Hypersensitivity Flashcards
What is the difference between the sensitization stage and the effector stage?
Sensitization stage is the primary immune response (clinically silent)
Effector stage is a secondary immune response
Hypersensitivity is…
An excessive or abnormal secondary immune response to a sensitizing agent
Explain the initial sensitization phase of type I hypersensitivity. How long does it take?
Specific allergen is present on APC eliciting a TH2 response which makes IL-4, IL-6. B cells are stimulated to make specific IgE’s for the allergen. [4 weeks]
Explain the effector phase of type I hypersensitivity. Time frame of reaction.
The next time you see the allergen you get allergen cross-linking to IgE and within ~15 minutes mediators are released from mast cells or basophils.
What are some of the immediate mediators released?
Histamine Tryptase [Mast cells] Leukotrienes PGD2 [Mast cells] IL-4
What happens 4-6 hours after a type I hypersensitivity reaction?
Damage to epithelium and cellular recruitment through the release of MBP/ECP/EDN, leukotrienes from Eosinophils
Explain the difference between an allergen and an irritant.
Allergens produce an IgE mediated disease, they require sensitization for a response and it affects only those that are sensitized to the allergen.
An irritant does not produce an IgE mediated response, it is dose dependent and will affect everyone at high enough doses.
What is the receptor on mast cells and basophils that allows them to bind IgE with high affinity?
FceRI
Has a short half life in the serum, is only produced by mast cells and basophils and has at least 3 receptors. It is toxic to parasites, increases vascular permeability and causes smooth muscle contraction.
Histamine
Remains identifiable in the serum for up to 4 hours later, only made my mast cells, single best marker of mast cell activation, leads to remodeling of connective tissue
Tryptase
What are the two forms of tryptase and which is released from mast cell activation??
alpha – constitutively released
beta – only released with mast cell activation
When and what cytokines are released in type I hypersensitivity?
Cytokines must be made by activation so their release is delayed (4-6 hours) after degranulation.
IL-4, IL-13: associated with TH2 cells and lead to Ig class switching in B cells to produce IgE IL-3, IL-5 and GM-CSF: promote the survival and activation of eosinophils TNF: activates endothelium and leads to adhesion molecule expression
When and what chemokines are released in type I hypersensitivity?
Must be made with activation so release is delayed (4-6 hours)
MIP-1alpha (CCL3): chemotactic for monocytes/macrophages/neutrophils/T cells and eosinophils
RANTES (CCL5) and Eotaxin (CCL11): chemotactic for T cells and eosinophils
What lipid mediators are released in type I hypersensitivity?
LTC4, LTD4, LTE4: lead to eosinophil migration, smooth muscle contraction, vascular permeability and mucus hyper secretion
Platelet activating factor (PAF): attracts eosinophils and other leukocytes; activates platelets
What do you clinically consider with an elevated eosinophil count?
Neoplasia Asthma Allergy Connective tissue disease Parasitic disease
What is the unique receptor on eosinophils? What does it bind?
CCR3 Binds Eotaxin (CCL11) -- found at sites of inflammation
How do steroids fight acute inflammation?
Induce apoptosis of eosinophils
Inhibit the production of IL-5
Mediated by steroid binding to GR-alpha and inhibiting AP-1 and NFkB
How does IL-5 effect eosinophils?
Prolongs survival
What are some of the main eosinophil products?
Lysophospholipase: degrades lysophospholipids
MBP: mast cell activation, helminthotoxic
ECP: same as MBP plus neurotoxic
EDN: neurotoxin
PAF: bronchoconstriction and activates platelets
LTC4: bronchoconstriction, mucus hypersecretion, edema
What are some clinical examples of type I hypersensitivity?
Allergic rhinitis
Asthma
Anaphylaxis
Urticaria
Explain Type II hypersensitivity.
Involves antibody (IgG or IgM) binding to cell or matrix bound antigen. Then phagocytic or NK cells bind to the antibody via the FC receptor. The target tissue is then destroyed. Complement could be involved (increased binding by C receptors on phagocytic cells).
What are some clinical examples of type II hypersensitivity?
Goodpasture syndrome: Ab to Type IV collagen in basement membranes of glomeruli and lung alveoli
Bullous pemphigoid: Ab to epidermal basement membrane proteins
Pernicious anemia: Ab to intrinsic factor and gastric parietal cells
Acute rheumatic fever: antibodies against strep antigens cross-react with heart
Explain how some drugs (penicillin, quinidine or methyldopa) can cause Type II hypersensitivity disease.
Some drugs maybe become antigenic when bound to erythrocytes or platelets –> IgG may be made against the combined drug-cell antigen this leads to destruction of the erythrocytes (hemolytic anemia) or platelets (thrombocytopenia) which may develop with the spleen as the major site of destruction.
IgG does not react with just the free drug, only the cell bound version.
Explain Type III hypersensitivity.
Occurs due to the production of IgG against a soluble antigen –> form an antigen-antibody immune complex that then activates complement – the complexes cause damage by both activation FCgammaR expressing cells as well as activating complement at sites of deposition
