Hypersensitivity Reactions Flashcards
Hypersensitivity (Allergy) (3)
- exaggerated and inappropriate reaction to an otherwise harmless antigen
- immune system is reacting in a damaging rather than a protective fashion
- may develop during humoral or cell-mediated immune responses
Immediate hypersensitivity reactions
-Hypersensitivity reactions involving antibody or antibody-antigen complexes (i.e., humoral) are characterized by symptoms that manifest within minutes or hours
Type I-IgE-mediated Hypersensitivity-First Exposure
- On first exposure, Th2 response to allergen results in IgE production by plasma cells
- IgE binds to high affinity Fcε receptors on the surface of eosinophils, basophils and mast cells, ‘sensitizing’ these cells.
Type I-IgE-mediated Hypersensitivity-Second Exposure
Second exposure to the allergen cross-links Fc(E)RI-bound IgE, causing degranulation and release of pharmacologically active mediators
Allergens
- nonparasitic antigens that stimulate type I hypersensitivity reactions in allergic individuals
- Most responses occur at mucous membranes
Atopy
A hereditary tendency in some individuals to make IgE in response to common environmental antigens
- This results in tissue-damaging IgE-mediated hypersensitivity reactions
- have high serum IgE and increased number of circulation eosinophils
Type 1 hypersensitivity-parasites
-believed to be related to clearance of parasites
Systemic anaphylaxis
a shock-like and often fatal type I hypersensitivity reaction
High affinity receptor for IgE (FcεRI)
- consists of 4 polypeptide chains
- The α chain interacts with IgE Fc region
- the β chain links the α chain to the disulfide- linked gamma chain homodimer.
- Each gamma and beta chain possesses an ITAM that interacts with TKs to transduce an activating signal
Low affinity receptor for IgE (FcεRII; CD23)
- The FcεRII consists of a single type II polypeptide chain
- involved in regulating IgE response and depends on interactions between IgE/CD23 and soluble CD23 binding to CD21 on the B cell.
Cell types expressing FCεR- Mast cells (4)
- Large, granulated mononuclear cells derived from bone marrow precursors
- Tissue mast cells are found in connective tissue near nerves and surrounding blood vessels
- Mucosal mast cells are found in the mucosa lining the gut and lungs
- Express high affinity receptors for the Fc portion of IgE
- Synthesize and secrete allergic mediators, as well as a large number of cytokines.
Cell types expressing FCεR-Basophils
- Circulating white blood cell that resembles mast cells
- Recruited from the blood into inflamed tissue.
- Granulated morphology with a multi-lobed nucleus; Express high affinity receptors for the Fc portion of IgE.
- Synthesize and secrete allergic mediators
Sensitization Phase of IgE mediated hypersensitivity reactions
- Following antigen presentation, Th2 cells make IL-4, IL-5 and IL-13, B cells switch to IgE
- IgE binds to high affinity IgE Fc receptors on tissue mast cells and blood-borne basophils
- IgE stable longer when bound to receptor
Sensitization Phase of IgE mediated hypersensitivity reactions-PCA
- passive cutaneous anaphylaxis
- passive transfer of IgE-containing serum will sensitize skin mast cells
Activation Phase of IgE mediated hypersensitivity reactions
-Cross linking of at least two high affinity IgE Fc receptors (and bound IgE) triggers mast cell and basophil degranulation
Cross linking by
-multivalent allergen
-anti-IgE antibody
-anti-Fc receptor antibody
-aggregated IgE.
