Immunopathology - Allergy & Hypersensitivity Flashcards
What are the four types of hypersensitivites?
- type I - immediate hypersensitivity
- type II - antibody mediated
- type III - immune complex
- type IV - delayed type hypersensitivity
What is allergy?
An immune mediated inflammatory response to common environmental allergens that are otherwise harmless
What is atopy?
A person who has high levels of circulating IgE, elevated numbers of eosinophils in circulation and in the tissues and large numbers of Th2 T cells secreting IL-4
What are the features of type I immediate hypersensitivity?
Inflammatory response to antigens mediated by IgE, involves a sensitisation followed by a response which is either local or systemic. The response has both an immediate and a late phase.
What are the 6 contributors to the allergic mechanism?
allergens, Th2 cells, IgE, FcepsilonR1 receptor, mast cells, eosinophils
What is the allergen associated with dust mites?
The der p 1 enzyme in dust mite faeces
What are the common features of allergens?
Stable, highly soluble in bodily fluids, introduced in very low doses, often are enzymes
What happens in the sensitisation?
The APC takes up the allergen and presents it to the T cell with the cytokine IL-4 to create Th2 cell. The Th2 cell interacts with B cells to induce proliferation and isotype switching to IgE which leads to IgE secretion. The IgE binds to mast cells via the FcepsilonR
Where does the cytokine IL-4 come from to induce Th2 differentiation?
Dendritic cells don’t produce IL-4 but do produce IL-33. Basophils are activated to secrete IL-4 either by the IL-33 secreted by DCs or by direct activation from the allergen. This either happens in combination with a dendritic cell acting as the APC or the basophil can act as an APC on its own. (Graphic)
What happens in the effector phase?
The allergen binds to the IgE antibody bound to the mast cell to cause cross linking of the receptor which induces release of granules - this is the immediate response. It also induces the synthesis and secretion of lipid mediators - also the immediate response. It also induces the the synthesis and secretion of cytokines- this is the slow response.
What do the granules of mast cells contain?
histamine, heparin, tryptase, chymase, TNFalpha
What are the lipid mediators?
Prostaglandins and leukotrienes
What are the cytokines?
IL-3, IL-4, IL-13, IL-5 and TNF alpha
What are the symptoms of the immediate phase?
Wheal and flare due to blood vessel dilation and leakage
What are the symptoms of the late phase?
Hard lump due to cellular infiltration and smooth muscle contraction
What is the allergic response in the GI tract?
fluid secretion and peristalsis - leads to diarrhoea and vomiting
What is the allergic response in the skin?
fluid secretion and vasodilation - leads to swelling, itching and urticaria
What is the allergic reaction in the airways?
bronchoconstriction and mucous secretion - leads to nasal blockage, phlegm, coughing, asthma
What is the allergic reaction in the blood vessels?
Increased blood flow and permeability leads to anaphylactic shock
What is the role of eosinophils in allergic response?
Eosinophils produce toxic intermediates from their granules which causes tissue damage and remodelling and produce chemical mediators to activate epithelial cells and recruit inflammatory cells
What leads to the increased production of eosinophils?
IL-5 secreted from Th2
What brings epithelial cells to the site?
CC chemokines from epithelial cells
What causes the increased sensitivity of eosinophils?
Increased number of FCepsilonR1 receptors on surface after activation
What is used for symptomatic treatment of allergy?
adrenaline for anaphylaxis, beta adrenoceptor agonists for asthma, antihistamines, coritcosteroids
What is involved in immunotherapy/desensitisation?
Administration of increasing doses of allergen under the skin - induces switching of Th2 to Th1, stimulation of apoptosis of T cells, increased production of Treg, decreased allergen induced proliferation
What is delayed type IV hypersensitivity?
persistent antigenic stimulation resulting in increased Th1 activity as well as CD8 T cells and macrophages
What happens in sensitisation in type IV hypersensitivity?
Antigen uptake by APC, APC secretes IL-12 to differntiate T cell to Th1 - antigen persists at the site so Th1 cells persist and accumulate at the site
What cytokine does Th1 secrete?
IFN gamma
What is the role of IFN gamma?
Induces macrophage release of inflammatory mediators
What is the result of release of TNFalpha?
Tissue destruction and adhesion molecules on local blood vessels
What is the result of release of IL-3
monocyte production in the bone marrow
What are the 3 kinds of type IV hypersensitivity?
contact sensitivity, mycobacterium tuberculosis, coeliac disease
What is an example of contact hypersensitivity?
Poison ivy
What is the mechanism contact hypersensitivity?
A sensitisation phase involves the antigen presenting to the T cell via a DC, activating T cells which migrate to the site. The response phase involves re-exposure to the antigen which activates effector memory T cells and central memory T cells which leads to a production of interferon gamma, activation of macrophages and excessive inflammation
What is the mechanism of type IV hypersensitivity due to mycobacterium tuberculosis?
The pathogen can survive in macrophages due to its thick waxy walls. Infection stimulates production of Th1 cells which activates macrophages. The delayed type hypersensitivity restricts the growth of the pathogen - however in a small number of individuals it results in an interruption of respiratory function. Macrophages and dendritic cells present the antigen to T cells which activates CD8 and Th1 cells. CD8 and Th1 cells migrate to site and secrete IFNgamma to active macrophages. Macrophage activation results in production of CXCL8, IL-1, TNFalpha which results in endothelial activation (all), phagocyte and lymphocyte migration (all), fever (IL-1), weight loss (TNF-alpha), granuloma formation (TNF-alpha). Granuloma can lead to impaired oxygen exchange.
What is the mantoux test?
A test for exposure (not immunity) to M. tuberculosis. Proteins from the organism are induced under the skin an if proteins interact with memory T cells then confirms exposure. Detect memory T cells with a hard lump present after 48-72 hours.
What is the HLA gene for patients with celiac disease?
DQ2 or DQ8
What is the mechanism for celiac disease?
Gliadin (a protein component of gluten) is made up largely of glutamine and proline. Tissue transglutaminase 2 deamidates the glutamine to glutamate. The glutamate allows the gliadin to bind to HLA DQ2 or DQ8. Presents to T cells and activates Th1 cells. Th1 cells produce cytokines which damage villi. This is a type IV hypersensitivity.