Lecture 30 - Hypersensitivity, Allergy Flashcards
Type I hypersensitivity
1)
2)
1) Immediate hypersensitivity
2) IgE, mast cell, lipid mediators
Type II hypersensitivity
1)
2)
1) Antibody-mediated hypersensitivity
2) IgM and IgG against cell-bound or ECM antigen
Type III hypersensitivity
1)
2)
1) Immune complex hypersensitivity
2) IgM and IgG form immune complexes with antigen, complex deposition
Type IV hypersensitivity
1)
2)
1) Delayed-type hypersensitivity
2) CD4+ mediated
Atopic
1) Genetic predisposition to allergies
2) Enhanced tendency to produce IgE against environmental antigens
Allergy
1)
2)
1) Type I hypersensitivity
2) Immune-mediated inflammatory response to otherwise harmless environmental antigens
Traits of an atopic individual
1)
2)
3)
1) High levels of IgE (exact level varies with condition)
2) High levels of eosinophils
3) High levels of IL-4-secreting Th2
Common features of allergens 1) 2) 3) 4) 5) 6)
1) Inhaled antigens are highly-soluble proteins carried by small particles
2) Ingested antigens are highly resistant to degradation
3) Very stable
4) High solubility in body fluids
5) Introduced in very low doses
6) Induce Th2 response
Most severe type of type I hypersensitivity
Anaphylaxis
Phases of type I hypersensitivity
1)
2)
1) Sensitisation
2) Response
Types of type I responses
1)
2)
1) Local (allergic rhinitis, bronchoconstriction, conjunctivitis)
2) Systemic (anaphylaxis, this is less common)
Example of type I sensitisation and response 1) 2) 3) 4) 5) 6) 7)
1) Enzyme Der p 1 from dust mites enters body
2) Der p 1 enzymatically degrades occludin in tight junctions between epithelial cells. Enters mucosa
3) Der p 1 is taken up by dendritic cells and presented in the nearest lymph node
4) Th2 is primed by DC presentation
5) Th2 induces B cell to differentiate to plasma cell, isotype switch to IgE (specific to der p 1)
6) Plasma cell travels to mucosa, releases IgE, which sensitise resident mast cells against der p 1 (FceR1)
7) Next time der p 1 is encountered, causes mast cell degranulation
Which cytokines do Th2 secrete in response to sensitisation to allergen?
IL-4, IL-13
Effects of mast cell stimulation in type I response
1)
2)
3)
1) Secretion of preformed mediators (histamine)
2) Synthesis and secretion of lipid inflammatory mediators (prostaglandin, leukotrienes)
3) Synthesis and secretion of cytokines (IL-3, IL-4, IL-5, IL-13)
Effects of mast cell degranulation on GIT 1) 2) 3) 4)
1) Increased mucus, fluid secretion
2) Peristalsis
3) Vomiting (more severe)
4) Diarrhoea (more severe)
Effects of mast cell degranulation on airways 1) 2) 3) 4) 5)
1) Decrease diameter
2) Increase mucus secretion
3) Wheezing
4) Coughing
5) Phlegm
Effects of mast cell degranulation on blood vessels 1) 2) 3) 4) 5) 6)
1) Systemic effects, anaphylaxis
2) Increase blood flow
3) Increase permeability
4) Increase cells and proteins in tissue
5) Increase fluid in tissue
6) Increase lymph flow, effector response
Immediate phase of type I response 1) 2) 3) 4) 5)
1) Redness (flare)
2) Soft swelling - leakage of plasma from venules (wheal)
3) IgE mediated
4) Caused by release of preformed mediators (histamine)
5) Minutes after exposure to intradermal antigen
Late phase of type I response 1) 2) 3) 4) 5)
1) Hard swelling
2) Accumulation of neutrophils, Th2, eosinophils
3) Involves oedema, smooth muscle contraction
4) Caused by induced mediators (chemokines, cytokines, leukotrienes)
5) Hours to days after exposure to intradermal antigen
Immediate phase wheal and flare
1)
2)
3)
1) Wheal - localised swelling around site of challenge
2) Flare - Blood vessels around wheal dilate, become more permeable
3) Due to preformed mediators (histamine)
Outcomes of type II response
1)
2)
1) Injury due to activation of effector mechanisms
2) Abnormal physiological response to antibody binding to antigen
How can antibody binding to an allergen cause injury?
1)
2)
3)
1) C’ activation
2) Recruitment of inflammatory cells
3) Activation via Fc receptor
Examples of diseases caused by abnormal physiological response in type II hypersensitivity
1)
2)
1) Grave’s disease
2) Myasthenia gravis
Which type of hypersensitivity leads to haemolytic disease of a newborn?
