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Year 2 MCD - Immunology > Hypersensitivity and Allergy > Flashcards

Hypersensitivity and Allergy Flashcards

1
Q

What is appropriate immune tolerance?

A

occurs to self, and to foreign harmless proteins:
-Food, pollens, other plant proteins, animal proteins, commensal bacteria

Involves antigen recognition and generation of:

  • Regulatory T cells
  • Regulatory (blocking) antibody (IgG4) production
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2
Q

When do hypersensitivity reactions occur?

A

when immune responses are mounted against:

  • Harmless foreign antigens (allergy, contact hypersensitivity)
  • Auto-antigens (autoimmune diseases)
  • Allo-antigens (serum sickness, transfusion reactions, graft rejection)
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3
Q

What is an allo-antigen?

A

an antigen present only in some individuals (e.g. of a particular blood group) and capable of inducing the production of an alloantibody in people that lack it

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4
Q

How is hypersensitivity classified?

A
  • Type I: Immediate Hypersensitivity
  • Type II: Antibody-dependent Cytotoxicity
  • Type III: Immune Complex Mediated
  • Type IV: Delayed Cell Mediated
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5
Q

When does type 1 hypersensitivity occur?

A
  • anaphylaxis
  • asthma
  • rhinitis (seasonal and perennial)
  • food allergy
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6
Q

What is the mechanism of type 1 hypersensitivity?

A

1st Antigen exposure:

  • Sensitisation not tolerance
  • IgE antibody production -> IgE binds to Mast Cells & Basophils

2nd Antigen Exposure:

  • More IgE antibody produced -> Antigen cross-links IgE on mast cells and basophils
  • leads to degranulation and release of inflammatory mediators
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7
Q

What are examples of type 2 hypersensitivity?

A

Organ-specific autoimmune diseases

  • Myasthenia gravis (Anti-acetylcholine R antibodies)
  • Glomerulonephritis (Anti-glomerular basement membrane antibodies)
  • Pemphigus vulgaris (Anti-epithelial cell cement protein antibodies)
  • Pernicious anaemia (Intrinsic factor blocking antibodies)

Pemphigus vulgaris:
- autoimmune attack of an antibody that cements epithelial cells together.

Bullous pemphigoid:

  • blistering skin disorder (antibodies are against BM proteins)
  • blisters tend to be a bit more robust - due to a deeper inflammation in the skin than pemphigus

Autoimmune cytopenias (antibody-mediated blood cell destruction)

  • Haemolytic anaemia
  • Thrombocytopenia
  • Neutropenia
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8
Q

How can you test for specific antibodies?

A

immunofluorecence

ELISA e.g anti-CCP

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9
Q

What happens in type 3 hypersensitivity?

A

Immune Complex Mediated Hypersensitivity
- Formation of Antigen-Antibody complexes in blood (IMMUNE COMPLEXES)
- can’t get through the small blood vessels easily -> complexes deposit in the vessels and tissues
- leads to complement activation and cell recruitment/activation
- Activation of other cascades e.g. clotting
- Tissue damage (vasculitis) [most common sites = renal (glomerulonephritis), skin, joints and lung]
> Systemic lupus erythematosus (SLE)
> Vasculitides (Poly Arteritis Nodosum, many different types)

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10
Q

What are examples of type 4 (delayed) hypersensitivity?

A
  • Chronic graft rejection
  • Graft-versus-host disease (GVHD)
  • Coeliac disease
  • Contact hypersensitivity
  • Many others: asthma, rhinitis, eczema
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11
Q

What do Th-1 and Th-2 do in hypersensitivity?

A

type 4

Th1 - characterised by producing lots of gamma-interferon. Th1 is important in most hypersensitivity reactions

Th2 releases: IL-4, IL-5 and IL-13.

  • mediates allergic inflammation e.g. asthma, rhinitis and eczema
  • Mechanisms involve either a transient antigen presence or a persistent antigen
  • T cells then activate macrophages and CTLs. Much of the tissue damage is dependent upon TNF-alpha; hence why neutralising TNF-alpha has marked clinical benefits
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12
Q

What are the features of inflammation?

A
  • Vasodilatation, increased blood flow
  • Increased vascular permeability ( caused by C3a, C5a, histamine, leukotrienes)
  • Inflammatory mediators & cytokines
  • Inflammatory cells & tissue damage
    o Cell trafficking – chemotaxis
    o Neutrophils, macrophages, lymphocytes, mast cells
    o Cell activation
  • Cytokine release: IL-1, IL-6, IL-2, TNF, IFN-γ
  • Chemokines: IL-8/CXCL8, IP-10/CXCL10
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13
Q

What is atopy?

