Type I Hypersensitivity

ReactionsEduardo Moreno

BIOL 4400 Dr. Dunkley

April 27th, 2015

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

Types of Hypersensitivity Reactions1

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

Identification of IgE in Skin Sensitization1

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

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

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

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

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

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

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

Effects Caused By Mediators1

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

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

Immune Basis For Some Food Allergies1

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

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

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

References

• Owen, Punt, and Stranford. Kuby Immunology. W.H. Freeman and Company, New York. Print.