L2. Immunopathology: Allergy and Hypersensitivity

Question 1

What are the 4 types of immune hypersensitivities. Describe each one briefly

Answer 1

1. Immediate hypersensitivity mediated by mast cells and IgE causing ALLERGY to exogenous antigens (anaphylaxis) <30 minutes
2. Antibody (cytotoxic) mediated hypersensitivity caused by IgM and IgG raised against cell bound or extracellular antigens to target and kill the cells. 5-12 hours
3. Immune complex hypersensitivity: IgM and IgG and their antigens form complexes that get deposited leading to damaging inflammation. 3-8 hours.
4. Delayed type immune hypersensitivity: CD4 (T cell) mediated sensitivity to kill the target cells

Question 2

What are the two types of hypersensitivities that cause allergy?

Answer 2

Types I and Types IV

Question 3

Define allergy

Answer 3

An immune mediated inflammatory response raised against common environmental antigens that are otherwise harmless.

Question 4

What is atopy? And what is the major consequence of IgE?

Answer 4

Atopy is a genetic predisposition to produce abnormally high levels of IgE. IgE mediates inflammatory responses by increasing eosinophil production (parasitic infections). Eosinophils release toxic granules that are the effector cells of allergy and harm the host. These secrete factors like IL-4 which prime for the TH2 response.

Question 5

Hypersensitivities have two major phases. What are they?

Answer 5

Sensitisation phase where the immune response is primed against the antigen
Response phase  (which often have immediate and delayed stages) which is what mediates the inflammation

Question 6

What are some common characteristics of allergens? Give some examples. What is the significance of these characteristics?

Answer 6

They are often common to the environment (repeated exposure). They are usually inhaled or ingested allergens and are slowly degraded molecules (persist). They are often soluble so can cross mucosal barriers and often introduced at small doses leading to a ‘tickling’ or priming of the immune response. Eg. pollen, dust mites, food. These characteristics are common to parasitic infections - TH2 response.

Question 7

Describe the sensitisation phase of Type 1 Hypersensitivity

Answer 7

The antigen is taken up by dendritic cells which matures and processes the antigen while migrating to the lymph node. It presents it to immature T cells which leads to the production of Th2 helper cells (skewed by the microenvironment of IL-4).
Th2 helper cells produce high amounts of IL4,5, 13
Activated Th2 helper cells interact with B cells to enable their activation and proliferation
IL-4 induces isotype switching to IgE and IgE secretion

Question 8

What is the significance to IL-4 secretion in the Th2 response in type 1 hypersensitivity?

Answer 8

It promotes eosinophil and mast cell activation

It promotes isotype switching to IgE

Question 9

What is the major source of IL-4 in the Th2 response? Knowing that DCs are unable to produce IL-4.

Answer 9

IL-4 is critical to shaping the response to Th2. The major source of IL-4 is from basophil which are also directly activated by the allergens leading to secretion of IL-4. (Basophils may also act as APCs).
DCs secrete high numbers of IL-33 which binds to IL-33 receptors on Basophils and this binding acts as a signal 3 in T-cell differentiation.

Question 10

Describe the Response (effector) phase of type 1 hypersensitivity

Answer 10

This is the activation of mast cells and eosinophils.
Mast cells degranulate leading to multiple effects through different time periods (see lecture 1) and local inflammation.
Eosinophil activation (late response) produces toxic proteins and free radicals responsible for tissue damage and remodelling.

Question 11

What is the normal eosinophilic response and production?

Answer 11

Eosinophis are found in the mucosal lining and play a protective role against parasites. They are normally under tight regulation but this is lost in allergy.
They are produced in the bone marrow and released into the circulation. Production and survival is increased by IL-5 and chemokines attract them to the tissues. In allergy, they have increased FcER1 expression (so have a decreased threshold for activation)

Question 12

Describe some symptomatic treatments for type 1 hypersensitivity allergies [4]

Answer 12

Adrenaline is used for anaphylaxis and asthma which reforms the tight junctions in the mucosal layers and reverses permeability as well as relaxing the smooth muscle.
Inhaled beta-adrenoreceptor agonists act as bronchodilators and are important in asthma
Antihistamines bind and block histamine receptors
Corticosteroids: have a broad immunosuppressive action:

Question 13

What are the advantages and disadvantages of corticosteroid use?

