1: Hypersensitivty and allergy

Question 1

When do hypersensitivity reactions occur?

Answer 1

Occur when immune responses are mounted against

• Harmless foreign antigens
• Autoantigens
• Alloantigens

Question 2

What are the 4 types of hypersensitivity reactions?

Answer 2

Type 1 = IMMEDIATE hypersensitivity
Type 2 = Antibody-dependent Cytotoxicity
Type 3 = Immune complex mediated
Type 4 = Delayed Cell Mediated

Question 3

What is type 1 hypersensitivity? Give clinical examples

Answer 3

Anaphylaxis, asthma, rhinitis, food allergy

1st antigen exposure: Develop sensitivity, NOT tolerance
IgE produced, binds to mast cells & basophils

2nd antigen exposure: MORE IgE produced, antigen CROSS-LINKS IgE molecules on mast cells/basophils, leading to DEGRANULATION

Question 4

What is type 2 hypersensitivity? Give clinical examples

Answer 4

Auto-antibodies

Clinical presentation depends on target tissue

Organ-specific autoimmune diseases - Myasthenia Gravis (Ab to Ach receptors) , Pemphigus vulgaris (Ab to epithelial cell cement protein)

Autoimmune cytopenias - haemolytic anaemia, thrombocytopenia, neutropenia

Question 5

Tests for antibodies?

Answer 5

Immunoflourescence

ELISA (e.g. anti-CCP for rheumatoid arthritis)

Question 6

What is type 3 hypersensitivity? Give clinical examples

Answer 6

Antigen-antibody complexes in blood get deposited in blood vessels/tissues and leads to complement/cell activation (+clotting)
Results in TISSUE DAMAGE (Vasculitis)

SLE (lupus)
Other vasculitides

Question 7

What is type 4 hypersensitivity? Give clinical examples

Answer 7

Antigens presented by antigen presenting cells to Th1 lymphocytes
Th1 produces interferon gamma (IFN gamma)
Activates macrophages that release Tumour necrosis factor (TNF)
Activates fibroblasts causing angiogenesis/fibrosis
Activates Cytotoxic T lymphocytes (CTL) by production of IL-2.
Most tissue damage from CTL + TNF

Th1 mediated:
Chronic graft rejection
GVHD
Coeliac disease
Contact hypersensitivity (skin)
Many autoimmune diseases

Th2 mediated:
Asthma, rhinitis, eczema

Question 8

Features of inflammation

Give examples of mediators

Answer 8

Vasodilation
Increased vascular permeability (caused by complement activation/histamine release)
Inflammatory mediators/cytokines (IL-1/2/6, TNF, IFNgamma)
Inflammatory cells + tissue damage

Question 9

Main cells involved in inflammation?

Answer 9

Neutrophils, macrophages, lymphocytes, mast cells

Question 10

Prevalence of atopy in UK?

Answer 10

50%

Question 11

Genetic risk factors of allergy?

Answer 11

80% of atopics have family history
Polygenic (many genes linked to asthma/atopy)

Examples of genes:

• IL-4 gene cluster (linked to raised IgE)
• Genes on chromosome 11q (IgE receptor)
• Genes linked to structural cells (filaggrin linked to eczema, IL-33 linked to asthma)

Question 12

Environmental risk factors of allergy?

Answer 12

1. Age - increases in infancy, peaks in teens, decreases in adulthood

2.Childhood - more common in males
Adulthood - more common in females

3. More common in small families
4. Early life infections protect from allergy
5. Animals - early exposure protects from allergy
6. Diet (anti-oxidants/breast-feeding, fatty acids protect)

Question 13

Prevalence of allergies in UK?

Answer 13

Asthma, eczema, hay fever all RISING

Question 14

Types of inflammation?

Answer 14

Asthma, rhinitis, eczema = MIXED inflammation (type 1+4 hypersensitivity) so both IgE mediated and chronic inflammation

Anaphylaxis, urticaria, angiodema = Type 1 hypersensitivity (IgE mediated)

Idiopathic/chronic urticaria = Type 2 (IgG mediated)

Question 15

What does expression of these diseases require?

Answer 15

Primary response (early life) = Development of SENSITISATION to allergens rather than tolerance

Memory/secondary response = FURTHER allergen exposure causing disease

Question 16

Explain the process of an allergic reaction

Answer 16

Allergen sampled by dendritic cells in epithelial layer
Dendritic cells processes allergen and presents peptides to naive T cell
Naive T cells differentiate into Th2 cells to produce allergic response (Th1 = autoimmune, regulatory T cells = tolerance)
Th2 proliferate and release IL-4/13 that signal B cells to produce IgE
IgE binds to plasma cells

On second exposure:
Processed allergen presented to memory Th2 cells
Leads to more IgE production
Antigens bind to IgE on MAST CELLS, causing degranulation of inflammatory mediators

Th2 also release IL-5 which activates EOSINOPHILS

Question 17

Structure of eosinophils?

