Hypersensitvity Type I - Hunter

Question 1

What is immunopathology?

Answer 1

When the immune system itself is the primary cause of disease. This is present to some extent in every infection.

Question 2

Type I Hypersensitivity (TIH) is mediated by what antibody?

Answer 2

IgE response to extrinsic substances. It is a disease following a response by the immune system to an otherwise innocuous antigen.

Question 3

Type I hypersensitivity is also called what?

Answer 3

Immediate hypersensitivity since some responses occur within seconds - however there may also be some delayed responses.

Question 4

What type of antigens are involved in TIH?

Answer 4

Usually small, soluble antigens.

Question 5

What cell types are involved in TIH?

Answer 5

Mast cells and eosinophils.

Question 6

What are some examples of TIH?

Answer 6

Allergic rhinitis, asthma, systemic anaphylaxis.

Question 7

What is the normal physilogical function of IgE, eosinophils and mast cells?

Answer 7

This system evolved to be the principle immune defense against metozoan parasites (worms). Normally, cross-linking of IgE on mast cells leads to release of mediators that promote the expulsion of parasites.

Question 8

What can elicit the same response as a metozoan parasite in some cases?

Answer 8

Certain innocuous environmental materials or allergens in a low dose delivered across a mucosal surface.

Question 9

TIH reactions are typically induced by what?

Answer 9

Extrinsic allergens that are inhaled - such as pollen, dander, mold OR injected materials such as insect venoms, vaccines and drugs OR ingested material such as food and orally administered drugs.

Question 10

In the case of an actual metozoan parasite what is the chain of events?

Answer 10

1. Dendritic cell encounters antigen and produces IL-4, IL5, IL-9 and IL-13
2. A TH0 cell under these cytokines will differentiate into a TH2.
3. immune system mounts a response, including producing antibodies.
4. The differentiation into the TH2 direction is needed for the allergic response also.

Question 11

Is there a genetic component to allergies?

Answer 11

Yes, you must have an MHCII that can display the allergen protein.

Question 12

What is necessary for allergic responses to occur?

Answer 12

1. You must have an MHCII that can display the allergen.
2. You must have a TH2 deviated environment.
3. An allergen specific B cell binds to and internalizes the allergen and presents it in MHCII to CD4 TH2 cells that produce IL-4.
4. The B cell will bind to the TH2 cell via CD40L/CD40 and will respond to IL-4 via its IL-4 receptor and this promotes isotope switching to IgE.

Question 13

What is special about an IgE immunoglobulin?

Answer 13

It is cytophilic, it can bind via its Fc region to the Fcepsillon receptor on Mast cells, basophils and eosinophils even without interacting with antigen first.

Question 14

Do mast cells and basophils express the Fc epsilon receptor constitutively?

Answer 14

Yes, but eosinophils must be activated first.

Question 15

Does an allergic response occur after the first exposure?

Answer 15

No, the primary exposure is what sensitizes the person.

1. The allergen enters the body and interacts with APC with a specific MHCII.
2. The APC releases cytokines that cause a TH2 deviated environment.
3. Thelpers interact with B cells of the same specificity. The B cell is activated and proliferates and starts secreting IgM.
4. TH2 helpers secrete lots of IL-4 and this leads to the B cell switching to IgE production.
5. The IgE molecules bind to mast cells.
6. On second exposure the IgE are triggered via cross-linking of antigen to release granules with histamine and start the inflammatory processes.

Question 16

Where are mast cells found?

Answer 16

In the skin, in all mucosal areas, and lining the blood vessels.

Question 17

What 3 pathways are triggered by IgE crosslinking on Mast cells?

Answer 17

1. granules with preformed mediators are exocytosed - in seconds to minutes - leading to vascular dilation and tissue damage.
2. prostaglandins andleukotrienes are released - in minutes to hours - leading to vascular dilation and smooth muscle contraction.
3. there is transcription al activation of cytokine genes - and cytokines are released - in hours. These cytokines lead to inflammation and leukocyte recruitment.

Question 18

What determines the type of IgE mediated allergic reaction?

Answer 18

The dose and route of allergen administration. For example inhalation can cause asthma while IV administration can cause anaphylaxis.

Question 19

Can enzymes act as allergens?

Answer 19

Yes, For example Der p1 is an enzyme in dust mite feces that cleaves occludin in tight junctions so that it can enter the body. Once inside it acts as an allergen.

Question 20

What is Eosinophilia?