A

a form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions (e.g. hay fever, allergic asthma, atopic eczema) in response to allergens (atopens). Individuals with this predisposition - and conditions provoked in them by contact with allergens - are described as atopic

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14
Q

What are the genetic risk factors for asthma and eczema?

A
  • The genetic component is polygenic: 50-100 genes associated with asthma/atopy
  • Genes of the IL-4 gene cluster (chromosme 5) linked to raised IgE, asthma and atopy
  • Genes on chromosome 11q (IgE receptor) are linked to atopy and asthma
  • Genes linked to structural cells are linked to eczema (filagrin) and asthma (IL-33, ORMDL3)
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15
Q

What are the environmental risk factors of allergy?

A
  • Age: increases from infancy, peaks in teens, and reduces in adulthood
  • Gender: asthma is more common in males in childhood, and females in adults
  • Family size: more common in small families
  • Infection: early life infections protect
  • Animals: early exposure protects
  • Diet: breast feeding, anti-oxidants and fatty acids protect
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16
Q

What are the types of inflammation in allergies?

A

Anaphylaxis, urticaria, angioedema: type I hypersensitivity (IgE mediated)

Idiopathic/chronic urticaria: type II hypersensitivity (IgG mediated)

Asthma, rhinitis, eczema: mixed inflammation

  • Type I hypersensitivity (IgE mediated)
  • Type IV hypersensitivity (chronic inflammation)
17
Q

Hw does sensitisation occur in atopic airway disease?

A

T cells are naïve before the have seen the antigen.
Once an antigen-presenting cell activates the CD4+ T cells, they then become specific to the presented antigen.
They could become Th1 (producing IFN-gamma).or Th2 cells, which leads to the activation of B cells. If the T cell was presented with a harmless antigen, they can become regulatory T cells.

subsequent exposure:
The allergens are presented by APCs to the memory Th2 cells cause degranulation of eosinophils by releasing IL-5. Th2 cells also release IL-4 and IL-13, which stimulate the production of IgE by plasma cells.
The IgE then becomes mobilised onto the surface of mast cells. The antigens then cross-link with the IgE on the surface of the mast cells and cause degranulation.
There is a massive release of inflammatory mediators, which gives rise to the effects seen in an allergic reaction.

18
Q

What cells are invilved in allergies?

A 
EOSINOPHILS
- 0-5% of blood leukocytes
- Recruited during allergic inflammation
- Generated from bone marrow
- Polymorphus nucleus: two lobes
- Contain large granules full of toxic proteins
 Lead to tissue damage

MAST CELLS
- Tissue resident cells
- They have IgE receptors on cell surface
- Cross-linking of IgEs leads to mediator release:
> Pre-formed: Histamine, Cytokines, Toxic proteins
> Newly synthesized: Leukotrienes, Prostaglandins

*THIS ALL LEADS TO ACUTE INFLAMMATION.

NEUTROPHILS
- Important in virus induced asthma, severe asthma and atopic eczema
0 55-60% of blood leukocytes
- Multi-lobed nucleus
- Granules contain digestive enzymes
- Neutrophils also synthesis:
    > Oxidant radicals
    > Cytokines

o Leukotrienes

19
Q

Describe the immunopathogenesis of asthma

A

mixture of type 1 + type 4

Mast cell activation and degranulation releases histamines (pre-stored mediators) and prostaglandins and leukotrienes (newly synthesised mediators) -> acute airway narrowing

airway narrowing is mainly caused by THREE processes:

  • Vascular leakage leading to airway wall oedema
  • Mucus secretion fills up the lumen
  • Smooth muscle contraction around the bronchi
20
Q

What are some clinical features of asthma?

A
  • Reversible generalised airway obstruction – causes chronic episodic wheeze
  • Bronchial hyper-responsiveness (they are much more sensitive to bronchial irritants)
  • Cough
  • Mucus production
  • Breathlessness
  • Chest tightness
  • Response to treatment
  • Spontaneous variation
  • Reduced and variable peak expiratory flow (PEF)
21
Q

What are the features of chronic asthma?

A
  • chronic inflammation of the airways
  • lumen of the airway is very narrow and the airway wall is grossly thickened
  • cellular infiltration of Th2 lymphocytes and - Smooth muscle hypertrophy
  • Mucus plugging
  • Epithelial shedding
  • Sub-epithelial fibrosis (if the inflammation has persisted for a long time)
22
Q

What causes allergic rhinitis?