Answer 13

Corticosteroids suppress chronic inflammation and tissue damage (blocks gene transcription) but is non-specific and has multiple side effects: demineralisation, skin thinning, weight gain and tolerance over time.

Question 14

Describe immunotherapy/desensitisation methods for type 1 hypersensitivity

Answer 14

This involves administration of increasing doses of the allergen to achieve a tolerance. It isn’t widely known how this occurs but may be due to decreased allergen proliferation (anergy of cells), diverting cytokines from Th2, stimulation of apoptosis, production of Treg cells and TGFb and IL-10.

Question 15

Describe the delayed type hypersensitivity response (type IV)

Answer 15

This is cell mediated with a heavy involvement of T cells and macrophages. (Th1r response with release of IFN gamma) - sometimes involves CD8 and cytotoxicity. s,

Question 16

What are the three major types of cell-mediated inflammations in type IV hypersensitivity

Answer 16

Hypersensitivity is often a result of persistent antigen exposure

1. Contact sensitivity to strong antigens
2. Persistant infection
3. Consistent exposure to antigens

Question 17

Describe the sensitisation phase of type IV hypersensitivity

Answer 17

This is the priming of the adaptive immune response. Which occurs in the same process as normal (ie. Antigen uptake, presentation and Th1 priming).
The PERSISTENCE of the antigen to cause multiple rounds results in the accumulation of macrophages and T cells, high levels of TNF alpha and IFN gamma and increased tissue damage and inflammation. These lead to production of memory cells.

Question 18

Not all allergens are protein based. How does the body mount an adaptive immune response to these allergens?

Answer 18

The small allergens HAPSONATE (somehow attaches to a protein) and enables it to be presented as a peptide antigen to be a target to the immune cells.

Question 19

Describe the effector phases of contact sensitivity. Give some examples

Answer 19

Re-exposure to the allergen results in re-activation of effector memory T cells that leads to increased production of IFN-gamma due to the Th1 response.
IFN-gamma increases the activation and recruitment of macrophages (which increases IFN-gamma)
Macrophages lead to excessive immune responses and inflammation.
EXAMPLES: poison ivy causing dermatitis,

Question 20

Describe the effector phases of the hypersensitivity in persistent infections (TB)

Answer 20

An inability to clear the organism leads to persistent activation of the immune response. Mycobacterium tuberculosis is a facultative intracellular bacterium that survives and replicates inside macrophages. Infection stimulates production of Th1 cells and the production of more macrophages and IFN-gamma.
High macrophages means high macrophage mediated release of factors like IL-8, IL-1, TNF alpha al leading to endothelial activation, phagocyte and lymphocyte migration, fever, weight loss, GRANULOMA FORMATION (TNF-alpha).
The granuloma in an important response to protect the body from the hypersensitivity

Question 21

Describe the effector phase of the type IV hypersensitivity occurring in continued exposure to the allergen. Eg. Coealic disease

Answer 21

Coealic disease is caused by constant exposure to wheat products causing a Th1 dependent immunopathology on the intestinal wall.
The allergen: gluten (gliadins) in wheat, rye and barely
The gliadins cause the sensitisation phases as normal leading to expression of the antigen on MHCII proteins to TH1 cells .
Thus activation of memory cells to exposure to gluten leads to cytotoxic inflammatory effects on the small intestine: hyperplasia, villi dysfunction (poor absorption of nutrients) and diarrhoea.

Question 22

What is the significance of the DQ2 HLA for MHC II for coealic disease sufferers?

Answer 22

> 90% of the sufferers have the DQ2 positive MHCII HLA haplotype which means they create autoantibodies to the gliadins.
Gliadins are rich in glutamine (positive charge) while the MHC II of DQ2 preferes negative chains.
The immune system targets the antigen swithcing it by an enzyme tissue called TRANSGLUTAMINASE 2 which is widely distributed in the intestinal lamina propria which deaminates it and causes glutaminde (negative charge).