H, A and I part 2

Question 1

Describe the important clinical features of asthma

Answer 1

Acute asthma:

• Asthma is a mixture of T1 and T4 hypersensitivities.
• Mast cell activation and degranulation releases histamines, prostaglandins and leukotrienes à narrowing airway.
• Airway narrowing caused by:

1. Vascular leakage – airway wall oedema.
2. Mucus secretion – fills lumen.
3. Smooth muscle contraction.

There is a two-phase response to single allergen challenges with an early and then late response.

Chronic asthma:

• Airway wall is grossly thickened with a narrow lumen.
• Cellular infiltrations of Th2 lymphocytes and eosinophils.
• Smooth muscle hypertrophy.
• Mucus plugging.
• Epithelial shedding.
• Sub-epithelial fibrosis.

Important clinical features of asthma:

• Reversible airway obstruction à chronic episodic wheeze.
• Bronchial hyperresponsiveness - cough
• Cough, mucus production, dyspnoea, chest tightness, responds to treatment, has spontaneous variation and a reduced PEF and VEF.

Question 2

Describe the important clinical features of hay fever, allergic eczema and anaphylaxis.

Answer 2

Allergic Rhinitis

• Seasonal – e.g. hay fever.
• Perennial – e.g. perennial allergic rhinitis (house mites etc.).
• Symptoms – sneezing, rhinorrhoea, itchy nose & eyes, nasal blockade, sinusitis and loss of small/taste.

Allergic Eczema

• Chronic itchy skin rash.
• Found in the flexures of the arm and legs.
• Can lead to house dust mite (HDM) sensitisation and dry cracked skin (HDMs through the cracked skin)
• AE is complicated by bacterial and viral infections.
• 50% clear in 7 years and 90% clear by adulthood.

Food Allergy T1 Hypersensitivity reaction

• Common food allergies change with age:
  
  • Infancy (3yo) – eggs and cow’s milk.
  • Children/adults – peanuts, shellfish, nits, fruits, cereals, soya.
• Reaction types:
  
  • Mild – itchy lips and mouth, angioedema, urticaria.
  • Severe – nausea, abdominal pain, diarrhoea, anaphylaxis.

Question 3

Describe the clinical features of anaphylaxis

Answer 3

Anaphylaxis – A severe generalised allergic reaction:

• Uncommon but are potentially fatal.
• Caused by generalised degranulation of IgE-sensitised mast cells.
• Symptoms:

1. Itchiness at mouth.
2. Wheeze/chest tightness.
3. Diarrhoea & vomiting.
4. Swelling if lips & throat.
5. Fainting/collapse.
6. Death.

Systems:

• CVS – vasodilation, CVS collapse.
• Respiratory – bronchospasm, laryngeal oedema.
• Skin – vasodilation, erythema, urticaria, angioedema.
• GI – vomiting and diarrhoea.

Question 4

Briefly describe the approach to investigation and management of patients with these disorders.

Answer 4

Investigations:

• Careful history.
• Skin prick testing.
• RAST – blood specific IgE ABs in blood.
• Measure total IgE.
• Lung functions (asthma).

Anaphylaxis treatment:

• Emergency – epi-pen and anaphylaxis kit – anti-histamine, steroids, adrenaline.
• Prevention – avoidance, emergency kits to hand, inform, medicalert bracelet.

Rhinitis and Eczema Treatment

• Allergic rhinitis:
• Anti-histamines.
• Nasal steroid therapy.
• Cromoglycate – for children in the eyes.

Eczema:

• Emollients – maintains moisture of skin.
• Topical steroid cream.
• If either are severe – anti-IgE, anti-IL-4/13, anti-IL-5 mAb.

Asthma Treatment

1. Short-acting beta2 agonist drugs – salbutamol.
2. Inhaled steroids (low-moderate dose):
   
   • Beclomethasone/Budesonide.
   • Fluticasone.
3. Add further therapy:
   
   • Long-acting beta2 agonist or a leukotriene antagonist.
   • High dose inhaled steroids.
4. Add courses of oral steroids.
   
   • Prednisolone.
   • Anti-IgE, anti-IL-4/13, anti-IL-5 mAb.

Immunotherapy

• Make people develop tolerance by exposing them to small amounts of the allergen that 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

Question 5

Outline the immunological mechanisms of immune disease

Answer 5

Genetic and Environmental Factors:

Factors that pre-dispose to auto-immunity:

• Genes – discovered through use of “twin studies” and GWAS – e.g. 40 loci key in SLE.
• Sex – females more susceptible – e.g. SLE.
  
