18. Atopy, allergy and dht 2 Flashcards Preview

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Flashcards in 18. Atopy, allergy and dht 2 Deck (23)
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1

Detection of allergen-specific IgE in vivo

Skin-prick testing

Allergen extract applied as drops

Top layers of epidermis punctured with lancet

A wheal with flare response after 15 minutes is positive

Result needs interpretation in clinical context

2

Detection of allergen-specific IgE in vitro

Performed by radioallergosorbant (RAST) assay a very long time ago

Now usually by ELISA, but term ‘RAST’ still widely used clinically

 

  1. Plastics coated with purified allergen of interest. Incubate with patient serum
  2. IgE antibodies in sera of sensitised patient bind to allergens
  3. Immobilised IgE antibodies detected with polyclonal anti-IgE detection antibody

3

Treatment of allergy

Pure symptom relievers (don’t act on mediators, but act on other pathways that oppose actions of mediators

1. Nasal decongestants 

  • eg oxymetazoline
  • Act on α1 adrenoreceptors to cause vasoconstriction
  • Only for short-term use
  • Topical and systemic

2. B2 agonists

  • Eg salbutamol
  • Act on lung B2 adrenoreceptors, cause smooth muscle relaxation

3. Epinephrine/adrenaline

  • Systemic adrenergic effects oppose vasodilatation and bronchoconstriction

4

Treatment of allergy: drugs acting on early-phase mediators

Mast cell stabilisers act on mast cells

H1 antihistamines act on histamine

Leukotriene receptor antagonists act on leukotrienes

5

Mast cell stabilisers

Eg sodium cromoglycate

Reduce mast cell degranulation by unknown mechanism

Not orally absorbed – topical use only - e.g. eye drops

Short half-life requires frequent dosing

Main benefit is steroid-free, but efficacy very poor

6

H1 antihistamines

Inverse agonists at H1 histamine receptor

Best used before exposure to allergen

1st generation eg chlorpheniramine

  • Considerable sedation, drug interactions

2nd generation eg cerizine, loratidine, desloratidine, fexofenadine

  • No/ minimal sedation, once-daily

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Leukotriene receptor antagonists

Only UK drug is montelukast

Effective in reducing early allergic responses, but inferior to H1 antihistamines

Unlike anti-histamines, beneficial in chronic asthma, which is the main indication for their use

8

Treatment of allergic disease: corticosteroids

Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system. 

Delayed onset of action and must be taken regularly

9

Corticosteroids

Inhaled

  • Eg beclamathosome, fluticasone

Nasal

  • Eg beclamathasone, mometasone, fluticasone

Also for skin (eg hydrocortisone) and ophthalmic drops

  • Topical may cause local and even systemic side effects

Oral , intravenous and depot preparations available

10

Treatment of allergic disease: omalizumab

Omalizumab is a monoclonal antibody directed against IgE, used for atopic asthma

Binds Fc region of IgE to complex it in serum and limit free amount of it which can bind antigen

 

11

Allergen-specific immunotherapy

Allergen doses administered by subcutaneous injection or sublingually

Provide long-term protection

Mainly venom allergy and rhinitis

Multiple immunological effects:

  • Induce regulatory T cell responses to allergens
  • Reduce Th2 responses
  • Induce allergen-specific IgG antibodies
  • Reduction in mast cell responsiveness
  • Reduce allergen-specific IgE levels

12

Type IV, delayed-type hypersensitivity

Mediated by antigen-specific effector T cells

  • Antigen-specific: specific antigen stimulus needed, which is processed and presented to relevant T cells which carry out the reaction
  • Effector T cell: T cells that have previously met antigen and are ‘primed’ to produce a rapid, robust response

Because it takes time to process and present antigen, these reactions do not develop for at least 24 hours following exposure

Example: contact dermatitis

13

Contact dermatitis: sensitisation

Sensitising agents are typically highly reactive small molecules which can penetrate skin

  1. These react with self proteins to create protein-hapten complexes that are picked up by Langerhans cells, which migrate to regional lymph nodes
  2. The Langerhans cells process and present the antigen together with MHCII
  3. In some susceptible individuals, the complexes are recognised as foreign
  4. The activated T cells then migrate to the dermis

Hapten = small molecule which cannot produce an immune response by itself, but can bind to a protein to alter its immunogenicity

14

Contact dermatitis: elicitation

Elicitation is when you meet antigen again after sensitisation

Chemokines recruit macrophages

  1. Th1 cells secrete IFN gamma: increases expression of vascular adhesion molecules, activates macrophages
  2. TNF alpha/ beta: local inflammation

15

Poison ivy

Pentadecacatechol is a poison ivy lipid that may cross the skin and modify intracellular proteins

These proteins are processed and presented with MHC1 to CD8 T cells which then cause contact dermatitis

Again, not everybody is susceptible

Native Americans would feed their babies poison ivy to generate tolerance

16

Patch test for contact dermatitis

Antigen-impregnated patch placed on back

Nickel, chrome, cobalt, epoxy resin, lanolin etc

Results read after 2 days (cw skin-prick testing which is immediate)

17

Difference between contact dermatitis and type 1 allergy

18

Skin prick testing vs patch testing

19

Tuberculin skin test (TST)

Used to determine EXPOSURE to TB

Chemoprophylaxis may be indicated to reduce risk of reactivation

Tuberculin injected intradermally (tuberculin=complex mixture of antigens derived from MTB)

Local inflammatory response evolves over 24-72 hours if previously exposed

Fairly poor test for active TB

20

Mechanism of TST

  1. Antigen is injected into subcutaenous tissue and processed by local antigen-presenting cells
  2. A TH1 effector cell recognises antigen and releases cytokines which cat on vascular endothelium
  3. Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion

21

IGRA (interferon gamma release assay) to detect TB-specific Th1 cells

  1. MTB peptides added to blood in laboratory
  2. Antigen presenting cell presents peptide with MHC2 and secretes IL-12

 

With previous TB exposure:

  • Effector memory Th1 cells recognise antigen. This is a secondary immune response so they are ‘primed’ and release cytokines within this short timeframe

 

With no previous TB exposure:

  • No primed effect memory T cells specific for MTB. No interferon gamma produced in a short timeframe

22

IGRA: positive test by two methods

ELISPOT method (T-SPOT)

ELISA method (quantiferon gold)

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