Hypersensitivity Flashcards
What is hypersensitivity?
A group of disorders where the normally beneficial components of the immune response act in an exaggerated or inappropriate fashion to environmental antigens which do not normally cause tissue damage.
What is responsible for tissue damage in hypersensitivity reactions?
The exaggerated response directed at the antigen rather than the antigen itself is responsible for the tissue damage which results.
What are the 4 types of hypersensitivity reaction?
Type 1:
Allergy/anaphylaxis
Type 2:
Cytotoxic (blood)
Type 3: Immune complex (complement)
Type 4:
Delayed
What mediates type 1 reactions?
IgE
What elements are involved in type 1 reactions?
- Allergen (antigen_
- IgE
- Mast cell/basophil
- Th2 cells
- Eosinophils
- Genes
Give examples of allergens involved in type 1 reactions.
Airborne
-Pollen, house dust mitre, animal products
Ingested
-Milk, egg, fish, shellfish, cereals, nuts
Occupational
-Latex, drugs, industrial
When do type 1 reactions occur?
Immediate reaction to stimulus
What are type 1 reactions due to?
Hypersensitive Th cells
What is atopy?
- Genetic potential to produce allergic reactions
- Genetic tendency to produce IgE to normally innocuous environemental allergens (40%)
What is allergy?
A clinical expression of atopic tendency (15-20%)
What are the 2 phases in type 1 reactions?
- Sensitisation phase
- Reaction phase
What is the pathogenesis of type 1 reactions?
- Allergen exposure
- Mast cell activation and IgE
- Leads to degranulation and release of preformed mediators
- Synthesis of new mediators
- Results in mucosal oedema, capillary leakage, secretions, smooth muscle contraction and vasodilation
What are the 2 response phases in type 1 reactions?
- Early phase response (within minutes of allergen exposure)
- Late phase response (hours)
What is the early phase response of type 1 reactions due to?
Preformed mediators
What is the late phases response of type 1 reactions due to?
- Due to newly synthesise mast cell -Th2 cytokines
- Eosinophil mediators
What mast cells mediators are preformed in type 1 reactions?
- Histamine
- Heparin
- Tryptase
- Chymase
- ECF
- NCF
What mast cell mediators are newly synthesised in type 1 reactions?
- Prostaglandins
- Leukotrienes
How can allergy present clinically?
- Allergic rhino conjunctivitis
- Some asthma
- Urticaria, angioedema, eczema
- Food allergies
- Anaphylaxis
What are some common precipitants of anaphylaxis?
-Foods: fish, shellfish, eggs, milk, nuts, wheat
Insect venoms: bee, wasp
Drugs: antibiotics, anaesthetic agents, antisera
Latex, seminal plasma
How is allergy diagnosed?
- History and examination
- Skin prick tests
- Patch testing
- RAST test (IgE levels)
- Serum histamine, tryptase, leukotriene
How is allergy treated?
-Avoidance
-Antihistamines
-Steroid
-Adrenaline
-Patient education
-Sodium cromoglycate
-Leukotriene antagonist
-Desensitisation therapy
Specific treatment for asthma and anaphylaxis
What mediates type 2 reactions?
IgG or IgM directed against antigens on cell surface or within tissues
What is the pathogenesis of type 2 reactions?
- Antibody binds to antigen
- Complement activation
- Fc binding and stimulation of phagocytes
- Antibody dependent cellular toxicity
- Inhibits or stimulates target cells
How can type 2 reactions present clinically?
- Haemolytic reactions (Autoimmune/blood transfusions)
- Haemolytic disease of the new-born
- Hyperacute graft rejection
- Some organ specific autoimmune disease
Give examples of organ specific autoimmune disease classed as type 2 reactions.
- Grave’s disease (TSH receptor)
- Myasthenia gravis (acetylcholine receptor)
- Goodpasture’s syndrome (Type IV collagen)
- Pemphigus (desmosomes)
How are type 2 reactions treated?
Prevention
- Cross matching of blood
- Tissue typing
- Detection of rhesus incompatibility in pregnancy
Immune suppression
- Autoimmune disease
- Transplant rejection
What are type 3 reactions mediated by?
By actions of antibody: condition arises as a result of antigen/antibody complex deposition in tissues
What is the physiology of a normal immune complex?
- Immune complex undergoes opsonisation either directly or via complement activation
- Uptake by phagocytes via Fc and complement receptors
- Destruction of immune complex
What is the pathophysiology of a type 3 reaction?