Answer 17

Mostly reside in tissues, some in blood
Bi-lobed nucleus
Have large granules containing toxic proteins (can lead to tissue damage)

Question 18

Structure of mast cells?

Answer 18

Present in tissue
Single-lobe nucleus, also granulated
IgE receptors on surface
Crosslinking of IgE by allergen causes release of mediators:
- Pre-formed histamines, cytokines, toxic proteins
- Newly synthesized prostaglandins, leukotrienes

Question 19

What kind of allergic diseases are neutrophils important in? Describe their structure.

Answer 19

Important in SEVERE or VIRUS-INDUCED ASTHMA + ATOPIC ECZEMA

Multi-lobed nucleus
Granules containing digestive enzymes
Synthesise oxidant radicals, cytokines, leukotrienes

Question 20

Pathogenesis of Acute inflammation in asthma

Answer 20

ACUTE Inflammation of airways due to:
MAST cell activation/degranulation

Release of pre-stored (histamine) and newly synthesized (prostaglandins, leukotrienes) mediators

Vascular leakage -> Airway wall oedema
Mucus secretions
SM contraction

TWO phase response - acute early response + late response (hrs later, lesser narrowing)

Question 21

Pathogenesis of Chronic inflammation in asthma

Answer 21

Chronic inflammation due to:
Dense cellular infiltrate (Th2, eosinophils)
Smooth muscle hypertrophy
Mucus plugging
Epithelial shedding
Sub-epithelial fibrosis

Question 22

List important clinical features of asthma

Answer 22

• Reversible generalised airway obstruction
• Chronic episodic wheeze
• Bronchial hyperresponsiveness (irritability)
• Cough
• Mucus production
• Breathlessness, chest tightness
• Reduced/variable Peak flow (PEF)

Question 23

Give Clinical features of allergic rhinitis?

Answer 23

Seasonal (hay fever) or Perennial (pets)

Sneezing
Rhinorrhoea
Itchy nose/eyes
Nasal blockage, sinusitis, loss of smell/taste

Question 24

Clinical features of allergic eczema?

Answer 24

Chronic itchy skin rash
Usually at flexures of arms/legs
Caused by House dust mite sensitisation, dry cracked skin
Can be complicated by bacterial/viral infections
50% clears by 7 years
90% clears by adulthood

Question 25

Clinical features of anaphylaxis?

Answer 25

Severe generalised allergic reaction
Due to generalised degranulation of IgE sensitised mast cells

Symptoms:
Itchiness around mouth/lips
Swelling (lips,throat, other body parts)
Wheeze, chest tightness, dyspnoea
Faintness/collapse
Diarrhoea/vomiting
DEATH if severe/untreated

Potential Systems affected: CVS (collapse), resp (bronchospasm), Skin (vasodilation, redness, angioedema), GI (vomiting/diarrhoea)

Question 26

Investigation of allergies?

Answer 26

Careful history
Skin prick test
RAST (test for IgE in blood)
Total IgE
Lung function (for asthma)

Question 27

Treatment and prevention of anaphylaxis?

Answer 27

EpiPen + anaphylaxis kit - antihistamines, adrenaline, streoids

Prevention:
Avoid allergen
Always carry epipen & kit

Question 28

Treatment of rhinitis?

Answer 28

Anti-histamines
Nasal steroid spray (for nasal blockage)
Cromoglycate (children, eyes)

If severe: anti-IgE monoclonal antibodies

Question 29

Treatment of eczema?

Answer 29

Emollients (keeps skin moist)

Topical steroid cream

Question 30

Treatment of asthma?

Answer 30

1. For mild/intermittent asthma use Short-acting b2 agonist drugs by inhalation (Salbutamol)
2. Inhaled steroid (low/moderate dose) e.g. Budesonide, fluticasone
3. Add long-acting bronchodilators/leukotriene antagonist
   HIGH dose inhaled steroids
4. Add Prednisolone (oral) daily for 7-14 days
   Add anti-IgE, anti-IL-5, anti-IL-4/13 monoclonal Abs

Question 31

Immunotherapy for allergy?

Answer 31

Effective for single antigen hypersensitivity
Starting with Injections of low does of purified allergen
Gradually building up to high dose over time
Develops TOLERANCE to allergen

Subcutaneous immunotherapy (SCIT)
or
Sublingual immunotherapy (tablet) (SLIT)
Both therapies need 3 years