  • There is a gradient of AI disease sex tropism though; DM affects more men whilst SLE and thyroid disease affects much more women.
• Infections – provide an inflammatory environment – e.g. EBV.
• Diet – obesity, effects on microbiome – diet modification may relieve
• Stress – can release stress-related hormones – e.g. cortisol.
• Microbiome – the microbiome helps shape immunity.

Mechanisms and Impact of Autoimmunity:

• Mechanisms: adaptive immune reactions against self-use the same mechanisms as reactions against path.
  
  • Autoimmune diseases involve breaking T-cell tolerance.
  • Because self-tissue is always present, AI diseases are chronic.
  • Effector mechanisms resemble those of hypersensitivity reactions – specifically T2, 3, 4.
• Impact of AI disease:
  
  • >100 chronic diseases linked to AI causes.
  • ~8% of people affected by AI diseases – remember T1DM is AI.
    
    • 80% of those affected are women – high prevalence might have to do with oestrogen
  • Incidence of AI diseases (and hypersensitivity) is increasing – the “hygiene hypothesis”.

Question 6

List examples of important autoimmune diseases

Answer 6

Important Clinical Examples:

From localized (thyroid) to generalized diseases (SLE)

• Rheumatoid Arthritis – 1 in 100.
• T1DM – 1 in 800.
• Multiple sclerosis – 1 in 700.
• SLE – 240,000 cases.
• Autoimmune thyroid disease – 5 in 1000 women, 0.8 in 1000 men.

Question 7

Overview the classifications of autoimmunity

Answer 7

Classifications:

• Organ affected – as seen on the first page with Grave’s disease being very specific and SLE being very systemic.
• Involvement of specific autoantigens – i.e. as in autoimmune haemolytic anaemia (AIHA).

Types of immune response:

• Type 2 hypersensitivity – antibody response (usually igG binds to something soluble and activates complement and recruits inflammatory cells) to cellular or ECM antigen
  ​

1. Goodpasture’s syndrome:
   Autoantigen – non-collagenous domain of BM collagen T4.
   ​Consequence – glomerulonephritis, pulmonary haemorrhage.
2. Grave’s disease:

Autoantigen – TSH receptor.

Consequence – stimulation of TSHR by autoantibody so lots of T4 production.

• Type 3 hypersensitivity – immune complex (formed by antigen against soluble antigens).
  
  • SLE – immune complex deposition in glomerulus.
    
    • Autoantigen – DNA, histones, ribosomes, snRNP, scRNP.
    • Consequence – glomerulonephritis, vasculitis, arthritis.
• Type 4 hypersensitivity – T-cell mediated (delayed type hypersensitivity) – CD8+(cytotoxic) and CD4+ (T-cell) responses may become involved AS WELL AS B-cell responses.

Diabetes mellitus:

• Autoantigen – pancreatic beta cell antigen.
• Consequence – beta-cell destruction.

Rheumatoid arthritis:

• Autoantigen – synovial joint antigen.
• Consequence – join inflammation & destruction.

Multiple sclerosis:

• Autoantigen – myelin basic protein, proteolipid protein.
• Consequence – brain degeneration (demyelination), weakness/paralysis

Normal T-Cell Response

Antigen is presented to T-cells by MHC.

• MHC II (DP, DQ, DR) à CD4+ TCR.
• MHC I (A, B, C) à CD8+ TCR.

MHC II is the dominant genetic factor affecting susceptibility to autoimmune disease – T-cells may initiate AI disease…

Question 8

Evidence for self-tolerance

Answer 8

Timing of Tolerance:

• Freemartin cattle share a placenta in utero and they exchange cells and antigens.
  
  • The cattle CAN have different blood groups – that don’t react with each other so tolerance must be present.
  • The cattle can accept skin grafts from each other and tolerate blood transfusions from a non-identical twin.
• Mouse models – these models show the TIMING of tolerance is important:
  
  • If the donor supplied spleen and BM cells to a NEONATAL mouse, then the same adult mouse can accept a skin graft.
  • If the donor supplied to an adult mouse, that same adult could not then accept a skin graft – cells had to be received in neonatal phase.

Specificity of Tolerance:

Mouse models – these models show the SPECIFICITY of tolerance:

If donor supplies cells to neonate then the same adult couldn’t accept a graft from a random other mouse.

Question 9

Explain the concept of immunological tolerance

Answer 9

Immunological Tolerance – the acquired inability to response to an antigenic stimulus.

• Defined by “The 3 As”:
  
  • Acquired – involves cells of acquired immune system and is learned.
  • Antigen specific.
  • Active process in neonates – effects of which are maintained throughout life.
• Mechanisms:
  
  • Central tolerance.
  • Peripheral tolerance – anergy, active suppression (T-reg cells), immune privilege (ignorance of antigen).
  • Failure in one or more of these systems may result in AI disease.

