Lecture 27: Hypersensitivity and autoimmunity Flashcards
How can hypersensitivity be classified and what are the mediators?
Type One: IgE mediated (Allergic or anaphylactic)
Type Two: IgG, Antibody mediated (Cytotoxic)
Type Three: IgG, Immune complex mediated
Type Four: T cell mediated (DTH - delayed - type)
Describe the concentration of IgE in the general population and atopic persons:
Everyone has varying degrees of circulating IgE antibody and in some people this causes allergy. However, most allergic people have very high levels of IgE whilst the general population have lower levels.
Describe why IgE is heavily involved in hypersensitivity reactions: What does degranulation of mast cells lead to?
IgE Fc region STRONGLY (high affinity) binds FcR on mast cells and stimulates degranulation. Allergen can then cross link the IgE bound to mast cells and enhance this process further.
Degranulation leads to:
- Chemoattractants
- Activators; Vasodilation, complement, platelets
- Spasmogens; SM contraction, mucus secretion
What are the common causes of allergies related to:
- Rhinitis
- Insect stings
- Foods
- Small molecules
Rhinitis (Upper respiratory)
- House dust mite (Dus mite dander)
- Pollens
- Animal dander
Insect stings
- Proteins in venom
- Anaphylaxis is common
Food allergies
- Wheat protein
- Milk proteins
- Peanuts
- Strawberries
Small molecules
- Penicillin
- Codiene
- Morphine
What are the common types of respiratory tract allergies?
- Allergic rhinitis (Hay fever)
- Sinusitis (Inflamed nasal sinuses)
- Conjunctivitis
- Asthma (Allergic component)
What are some common types of skin, gut and multiple organ allergies?
Skin:
- Urticaria
- Angioedema
Gut:
- Food allergy
Multiple organs
- Anaphylaxis
How can allergies be treated? 5 examples
Avoidance
Antihistamines (esp. mild forms)
Corticosteroids (Chronic forms i.e asthma)
Sodium cromoglycate (Stablises mast cells)
Sympathomimetics (Adrenalin)
Whats a new method of allergy treatment / cure?
Desensitisation: Gradually increasing doses of allergen to induce high affinity IgG antibodies (Compete with IgE for allergen)
Describe type two hypersensitivity:
Antibodies against cell surface antigens.
- Antibody dependent cellular cytotoxicity.
- Complement activation
- Frustrated phagocytosis
What is frustrated phagocytosis in T2 hypersensitivity?
A phagocyte i.e neutrophil recognises i.e C3B bound to cell in tissue (not bacteria) and cant phagocytose so it release vacuole contents = cell damage
Describe how T2 hypersensitivity can be organ specific:
T2 hypersensitivity can underpin organ specific auto-immunity i.e
Haemolytic disease of newborn
= Anti RhD red cell IgG antibodies
Describe type 3 hypersensitivity:
High levels of antibody develop because of high antigen concentrations, but after antigens are gone these levels remain high. This can result in:
Immune complex (I.e compliment, AB, platelets) mediated ; Vasculitis, nephritis, pneumonitis
Reaction all kicked off by excess immune complexes
Can lead to microthrombus formation and neutrophil activation
Describe how in T3 hypersensitivity vasculitis takes place:
- Deposition of immune complex and platelet aggregation leads to microthrombus formation.
- This can lead to activation of compliment system and thus neutrophils.
- Chemotaxis of activated neutrophils migrates them to microthrombus and leads to vascular damage as they release their vacuole contents
Whats a clinical example of T3 hypersenstivity?
Extrinsic allergic alveolitis (Hypersensitivity pneuomonitis)
Write some notes on extrinsic allergic alveolitis:
- Circulating antibodies against inhaled antigens
- i.e Farmers lung (mouldy hay)
- Immune complex formation in alveoli
- Compliment mediated and neutrophil mediated lung function compromised
What are some examples of T4 hypersensitivity? Describe the process
Contact sensitivity
- Antigen uptake, processing and presentation to memory Th1 cells
- CD4 TH1 cytokine mediated inflammation
= Lymphocyte and macrophage recruitment
Describe how exactly T4 hypersensitivity; contact sensitivity occurs:
Normal proteins acts as carrier proteins for small molecules i.e metal ions “hapten”, metal ions are normally too small to be recognised but once bound to haptens they form new epitopes and these are transported to the lymph node and T cell stimulation occurs. ; Memory Th1 cells return and provoke inflammation
Which hypersensitivity reactions facilitate auto-immunity?
Type 2; Organ specific, AB mediated (Cytotoxic)
Type 3; Immune complex mediated (Systemic)
Describe how common autoantibodies might be and the implications of this? What are some examples
- Natural IgM low affinity autoantibodies are common (but lack affintiy and concentration)
i. e
Anti-nuclear antibody seen in elderly in low conc. and high conc. in patients with SLE
Anti-thyroid antibody seen in elderly too but <2% have thyroid disease
Therefore, its possible regulation dysfunction is the cause of disease
What are the mechanisms of tolerance for AB?
Clonal deletion (Central) : Bone marrow and thymus Clonal regulation (Peripheral) : No con-stim - anergy Suppression (Peripheral) : Tregs control self reactive
Give examples 1-3 of organ specific autoimmunity:
- Goodpastures syndrome: AB against type 4 collagen in glomerular basement membrane
- Myasthenia gravis: AB block AcH receptor
- Hashimotos thyroiditis: AB and T cells destroy thyroid tissue
Give examples 4-6 of organ specific auto-immunity:
- Idiopathic thrombocytopenic purpura: AB against platelets
- Addisons disease: Destruction of adrenal cortex, hyperpigmentation
- T1D
Describe pernicious anaemia as another auto-immune example:
AB against IF released from parietal cells prevents B12 absorption
Describe Graves disease as another auto-immune example:
AB against TSH receptor
= Thyrotoxicosis - chronic thyroid stimulation by autoantibody
What are some examples of type 3 hypersensitivity auto immunity:
SLE
Rheumatoid athritis
Describe the genetic relation to autoimmunity:q
Genetic mutations in:
- Antigen receptor genes
- Antigen presenting genes
- Complement genes i.e impaired clearance
- Regulatory genes i.e cytokines and costimulators
What are the treatments for these auto-immunity?
T1D, Hashimotos, Addisons = Replacement of hormones
SLE, Rheumatoid athritis = Suppression (immunosupressive drugs)
