Hypersensitivity, allergy and inflammation

Question 1

Outline the mechanism of normal immune function and the four types of hypersensitivity

Answer 1

Immune Reactions

• Appropriate immune reactions occur to foreign harmful agents – remove pathogens, possible concomitant tissue damage to remove pathogen but this is acceptable as can be repaired.
  
  • Involves antigen recognition by immune cells and antibody production.
• Appropriate immune tolerance can occur to self AND to foreign harmless proteins – food, pollens, etc.
  
  • Involves antigen recognition and generation of TReg cells and regulatory (blocking) antibody production (IgG4)
  • antigen recognition in the absence of danger leads to immune tolerance

Hypersensitivity Reactions:

• Hypersensitivity reactions occur when immune responses are mounted against:
  
  1. Harmless foreign antigens (allergy, contact hypersensitivity from pollen)
  2. Autoantigens (autoimmune disease)
  3. Alloantigens (serum sickness, transfusion reactions, graft rejection)

Allo-antigens are antigens present in only SOME individuals (i.e. ABO blood groups).

Note – many diseases involve a mixture of the types

Classification:

Type 1: Immediate hypersensitivity (IgE)

Type 2: Antibody-dependent cytotoxicity (antibody)

Type 3: Immune complex mediated (immune complex)

Type 4: Delayed cell mediated (T-cells)

Question 2

Outline type 1 immediate hypersensitivity

Answer 2

Type 1 Immediate Hypersensitivity:

• Anaphylaxis.
• Asthma.
• Rhinitis – seasonal and perennial.
• Food allergies.

1st exposure –

• SENSITISATION not tolerance
• IgE antibody production
• IgE binds to mast cells and basophils

2nd exposure –

• More IgE antibody produced
• Antigen cross-­‐links IgE on the mast cells and basophils
• This leads to degranulation and release of inflammatory mediators

Question 3

Outline type 2 antibody-dependent hypersensitivity

Answer 3

The clinical presentation depends on the target tissue

Organ specific autoimmune diseases:

• Myasthenia gravis (anti-­‐acetylcholine receptor antibodies)
• Glomerulonephritis (anti-­‐glomerular basement membrane antibody)
• Pemphigus vulgaris (anti-­‐epithelial cell cement protein antibody)
• Pernicious anaemia (intrinsic factor blocking antibodies which block absiprtion of vitamin B12 in the gut)

Autoimmune cytopenias (antibody mediated blood cell destruction)

• Haemolytic anaemia.
• Thrombocytopaenia.
• Neutropenia.

Test for specific antibodies:

• Immunofluorescence.
• ELISA (e.g. anti-­‐CCP antibodies in rheumatoid arthritis)

NOTE: pemphigus vulgaris -­‐ due to autoimmune attack of an antibody that cements epithelial cells together

Question 4

Type 3 - Immune Complex Mediated Hypersesnitivity

Answer 4

• Formation of antigen-­‐antibody complexes in the blood
• They can’t get through the small blood vessels very easily
• These complexes become deposited in various tissues
• It leads to complement activation and cell recruitment/activation

1. Activation of other cascades e.g. clotting
2. Tissue damage (Vasculitides (polyarteritis nodosa, many different types)

NOTE: vasculitides = plural of vasculitis

Most common sites of vasculitis: renal (glomerulonephritis), skin, joints and lung

Question 5

Type 4 - Delayed type hypersensitivity

Answer 5

Apparent in:

• Chronic graft rejection.
• Graft-versus-Host disease (GVHD).
• Coeliac disease.
• Contact hypersensitivity.
• Others – asthma, rhinitis, eczema.

Three main varieties of cells:

1. Th1 (pictured) – produces lots of gamma-interferon.
2. Cytotoxic (pictured).
3. Th2 – releases IL-4, IL-5, IL-13 (allergic inflammation).

Mechanisms:

1. Transient or persistent antigen presence
2. T-cell activation of macrophages, CTLs
3. TNF-a damage.

• Th1 -­‐ characterised by producing lots of gamma-­‐interferon
• Th1 is important in most hypersensitivity reactions
• Th2 releases: IL-­‐4 o IL-­‐5 o IL-­‐13
• Th2 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 cytokines such as TNF-­‐alpha, hence why neutralising TNF-­‐alpha has marked clinical benefits

NOTE: hypersensitivity types 1-­‐3 are mediated by antibody and they are distinguished by the type of antigen that they recognise.