Question 10

Explain the mechanisms that underlie immunological tolerance

Answer 10

Mechanisms – CENTRAL Tolerance:

• T-cells mature in the thymus.T-cells recognise peptides presented on MHC in the thymus – Thymic epithelial cells (TEC) or DC:
  
  • MHC II (DP, DQ, DR) à CD4+ TCR.
  • MHC I (A, B, C) à CD8+ TCR.
• Thymus selection – end results:
  
  • Useless – can’t see MHC – apoptosis.
  • Useful – see MHC weakly - +ve selection.
  • Dangerous – see MHC strongly - -ve selection and signal to apoptose.
  • Only 5% of thymocytes survive the process.

B-cells mature in the bone marrow:

B-cell selection:

• No self-reaction à migration to periphery à mature b-cell.
• Multi-valent self-molecule à clonal deletion or receptor editing à apoptosis or mature b-cell.
• Soluble self-antigen à migrate to periphery à anergic b-cell.
• Low-affinity, non-crosslinking self-molecule à migrates à mature b-cell that is clonally ignorant.
  
  • This last one has potential to become autoreactive.
• B-cell selection occurs by x-linking of surface IG by polyvalent antigens expressed on BM stromal cells to facilitate deletion.

Central tolerance failure -> APECED – Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy.

• Affects – kidneys, thyroid, gonadal failure, DM, pernicious anaemia, chronic mucocutaneous candidiasis.
• Caused by a mutation in transcription factor AIRE – Autoimmune Regulator.
• AIRE is important for expression of “tissue-specific” genes in the thymus and is therefore involved in negative selection of self-reaction T-cells.
• Most AI disease is associated with multiple defects and genetic traits:SLE – 40-50 genes implicated in genetic susceptibility involved in…
  
  • Induction of tolerance – failure of tolerance.
    
    • CD22, SHP-1.
  • Apoptosis – failure of cell-death.
    
    • Fas, Fas-L mutations.
  • Clearance of antigen – abundance of autoantigen.
    
    • C1q, C1r, C1s complement proteins.

Question 11

Explain how defects in tolerance lead to autoimmune diseases, and list factors that may lead to breakdown of self-tolerance.

Answer 11

Induction and Maintenance of Tolerance in Periphery

• Some antigens may not be expressed in the thymus or BM and may only be expressed after maturity of the immune system à mechanisms required to prevent the auto-immunity here.
  
  • Anergy.
  • Suppression by T-reg cells.
  • Ignorance of antigen.

Anergy

• Naïve T-cells require co-stimulation for activation:
  
  • Co-stimulatory molecules – CD80, 86, 40.
  • These are absent on most cells of the body.
• Without co-stimulation, cell proliferation wouldn’t proceed.
• Subsequent stimulation then leads to a refractory state termed – anergy.

Ignorance

Ignorance occurs when:

• Occurs when antigen concentration is too low.
• Occurs when relevant APC is absent – most cells in periphery are MHC II –ve.
• Occurs at immunologically privileged sites – immune cells cannot penetrate as an immune reaction could do more harm than good – i.e. the brain.

Example of failure of ignorance – Sympathetic Ophthalmia:

• Trauma to an eye leads to release of intraocular proteins which trigger immune system.

Suppression/Regulation

• Autoreactive T-cells may be present but DO NOT respond to auto-antigen.
• Controlled by T-reg cells:
  
  • CD4+, CD25+, CTLA-4+, FOXP3+ (transcription factor important in T-cell regulation).
• CD25 – IL-2 receptor.
• CTLA-4 – binds to B7 and sends a –ve signal.
• FOXP3 – TF required for T-reg cell development.
• IPEX is when there is a mutation in FOXP3 à fatal recessive disorder presenting early in childhood and leads to an accumulation of autoreactive T-cells causing:
  
  • Early onset DM, enteropathy, eczema, infections and AI symptoms.

Infection Breaking Peripheral Tolerance

• Infection can lead to a break in tolerance and then lead to AI disease – i.e. EBV & measles and Multiple Sclerosis.
• This can be done via:
  
  • Molecular mimicry of self-molecules – i.e. Grave’s disease.
  • Induce changes in expression and recognition of self-proteins.
  • Induction of co-stimulatory molecules or inappropriate MHC II expression.
  • Failure of regulation – effects in T-reg cells.
  • Immune deviation – shift in type of immune response – e.g. Th1 à Th2.
  • Tissue damage at immunologically privileged sites such as the eye.