type 1 hypersensitivities
DESCRIPTION
ImmunityTRANSCRIPT
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Type I Hypersensitivity
ReactionsEduardo Moreno
BIOL 4400 Dr. Dunkley
April 27th, 2015
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Background
• Paul Portier and Charles Richet • First to recognize and describe hypersensitivities • Studies
• Two types of hypersensitivities • Immediate • Delayed
• P.G.H Gell and R.R.A. Coombs • Type I• Type II • Type III• Type IV
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Types of Hypersensitivity Reactions1
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Allergy: A Type I Hypersensitivity Reaction
• More than half of the US population suffer from T1HR• Hay fever, asthma, atopic dermatitis, and food allergies
• IgE antibodies are responsible
• K. Ishizaka and T. Ishizaka • Studies • They were the ones to confirm that IgE antibodies are responsible for T1HR
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Identification of IgE in Skin Sensitization1
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Allergens that Elicit Type I Hypersensitive Reactions
• Healthy individuals generate IgE antibodies to fight parasitic infections • Atopic individuals • Generate large amounts of IgE antibodies against common environmental
antigens
• Most antigens are either protein or glycoprotein in nature and have more than one antigenic sites or epitopes • Shared features • Enzymatic activity • Contain potential PAMPs • Enter via mucosal tissues
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Mechanism Cross-Linking of IgE Antibodies with FcεR Receptors
• FcεR receptors are found on mast cells, basophils, and eosinophils • Binding causes degranulation of host
cells • Two types of receptors
• FcεRI• Mast cells and basophils contain high levels • Affinity 1010 M-1
• FcεRIII (CD23)• Affinity 106 M-1 • Two isoforms • Membrane bound or soluble
FcεRIII Receptor1
FcεRI Receptor1
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Mechanism (cont.) Regulation of Receptor Signaling
• Inhibitory Receptors • FcγRIIB• ITIMs • Causes inhibition • Caused by the binding of IgG • Useful in therapies
• Inhibition of Downstream Molecules • Phosphatases • Kinases
• Lyn• Ubiquitin ligases
Signaling Pathways Initiated By IgE Cross-Linking1
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Molecules Produced
• They act on secondary effector cells• Mast cells, basophils, eosinophils, neutrophils, T cells, monocytes, and
platelets
• Two types • Primary
• Preformed and stored in granules • Histamines, proteases, ECF, NCF, and heparin
• Secondary • Synthesized after target cell activation or released by breakdown of cell membrane • PAF, leukotrienes, prostaglandins, bradykinins, cytokines, and chemokines
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Molecules Produced (cont.)Histamines
• Formed by decarboxylation of histidine • Accounts for 10% of granule mass • Four different receptors • H1
• Most allergic effect is accounted to this receptor
• H2• Binding on receptors found on mast cells and
basophils suppresses degranulation • H3• H4
Decarboxylation of Histidine
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Molecules Produced (cont.)Leukotrienes and Prostaglandins
• Formed after cell degranulation and phospholipase signaling initiates breakdown of phospholipids in the plasma membrane • Asthmatic response • Initial contraction is mediated by histamines • Further contraction mediated by leukotrienes and prostaglandins • 1000 times more effective
• Most potent stimulators of vascular permeability and mucus secretion
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Molecules Produced (cont.)Cytokines and Chemokines
• Many are released • IL-4 and IL-13
• Stimulate Th2 response • IL-5
• Recruitment and activation of eosinophils • TNF-α
• High concentrations contribute to systemic anaphylaxis • IL-8
• Chemotactic factor • GM-CSF
• Stimulates activation and production of myeloid cells
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Effects Caused By Mediators1
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Categories of Type I Hypersensitive Reactions
Systemic Anaphylaxis • Anaphylaxis: shock-like and often fatal state that occurs within minutes of
exposure to an allergen • Allergen is either introduced directly into the blood stream or it’s absorbed
in the GI tract • Symptoms
• Labored respiration and a precipitous drop in blood pressure anaphylactic shock contraction of smooth muscles defecation, urination, and bronchial constriction asphyxiation and death in 2 to 4 minutes
• Triggers• Venom • Drugs • Foods
• Epinephrine
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Categories of T1HRLocalized Hypersensitivity Reactions
• Limited to a specific tissue or organ • Examples • Allergic rhinitis, asthma, atopic dermatitis, and food allergies
• Allergic rhinitis • Affects more than 50% of the US population
• Food allergies • Incidence is on the rise • Accounts for more anaphylactic responses in children • Common allergens
• Adults: nuts, fish, and shellfish • Children: cow’s milk, eggs, peanuts, tree nuts, soy, wheat, fish, and shellfish
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Immune Basis For Some Food Allergies1
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Diagnosis and Treatments
• Commonly assessed by skin testing • Allergens are introduced • Reexamined 30 minutes later • Redness and swelling indicates allergic response
• Treatments • Avoid causative agent • Hyposensitization
• Repeated exposure to low doses of antigen • It may increase the abundance of non-inflammatory antibodies • Most successful treatment
Skin Test1
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Diagnosis and Treatments (cont.)
• Treatments (cont.) • Antihistamines
• Allergic rhinitis • Leukotriene antagonists
• More effective than antihistamines • Inhalation of corticosteroids • Immunotherapeutics
• Anti-IgE antibodies • Other medications
• Epineprhine • Theophylline
Mechanisms Underlying Hyposensitization1
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The Hygiene Hypothesis
• T1HR have increased dramatically over the past two decades. WHY?• Studies conducted in Europe, US, Australia, and New Zealand • Results
• Children exposed to farm environment were less likely to suffer from T1HRs• Exposure of pregnant women or babies to barns and stables resulted in a decreased
tendency to develop T1HRs later in life
• Hygiene Hypothesis • Exposure to some pathogens during infancy and youth benefits individuals • Has been advanced to explain increases in the incidence of all allergic
responses • Studies are still ongoing
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References
• Owen, Punt, and Stranford. Kuby Immunology. W.H. Freeman and Company, New York. Print.