68 - Immunopathology Flashcards
Types of hypersensitivity
Type 1 - Immediate type (IgE, mast cells, lipid mediators)
Type 2 - Antibody mediated (IgM, IgG bound to antigen)
Type 3 - Immune complex (IgM, IgG complex deposition)
Type 4 - Delayed type hypersensitivity (CD4+ mediated)
Aspects of atopy
1)
2)
3)
1) High levels of IgE
2) Large numbers of eosinophils
3) Large numbers of Il-4-secreting Th2 cells
Allergy
Immune-mediated inflammatory response to common environmental antigens that are otherwise harmless
Relationship between [IgE] and atopy
Positive correlation. Those at risk of anaphylactic shock have more IgE than those predisposed to hayfever.
Common features of allergens 1) 2) 3) 4) 5) 6)
1) Individuals are repeatedly exposed to allergens via mucosal route
2) Allergens are highly soluble proteins, carried by small particles (if inhaled)
3) If ingested, slowly-degraded molecules
4) Very stable
5) High solubility in body fluids
6) Introduced in very low doses
Adaptive immune response induced by allergens
Th2
Examples of type 1 reactions 1) 2) 3) 4)
1) Systemic anaphylaxis (EG: antibiotics, venoms, peanuts)
2) Allergic rhinitis (pollen, dust mites)
3) Asthma (blockage of the airways)
4) Food allergens
Phases of type 1 allergic response
1)
2)
1) Sensitisation
2) Response (have an immediate and a delayed phase)
Sensitisation
1)
2)
3)
1) Low dose antigen through mucosal route promotes Th2 activation (IL-4 stimulates Th2 differentiation)
2) Th2 release IL-4, IL-5 and IL-13
3) IL-5 stimulates IgE isotype switching
What releases IL-4?
Th2 cells, basophils
What do DCs release to stimulate Th2 bias?
IL-33, which recruits basophils, which then release IL-4
How do DCs bias to Th2?
Indirectly, through recruiting basophils with IL-33.
Basophils then release IL-4, which biases Th2 differentiation
Locations of mast cells
Mucosal, epithelial tissues, near blood vessels
Effects of mast cell IgE crosslinking
1)
2)
1) Degranulation
2) Synthesis of inflammatory lipid mediators, cytokines and chemokines
Preformed mediators in mast cells
Histamine
Lipid mediators synthesised by mast cells
Leukotrienes, prostaglandins
Cytokines synthesised and secreted by mast cells
IL-3, IL-4, IL-5, IL-13 (Th2-type cytokines)
Immediate phase of allergy
1)
2)
3)
1) Redness - vasodilation
2) Soft swelling - oedema
3) Dependent upon IgE
Soluble mediator phase
Late phase of allergy
1)
2)
1) Hard swelling - accumulation of leukocytes
2) Neutrophil, Th2, eosinophil infiltration
Cellular phase
Wheal
Localised swelling around allergic challenge
How long after challenge does late phase occur?
8-12 hours
Effect of allergy on GIT
1) Increased fluid secretion
2) Increased peristalsis
3) Leads to diarrhoea, vomiting
Effect of allergy on skin
1)
2)
3)
1) Increased fluid secretion
2) Increased vasodilation
3) Leads to swelling, itching, urticaria
Effect of allergy on airways
1)
2)
3)
1) Decrease bronchial diameter
2) Increase mucus
3) Leads to nasal blockage, coughing, phlegm, asthma
Effect of allergy on blood vessels
1)
2)
Increased blood flow
Increased permeability
Where ar eeosinophils present?
Mucosal linings
Which stage of allergic response are eosinophils found?
Late stage
What do eosinophils release?
Toxic granule-derived basic proteins and free radicals
Chemical mediators which activate epithelial cells, recruit and activate inflammatory cells
Regulation of eosinophils
Very tight, as can release very toxic products.
IL-5 stimulates eosinophil release from the bone marrow
Why are too many eosinophils recruited in allergy?
Mast cells, Th2 release IL-5
How are eosinophils attracted to site of allergy?
Epithelial cells release eotaxins (chemokines)
Effect of activation on eosinophils
Increased number of FceRI on surface, increased IgE binding, which lowers threshold of activation
Examples of drugs used to to treat hypersensitivity 1) 2) 3) 4)
1) Epinephrine
2) Inhaled beta-adR agonists
3) Antihistamines
4) Corticosteroids
Epinephrine effects 1) 2) 3) 4)
1) To treat anaphylaxis, asthma
2) Reforms tight junctions between epithelial cells (reduce oedema)
3) Bronchodilator
4) Accelerates heart rate (if too much oedema, drop in bp)
Chemical in Ventolin
Albuterol (beta-adR agonist)
Side effects of corticosteroids 1) 2) 3) 4)
1) Bone demineralisation
2) Skin thinning
3) Weight gain
4) Immunosuppression
Effectiveness of corticosteroids over time
Effectiveness wanes over time
Treatment for allergy that addresses cause
Desensitisation.
Administration of increasing doses of allergen.
Induces T cell tolerance
How does tolerance induce T cell tolerance? 1) 2) 3) 4)
1) Decreased allergen-induced proliferation (anergy)
2) Deviation of secreted cytokines
3) Stimulation of apoptosis
4) Production of Treg
Exact mechanism not well-known
T cells involved in type IV hypersensitivity
CD4+, sometimes CTL
How is a type IV hypersensitivity elicited?
1)
2)
3)
1) Microbial infection (Chronic infection, EG: TB)
2) Intradermal injection of protein antigens
3) Contact with chemicals which are absorbed through skin
Cytokine most implicated in type IV hypersensitivity
IFNg
Examples of type IV hypersensitivity
1)
2)
3)
1) Contact sensitivity (EG: Poison ivy, adhesives, Mantoux test)
2) TB infection
3) Coeliac disease
How long does it take for a type IV hypersensitivity response to come about?
A few days
DTH
Delayed-type hypersensitivity (type IV)
Allergen in poison ivy
Pentadecacatechol
Mechanism of contact hypersensitivity 1) 2) 3) 4) 5)
1) Pentadecacatechol haptenates
2) Taken up by an APC, taken to a lymph node (DC is licensed)
3) Memory T cells are formed (sensitisation)
4) On re-exposure, activation of effector memory T cells, central memory T cells.
5) IFNg release. Leads to recruitment of macrophages to site, which leads to redness, soreness, blister
How does TB lead to type IV?
1) Infects alveolar macrophage
2) Macrophage releases IFNg, is activated
3) Activated macrophages release IL-8, TNFa
Proportion of those infected with TB who clear disease
90%
Haplotype that predisposes to coeliac
Over 90% of patients are DQ2 positive
Diagnostic test for coeliac
Test for autoantibodies to gliadins and tissue transglutaminase
Foods that contain gliadins
Wheat, rye, barley
Amino acids that gliadins are rich in
Glutamine (30%) and proline (15%)
Peptides that HLA DQ2 preferentially binds to
Those with negatively charged anchoring chains are positions 4, 7
Ability of unmodified gluten to bind HLA DQ2
Poor. Positively-charged anchoring chains at positions 4,7
How is gluten made to bind to HLA DQ2?
Modified by tissue transglutaminiase.
Deamidated gliadin peptides have negatively-charged side chains at positions 4, 7
Sensitisation phase of coeliac
1) Gliadin from food changed by tissue transglutaminase.
2) This is detected by HLA DQ2 on an APC
3) This goes to MALT, stimulates Th1 cells.