Type II (due to preformed maternal IgG antibodies against newborn Rh+ blood cells)
Haemolytic disease of a newborn 1) 2) 3) 4)
1) When a Rh+ baby is delivered from a Rh- mother
2) During delivery, baby’s RBCs enter mother’s bloodstream
3) Mother produces anti-Rh IgG - is now sensitised
4) If the mother has another child who is Rh+, maternal IgG cross the placenta, bind to foetus RBCs, cause C’ removal of them
How is haemolytic disease of a newborn treated?
1)
2)
1) During delivery of the first child, administer anti-Rh antibodies to mother within 24 hours of delivery
2) These clear Rh+ RBCs from mother, so mother doesn’t produce anti-Rh antibodies
What causes type III hypersensitivity?
Immune complexes formed from antibodies and antigens (self or foreign), that are either overproduced or improperly cleared
What determines the pathology of type III hypersensitivities?
Where the immune complexes deposit.
EG: Cationic complexes can deposit on blood vessel walls and the kidney glomeruli
Mechanism of type III hypersensitivity 1) 2) 3) 4) 5) 6) 7)
1) Immune complexes aren’t cleared (low Ab affinity, excess antigen, inefficient C’ activation)
2) Complexes deposited on blood vessel walls
3) Deposition eventually leads to C’ activation
4) Anaphylatoxins are generated (C3a, C4a, lead to neutrophil, mast cell degranulation)
5) Macrophage cytokine release stimulated
6) Immune complexes directly activate platelets, basophils, mast cells
7) Vasoactive amines lead to increased vascular permeability
Immune complex-mediate damage 1) 2) 3) 4)
1) Immune complexes deposit on vascular wall, lead to disrupted blood flow, turbulence
2) Vasculitis
3) Glomerulitis (form deposition in kidney basement membrane)
4) Arthritis (deposition in joint synovium, vessels)
What can elicit a type IV response?
1)
2)
3)
1) Microbial infection
2) Intradermal injection of protein antigens
3) Contact with chemicals (EG: absorbed through the skin)
Stages of delayed-type hypersensitivity reaction 1) 2) 3) 4)
1) Antigen enters subcutaneous tissue, is taken up by resident DCs
2) DCs present antigen, tissue-resident Th1 detects antigen, proliferates
3) Cytokines released that act on vascular endothelium
4) Phagocytes, plasma recruited to region
How long does a delayed type hypersensitivity response take?
12-72 hours, because Th1 need to be recruited
Th1 cytokines in a delayed-type hypersensitivity reaction 1) 2) 3) 4)
1) Chemokines recruit macrophages to site of inflammation
2) IFNg - Induces expression of vascular adhesion molecules, macrophage activation
3) TNFa, LT - Induces expression of vascular adhesion molecules, local tissue destruction
4) IL-3/GM-CSF - stimulates macrophage production in bone marrow
Skin-contact delayed type hypersensitivity reaction 1) 2) 3) 4)
1) Hapten crosses epithelium, is taken up by Langerhans cell
2) Langerhans cells present haptenated self peptides to resident Th1 (only happens if antigen has been contacted previously)
3) Th1 secrete IFNg, cytokines
4) Keratinocytes secrete chemokines, IL-1, TNFa
Examples of pathogens that cause delayed-type hypersensitivity 1) 2) 3) 4) 5) 6)
1) Mycobacteria tuberculosis
2) M leprae
3) Leishmania spp
4) Schistosoma spp
5) Actinomycetes
6) Hepatitis B and C viruses
Examples of antigens that cause delayed-type hypersensitivity 1) 2) 3) 4)
1) Hair dyes
2) Nickel salts
3) Poison ivy (pentadecacatechol)
4) Thiomersol (in eye drops)
Diagnostic test that makes use of delayed-type hypersensitivity
Mantoux test for TB
Mantoux test
1) Tests for exposure to TB
2) Inject purified protein derivative (tuberculin) intradermally
3) If positive, after 48-72 hours, swelling at injection site, because of migration of lymphocytes
How does TB cause type IV inflammation? 1) 2) 3) 4) 5)
1) TB is inhaled, multiplies in alveolar macrophages
2) Macrophage secretes IL-1, IL-12, TNFa. Presents TB antigen on MHCI, II
3) DC, macrophage, take up antigen, migrates to lymph node, presents antigen
4) Activated CD8+, Th1, migrate to lungs, secrete IFNg, further activate macrophages.
5) This process loops, as TB bacteria persist.
