptibility to allergies

38 Susceptibility loci identified by genome screens for asthma, atopic dermatitis, and other immune disorders Clustering of disease-susceptibility genes is found for the MHC on chromosome 6p21, and several other regions Little overlap between susceptibility genes for asthma and atopic dermatitis Some overlap of susceptibility genes for asthma and autoimmune diseases, and between those for psoriasis and atopic dermatitis

39 Development of Allergies
Genetic susceptibility Environmental factors Exposure to environmental pollutants (common in industrialized societies) is a predisposing factor for allergy Viral infection of airways triggers bronchial asthma Bacterial skin infections are strongly associated with atopic dermatitis

40 Hygiene hypothesis Incidence of many allergic disease is increasing in developed countries Possibly related to decreased infections in early life Early childhood/prenatal exposure to microbial antigens educates the immune system such that subsequent pathologic responses against common environmental allergens are prevented

41 Why does this immune response exist?
Why has evolution preserved an IgE antibody-mediated and mast cell-mediated immune response, whose major effects are pathologic? Likely evolved to protect against pathogens or toxins IgE and eosinophils are important mechanisms of defense against helminthic infections Mast cells play a role in innate immunity against some bacteria and in destroying venomous toxins

42 Summary: Immediate (type I) hypersensitivity
Allergic reactions induced by environmental Ags that stimulate strong TH2 responses and IgE production in genetically susceptible individuals IgE coats mast cells by binding to Fce receptors; reexposure to allergen leads to cross-linking of the IgE and FceRI, activation of mast cells, and release of mediators Principal mediators: histamine, proteases, and other granule contents; prostaglandins and leukotrienes; and cytokines Mediators are responsible for the immediate vascular and smooth muscle reactions and the late-phase reaction (inflammation) Clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis

43 Extras

44 Asthma subgroups ● Atopic or Extrinsic: Type I hypersensitivity, generally due to allergens; begins in childhood, triggered by environmental allergens (dander, dust, pollen, food), often positive family history; more common in African American children; evidence of allergen sensitization; skin test causes wheel and flare reaction ● Noneosinophilic (“neutrophilic”) asthma; a subgroup of atopic asthma not associated with eosinophilia; IL8 recruiting neutrophils are an important mechanism; patients tend to be less responsive to corticosteroids ● Nonatopic or Intrinsic: non-immune; due to aspirin ingestion, pneumonia, cold, stress, exercise; follows respiratory infection (rhinovirus, parainfluenza virus); usually not familial; no evidence of allergen sensitization; normal serum IgE, negative skin tests; viral induced inflammation may lower threshold of subepithelial vagal receptors to irritants ● Occupational asthma: due to repeated exposure to fumes, dusts, gases, chemicals, often in minute quantities; varying mechanisms of disease depending upon the stimulus ● Drug induced asthma: associated with several drugs, but most noteworthy is aspirin use; rare, aspirin related cases are associated with recurrent rhinitis, nasal polyps and urticaria; patients are sensitive to small doses of aspirin; may be due to direct effects of aspirin on cyclooxygenase pathway ● Status asthmaticus: unremitting attacks due to exposure to previously sensitized antigen; may be fatal, usually in patients with a long history of asthma


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