A

Seasonal – e.g. hay fever (grass and tree pollens)

Perennial – perennial allergic rhinitis (e.g. house dust mites, animal allergens)

23
Q

What are the symptoms of allergic rhinitis?

A
  • Sneezing
  • Rhinorrhoea
  • Itchy nose and eyes
  • Nasal blockage, sinusitis, loss of small/taste
24
Q

What are the features of allergic eczema?

A
  • Chronic itchy skin rash
  • Most commonly found in the flexures of the arms and legs
  • can lead to house dust mite sensitisation - house dust mite proteins can get through the dry, cracked skin
  • complicated by bacterial and (rarely) viral infections (e.g. HSV)
  • 50% clears by 7 years
  • 90% cleared by adulthood
25
Q

What type of hypersensitivity is a food allergy?

How does it change with age?

A

Type 1 (IgE mediated) hypersensitivity

  • Infancy – 3 years: Eggs, cows milk
  • Children/adults: Peanuts, shellfish, nuts, fruits, cereals and soya
26
Q

What are examples of food allergy reactions?

A

Mild reaction:

  • Itchy lips and mouth
  • Angioedema
  • Urticaria

Severe reaction:

  • Nausea
  • Abdominal pain
  • Diarrhoea
  • Anaphylaxis
27
Q

What is anaphylaxis?

A

severe generalised allergic reaction

uncommon and potentially fatal

generalised degranulation of IgE sensitised mast cel

28
Q

What are the symptoms of anaphylaxis?

A
  • Itchiness around mouth, pharynx and lips
  • Swelling of the lips, throat and other parts of the body
  • Wheeze, chest tightness and dyspnoea
  • Faintness, collapse
  • Diarrhoea and vomiting
  • DEATH if severe and untreated
29
Q

How are different systems affected in anaphylaxis?

A

Cardiovascular

  • vasodilation
  • cardiovascular collapse

Respiratory

  • bronchospasm
  • laryngeal oedema

Skin

  • vasodilation
  • erythema
  • urticaria
  • angioedema

GI
- vomiting and diarrhoea

30
Q

How can you diagnose anaphylaxis?

A
  • Careful history is essential
  • Skin prick testing
  • RAST (radio-allergosorbent test) – tests for specific IgE antibodies in the blood
  • Measure total IgE
  • Lung function (in asthma)
31
Q

How do you treat anaphylaxis?

A

EMERGENCY treatment:

  • EpiPen and anaphylaxis kit
  • Emergency treatment if mild = antihistamine (this can be backed up with a steroid injection)
  • Emergency treatment if SEVERE = ADRENALINE

Prevention:

  • Avoidance of the known allergen
  • Always carry an anaphylaxis kit and EpiPen
  • Inform immediate family and caregivers
  • Wear a MedicAlert bracelet
32
Q

How do you treat allergic rhinitis?

A
  • Anti-histamines (will help the sneezing, itching and rhinorrhoea)
  • Nasal steroid therapy (nasal decongestant)
  • Cromoglycate (in children, eyes)
33
Q

How do you treat eczema?

A
  • Emollients (maintain the moisture in skin thus reinforcing its barrier function)
  • Topic steroid cream
34
Q

How do you treat asthma?

A

STEP 1: Use a short-acting beta-2 agonist by inhalation e.g. SALBUTAMOL

STEP 2: Inhaled steroid low-moderate dose

  • Beclomethasone/Budesonide (50-800 mg/day)
  • Fluticasone

STEP 3: Add further therapy

  • Add long-acting beta-2 agonist or a leukotriene antagonist
  • High dose inhaled steroids – up to 2 mg/day via a spacer

STEP 4: Add courses of oral steroids, SLT, azithromycin

  • Prednisolone 30 mg/day for 7-14 days
  • Anti-IgE, Anti-IL4/13, Anti-IL5 mAbs
35
Q

How can immunotherapy be used to treat allergies?

A
  • Make people develop tolerance by exposing them to small amounts of the allergen they are allergic to
  • Effective for single antigen hypersensitivities e.g venom allergies (bee or wasp stings), pollens, house dust mites
  • The antigen used is purified
  • Subcutaneous immunotherapy (SCIT) - 3 years needed (weekly/monthly 2 hr clinic visits)
  • Sublingual immunotherapy (SLIT) - can be taken at home, 2-3 years enough

Year 2 MCD - Immunology (5 decks)

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