- Excessive or abnormal immune complex formation
- Complement activation and recruitment of inflammatory cells
- Tissue damage
What can type 3 reactions occur as a result of?
Antigen factors
- Chronic persistence of antigen
- An abnormal ratio of antigen to antibody
- Rate of immune complex formation
Host response factors
- Antibody defects
- Complement defects
- Fc or phagocyte defects
How do type 3 reactions present?
Systemic illness where immune complexes form in the circulation and are deposited in a widespread fashion throughout many tissues (serum sickness)
More localised disorder where complexes are actually formed locally in tissues rather than being deposited from the blood (arthus reaction)
When do symptoms occur in type 3 reactions?
4-10 hours after antigen exposure
What clinical disorders can type 3 reactions manifest as?
- Extrinsic allergic alveolitis
- Post-streptococcal glomerulonephritis (complexes of streptococcal and anti-strep antibody)
- Chronic infections such as leprosy and malaria
- Tumours
- SLE
How are type 3 reactions diagnosed?
- Clinical features
- Tissue biopsy
- Circulating immune complex tests
- Precipitating antibody tests
How are type 3 reactions treated?
- Antigen elimination (e.g. infection, tumour)
- Removal of immune complexes
- Immunosuppressive therapy
What mediates type 4 reactions?
No detectable Ab component and are mediated by Th1 and/or Th17 and the cytokines they secrete
What do type 4 reactions occur in response to?
Occur in response to contact with inert environmental substances or as a reaction to infection with certain micro-organisms
Why do type 4 reactions occur?
Generally take place as the immune system finds it difficult to destroy the agents. Due to:
- Structure of the agent
- Evolved ability of the organism to evade, confound or counteract the immune response
What is the pathogenesis of type 4 reactions?
- Exogenous low molecular weight antigen (hapten) binds to endogenous protein (carrier) or a micro-organism
- Presented to antigen presenting cell (HLA-2)
- Th1 (Th17) cytokine produce, dysregulation and overactivity
What are the clinical presentations of type 4 reactions?
- Tissue damage which occurs during mycobacterial infections or autoimmune disease
- Mantoux test (skin test of delayed type hypersensitivity to mycobacterial peptides)
- Contact dermatitis
What can trigger contact dermatitis?
- Metals
- Drugs
- Plastics
- Rubber
- Plants
- Cosmetic
What is the treatment for type 4 reactions?
- Prevention and avoidance of contact with antigens
- Antimicrobial therapy as required for specific infections
- Anti-inflammatory drugs including corticosteroids
- Immunosuppressive drugs in autoimmune disease where antigen cannot be avoided
- Drugs that exploit knowledge of the immune response e.g. block TNF, IL6, B cells, often monoclonal antibodies
Hapten
Low weight environmental stimlus
What is a ‘carrier’ in type 4 reactions?
Host protein
When do type 4 reactions manifest?
Clinical effects occur 48-72 hours after antigen exposure
Why do type 4 reactions occur?
• The environmental stimulus generally does not cause any adverse effects, it is the immune system itself which causes the tissue damage
Give examples of autoimmune disease associated with type 4 reactions.
T1DM
-Th1 respond to pancreatic islet cell antigens
MS
-Th1 and Th17 initiate damage but B cells and Abs also involved
Rheumatoid arthritis
-Many features of DTH with Th1 and Th17 and the TNF secretion but also autoantibodies involved
Why do haptens need carriers?
Environmental agents involved are generally too small to produce an immune responses so they bind to host proteins to produce an antigenic stimulus that is big enough to cause a response
What type of reaction is associated with atopic dermatitis?
Type 1
What type of reaction is associated with contact dermatitis?
Type 4
What is the cause of atopic dermatitis?
Degranulation of basophils and mast cells in response to sensitised IgE
Who is atopic dermatitis common in?
Children
Where does atopic dermatitis commonly affect?
Exposed and flexor surfaces
Why does the skin get dry and itchy in atopic dermatitis?
Leaky skin allows more allergen in and water out
What is the pathogenesis of contact dermatitis?
- Haptens cross stratum corneum and act as antigen
- Langerhans cells present TNF alfa and IL-1, 13 and 18 to Th1 cells
- LCs become differentiated dendritic cells presenting allergenic epitope and multiply
How does the 2nd time response in contact dermatitis compare to the first exposure?
More aggressive response 2nd time