Answer 20

Eosinophilia occurs when either a large number of eosinophils are recruited to a specific site in your body or bone marrow produces too many eosinophils.This can occur with allergies.

Question 21

Eosinophilia can be induced by what cytokine?

Answer 21

Il-5. This cytokine goes to the bone marrow to increase the production of eosinophils. They are then recruited to to sites of inflammation via chemokines (Eotaxins 1 and 2 also called CCL11). These chemokines bind to eosinophil CCR3.

Question 22

Do eosinophils have the Fc epsilon receptor?

Answer 22

Yes, but only in their activated state when they get to the tissues.

Question 23

What is the normal serum level of eosinophils?

Answer 23

About 1-3% - so if they are elevated then this can be diagnostic for a parasite infection or for chronic HTI.

Question 24

Does Asthma have both acute and chronic components?

Answer 24

Yes.

1. The acute response - inflammatory mediators causing increased mucus, smooth muscle contraction leading to airway obstruction and recruitment of other cells from circulation including TH2 cells.
2. The chronic response - caused by cytokines and eosinophil products. This leads to airway remodeling where the damage heals by fibrosis and scarring. This in turn leads to COPD and the airway becomes hyperactive responding to innocuous things like cold weather.

Question 25

Do most allergic reactions have both an immediate and a late-phase response?

Answer 25

Yes, The early phase is characterized by edema and vasodilation, lots of mast cells and congestion of blood vessels. The late phase is characterized by tissue edema with inflammatory infiltrate, lots of eosinophils, neutrophils and T cells.

Question 26

What is Atopy?

Answer 26

The tendency to make exaggerated IgE responses. Both genetic and environmental factors contribute.

Question 27

What is the hygiene hypothesis?

Answer 27

This hypothesis states that early exposure microbes promotes a TH1 deviation rather than TH2 and allergies don’t occur.

Question 28

What is the susceptibility loci for allergic and autoimmune diseases?

Answer 28

This is the MHC locus on chromosome 6p21 -you must have an MHC that can display allergens for allergies to occur.

Question 29

Specific allergens can be identified with what test?

Answer 29

An intradermal or epicutaneous skin test.

Question 30

What can anti-histamine drugs do?

Answer 30

1. block histamine H1 receptors
2. decrease vascular permeability
3. inhibit itching

Question 31

How is acute asthma treated?

Answer 31

With inhaled bronchodilators to relax bronchial smooth muscle. ie - Albuterol, a B-adrenergic receptor agonist.

Question 32

What other drugs can relieve symptoms of allergy and asthma?

Answer 32

Cysteinyl leukotriene receptor agonists such as Singulair - These drugs block the leukotrienes D4, C4 and E4 as well as inhibit bronchoconstriction.

Question 33

How is anaphylaxis treated?

Answer 33

With epinephrine which relaxes bronchial smooth muscle, constricts vascular smooth muscle and reforms endothelial tight junctions.

Question 34

How is chronic inflammation treated?

Answer 34

With topical corticosteroids. These suppress inflammation by inhibiting the transcription of pro-inflammatory genes by blocking NF-kB. They will also block the leukotriene/prostaglandin pathway.

Question 35

What is a risk with corticosteroid use?

Answer 35

Too much use can lead to increase in susceptibility to other infections.

Question 36

What are some other possible treatments for allergic disease?

Answer 36

1. Desensitization therapy - injection of specific antigen leads to induction of Tregs.
2. Anti-IgE antibodies - such as omalizumab - prevent binding of IgE to mast cell.

Question 37

How can desensitization work?

Answer 37

It works only if you know the allergen. Allergen is then injected intradermally in escelating amounts to favor IgG production instead of IgE production. The IgG then clears the allergen before it can cross link IgE on mast cells. It also induces the production of T regs which secrete IL-10 and TGF-B which promote isotype switching to IgG.

Question 38

Give an example of IgE mediated drug hypersensitivity.

Answer 38

Anaphylaxis from B-Lactam antibiotics.

Question 39

How does penicillin induce an allergic response?

Answer 39

1. penicillin has a beta-lactam ring which is highly reactive. It can bind covalently to macromolecules on cells surfaces to form a hapten-carrier complex.
2. If haptenation results in a sufficient density of drug epitopes it fools the body into making a reaction. Specifically, the hapten-carrier complex is taken up by an APC in the presence of a danger signal leading to IgE anti-penicilloyl antibodies that arm mast cells and cause a response on second exposure to penicillin or even to other B-lactam drugs.