-non IgE activators of mast cells include C3a, C5a, cold, exercise, neuropeptides
Early Effector Phase of IgE mediated hypersensitivity reactions- Mediators
-effector phase mediated by primary and secondary mediators that are released by activated mast cells and basophils
Effector Phase of IgE mediated hypersensitivity reactions-Primary Mediators (preformed) (5)
- histamine
- eosinophil chemotactic factor-attract to site of mast cell degranulation
- neutrophil chemotactic factor
- proteases (degrade blood vessel basement membrane, stimulate mucus secretion, generate complement split products)
- stored in granules attached to matrix protein (heparin) by electrostatic attraction
Effector Phase of IgE mediated hypersensitivity reactions-Primary Mediator Histamine
- binds to H1-4 receptors
- histamine interaction w/ H1 receptors causes intestinal and bronchial smooth muscle contraction, increased vascular permeability, increased mucus secretion by goblet cells
- H2 receptors cause vasodilation, increases vascular permeability, stimulates exocrine glands, causes acid release in the stomach
- H2 receptors on mast cells and basophils suppresses further degranulation, acting as negative feedback control mechanism
Effector Phase of IgE mediated hypersensitivity reactions-Secondary Mediators
- must be synthesized
- leukotrienes
- prostaglandins
- bradykinin
- cytokines
leukotrienes
- a set of peptides that cause prolonged smooth muscle constriction (bronchoconstriction) that is independent of H1 receptor engagement
- Vascular permeability and mucus production are also increased by leukotrienes.
Prostaglandins
-cause platelet aggregation, vasodilation, and bronchoconstriction
Platelet Activating Factor (PAF)
-causes platelets to aggregate and degranulate, releasing additional histamine that causes bronchoconstriction and vasodilation
Bradykinin
-increases vascular permeability and causes smooth muscle contraction
Cytokines
- IL-4
- IL-5
- IL-6
- IL-13
- TNF
Late Effector Phase of IgE mediated hypersensitivity reactions
- localized inflammatory reactions within 4-6 hours of the initial allergic response that may persist for 1-2 days
- infiltration of neutrophils, eosinophils, basophils, macrophages, and Th2 cells, likely a response to cytokines released by activated mast cells
Late Effector Phase of IgE mediated hypersensitivity reactions-Eosinophils
- attracted by eosinophil chemotactic factor
- activated by binding to antibody-coated allergen via FcR for IgE and IgG, releasing inflammatory mediators (such as Major Basic Protein: MBP) that cause tissue damage.
- IL-3, IL-5, and GM-CSF secreted by activated mast cells promote eosinophil growth and differentiation.
Late Effector Phase of IgE mediated hypersensitivity reactions-Neutrophils
neutrophils are also attracted to the site of degranulation by NCF and IL- 8 released at the site
-Neutrophils release their granule contents including lytic enzymes, platelet-activating factor, and leukotrienes
Systemic Anaphylaxis
- life-threatening impaired breathing due to airway swelling
- Uterine cramps, involuntary urination and defecation additional symptoms
- due to smooth muscle contraction
- hives, edema may result from fluid leaking into tissue spaces
- blood pressure may drop, leading to anaphylactic shock
Localized anaphylaxis
reaction in a specific tissue or organ
-allergen into the skin, cutaneous anaphylaxis characterized by
erythema (redness, blood vessel dilation) and edema (swelling due to release of serum into tissue)
- peaks ~10-15 min of challenge with the allergen (wheal and flare reaction)
-allergic rhinitis (hay fever) and asthma
-In asthma patients, infiltrating eosinophils and neutrophils can cause significant tissue damage.
RAST and RIST
- measure serum IgE levels
- radioimmunosorbent test
- radioallergosorbent test
Environmental Medical Treatment of type1 hypersensitivity
-avoid the allergen
Pharmacologic Medical Treatment of type1 hypersensitivity
- antihistamines
- Leukotriene antagonists
- cortisone
- epinephrine
Immunologic Medical Treatment of type1 hypersensitivity
Hyposensitization
- repeated subcutaneous injections of the
allergen to induce the production of circulating allergen-specific IgG, to remove the allergen before it can trigger IgE sensitized mast cells and basophils
-May also cause a shift to a Th1 response
-Humanized monoclonal anti-IgE Ab that bind only to free IgE, can lower serum IgE levels and prevent mast cell/basophil sensitization
