A5 - Hypersensitivity and allergy

What is a hypersensitivity reaction?

An inappropriate immune response which leads to tissue damage or other symptoms.

Which types of hypersensitive responses are, immediate, antibody mediated?

Type I, II and III

Which types of hypersensitive responses are, delayed, cell mediated?

Type IV

Which cells are involved in Type I, II and III hypersensitive responses?

CD4 Th2/Th1

Which cells are involved in Type IV hypersensitive responses?

CD4 Th1/Th2/Th17

AND

CD8 T cells

What triggers Type I hypersensitivity?

Antigen (Termed an allergen) which induces B cells to switch to IgE

IgE then binds to mast cell FcRε receptors.

List some common 'allergens’

• Anaphylaxis

  • Drugs

  • Venoms

  • Food (e.g. peanuts)

• Asthma

  • Pollens

  • Dust-mite feces

• Food allergy

  • Peanuts

  • Fish

  • Egg

  • Soy

• Hay fever

  • Pollens

  • Dust-mite feces

What immune response does presentation of many allergens by activated DCs do? (Type I)

Drives a CD4 Th2 response

Th2 cells express CD40L (which bind to B cell CD40) and secrete IL-4 and IL-13 which both help promote class switching to IgE

What do IL-4 and IL-13 do?

Promote IgE production.

What does IL-5 do?

Increases eosinophil production

What does subsequent exposure to the same allergen cause? (Type I)

Allergen cross-links IgE bound to FcRε on mast cells

Mast cells degranulate and release mediators

Mediators cause inflammation/anaphylaxis

What types of mediators are released during Type I hypersensitivity response?

Pre-formed:

• Histamine

• TNF-alpha

Newly synthesised

• Leukotrienes

• Cytokines/chemokines

Where are Type I allergens often encountered?

Mucosal surfaces (e.g. pollen/food allergens)

However, could also be injected (e.g. bee sting)

What triggers Type II hypersensitivity?

Antibody (IgG or IgM), produced to an allergen, which is present on a cell/tissue surface

Cell/Tissue damage then results from interaction of antibody-allergen complex with effector cells/complement

What are the three ways Type II hypersensitivity response can cause damage?

• Antibody-dependent cell-mediated cytotoxicity (ADCC)

• Complement-mediated lysis

• ‘Frustrated phagocytosis’

What is Antibody-dependent cell-mediated cytotoxicity (ADCC)?

Killing of target cells expressing allergen by immune cells (e.g. NK cells) that express Fc receptors

What is complement-mediated lysis?

Antibody bound to allergen activates complement to generate membrane attack complexes which will kill the cell

What is ‘frustrated phagocytosis'?

Immune complexes formed on host cells promote phagocytosis

However, host cells may be too large to be phagocytosed which causes phagocytes to release lysosomal contents and damage tissues.

What are some examples of Type II responses?

• Transfusion reactions

• Haemolytic disease of the newborn

  • Blood types of mother and baby are not compatible

• Autoimmune haemolytic anaemia

• Hyperacute graft rejection

What triggers Type III hypersensitivity?

Immune complex (IC)-mediated

IgG antibodies complex with soluble allergens to form an IC

ICs are usually cleared by phagocytes but if not they can be deposited in susceptible sites and cause inflammation

Which are cleared better? Large ICs or Small ICs?

Large ICs interact well with complement and can generally be cleared better than small ICs

What can small IC binding to FcRs cause in: a) Mast cells b) Neutrophils c) Macrophages?

• Mast cells

  • Degranulation and activation of C3a/5a which bind complement receptors

• Neutrophils

  • Failure to phagocytose can lead to release of lysosomal contents

• Macrophages

  • Release of cytokines and other inflammatory mediators

What triggers Type IV hypersensitivity?

T-cell mediated and not due to antibodies

• Due to T-cells inappropriate response to allergens

Also referred to as delayed type hypersensitivity (DTH)

What occurs during first exposure to an allergen in Type IV hypersensitivity?

• Allergen is taken up by APCs (e.g. skin DC)

• APCs the migrate to lymph nodes where naive CD4 T cells are activated into Th1 cells

What happens upon re-exposure to an allergen in Type IV hypersensitivity?

• APCs re-encounter the allergen

• Circulating Th1 cells become activated and secrete cytokines which leads to inflammation

What are some examples of Type IV hypersensitivity?

• Allergic Contact dermatitis

• Poison ivy

What is the ‘Hygiene hypothesis’?

‘A lack of exposure to infection at a young age predisposes to allergy’

• A reduces pathogen load (improved environmental hygiene) results in an imbalance in Th1/Th2/Treg cells

• This increases the likelihood of Type I/II/III hyperpersentivity responses

Which type of hypersensitive response is the most prevalent?

Type I responses

What are allergies mediated by?

IgE

Allergen-specific IgEs are likely to be present.

What are the positive and negative controls of a skin allergy test?

Positive: Histamine

Negative: Carrier

What are the three ‘phases’ of asthma?

Early phase

Late phase

Chronic phase

• Usually a chronic airway obstruction causing the airway to narrow

What occurs in the early phase of asthma?

Broncho constriction

Increased mucus production, vasodilation and increased vascular permeability

What occurs in the late phase of asthma?

Cytokine production

Recruitment of eosinophils, neutrophils and T cells

Inflammation and further oedema

What are symptoms of a food allergy?

Oral irritation

Swelling of lips, tongue, pharynx

Nausea

Occasionally anaphylaxis

How is a food allergy caused?

Allergen-induced IgE crosslinking in the GI tract can cause localised smooth muscle contraction and vasodilation

• This can cause nausea/diarrhoea

Symptoms depend on the site of primed mast cell activation

• ‘Wheezing’ can result from activation in lungs

• Hives can result from allergen being carried to the skin

What is anaphylaxis and what can it cause?

• Rapid swelling of throat tissues

• Swelling of tongue which makes it hard to swallow

• Hives

• Usually results in a loss of consciousness as those affected struggle to breathe

What treatments can be given for allergies?

Treatment/management of symptoms

• Anti-histamines

• Corticosteroids

• Bronchodilators (asthma)

• Epinephrine (anaphylaxis)

In the long-term

• Avoid the allergens whenever possible

What is desensitization and how can it help treat allergies?

Form of immunotherapy

• Allergen is given in very small doses which are gradually increased

• Patients respond with decreased production of allergen-specific IgE and increased production of allergen-specific IgG4

• May also see changes in cytokine production as Treg responses are induced

What biological allergy treatments are there?

Anti-IgE monoclonal antibodies

• Xolair (Omalizumab)

  • Binds Fc region of IgE and prevents it binding to FcεRI on mast cells