Type 2 = cell surface or matrix bound antigens

Type 3 = soluble antigens

NOTE: asthma is caused by IgE binding to mast cells and by the induction of T cells producing Th2 type cytokines

Question 6

Outline the mechanisms by which hypersensitivity causes tissue damage and inflammation.

Answer 6

Immunce cell activation –> recruitment of white cells to sites of injury -> activation -> inflammatory mediators production (complement,cytokines)

Features:

1. Vasodilation
2. Increased vascular permeability
3. Inflammatory mediators and cytokines
4. Inflammatory cells and tissue damage

​ Signs:

• Rubor.
• Calor
• Tumour.
• Dolor.

Cytokines:

C3a, C5a, histamine, leukotrienes.

Cytokines include – IL-1, IL-2, IL-6, TNF-a, IFN-g.

Chemokines include – IL-8 (CXCL8), IP-10 (CXCL10).

Neutrophils, macrophages, lymphocytes and mast cells recruited for cell activaiton

Question 7

Give examples of clinical syndromes associated with each.

Question 8

Outline the factors underlying the development of atopic/allergic diseases.

Answer 8

Atopy -­‐ 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.

• Atopy is very common – 50% of young adults.
• Severity varies from mild -> severe -> life-threatening anaphylaxis

Risk factors:

Genetic –

• 80% of atopies have a family history
• Polygenic
• 50-100 genes are associated with asthma and atopy
• IL-4 gene cluster – Chr5 – linked to raised IgE, asthma and atopy.
• Chr11q IgE Receptor – genes linked to atopy and asthma.
• Genes linked to eczema (filaggrin:protein in skin promotes adher) and asthma (IL-33, ORMDL3).

Environmental -

• Age – increases in infancy to a peak in teens and then drops into adulthood.
• Gender – more common in males (childhood) and females (adulthood).
• Family size – more common in small families.
• Infections – lends to early life protection.
• Animals – early exposure protects.
• Diet – breast feeding, anti-oxidants and fatty acids protect against atopy.

Types of inflammation in allergy:

1. Anaphylaxis, urticaria, angioedema -> T1-hypersensitivity (IgE-mediated).
2. Idiopathic/chronic urticaria -> T2-hypersensitivity (IgG-mediated).
3. Asthma, rhinitis, eczema -> Mixed T1 (IgE), T4 (chronic inflammation) hypersensitivity

NOTE: Development of sensitisation to allergens to sensitise instead of develop tolerance (primary response -­‐ usually early in life) to produce disease (memory response -­‐ any time after first exposure)

Question 9

Describe the sensitization process in atopic airway disease

Answer 9

• Airway in the lung with ciliated mucus secreting cells
• Dendritic cells present peptides to CD4 T helper
• T cells are naïve before the have seen the antigen
• Once the CD4+ T cells are activated by an antigen presenting cell, they then become specific to the presented antigen
• They could become Th1 (producing IFN-­‐gamma)
• They could become Th2 cells that leads to the activation of B cells
• B cells switch to IGE production rather than IDG or IgM
• If the T cell was presented with a harmless antigen, they can become regulatory T cells

Question 10

Discuss the events that occur in the subsequent exposure in atopic airway disease

Answer 10

• Dendritic process antigen into peptide and present it to membrane T cells which produce IL4
• The allergens are presented by APCs to the memory Th2 cells
• These then 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 – eosinophil

Question 11

Name and describe the functions of allergic cell mediators

Answer 11

Eosinophils:

• 2-5% of blood leukocytes.
• Present in the blood but most are in the tissue.
• Recruited during allergic inflammation.
• Generated from bone marrow.
• Have polymorphic nuclei – bi-lobed.
• Have large granules full of toxic proteins.

Neutrophils:

• Important in – virus induced, severe and atopic asthma.
• 55-70% of blood leukocytes.
• Multi-lobed nuclei with digestive enzyme granules.
• Synthesise – oxidant radicals, cytokines and leukotrienes.

Mast cells:

• Tissue resident cells.
• IgE receptors on the cell surface.
• Cross-linking with IgEs leads to release of inflammatory mediators:
• Pre-formed:
  
  • Histamine.
  • Cytokines.
  • Toxic proteins.
• Newly synthesised:
  
  • Leukotrienes.
  • Prostaglandins.
  • Leads to acute inflammation.