68 - Immunopathology Flashcards by Jack Cuthbertson

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)

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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

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Allergy

Immune-mediated inflammatory response to common environmental antigens that are otherwise harmless

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Relationship between [IgE] and atopy

Positive correlation. Those at risk of anaphylactic shock have more IgE than those predisposed to hayfever.

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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

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Adaptive immune response induced by allergens

Th2

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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

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Phases of type 1 allergic response
1)
2)

1) Sensitisation

2) Response (have an immediate and a delayed phase)

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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

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What releases IL-4?

Th2 cells, basophils

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What do DCs release to stimulate Th2 bias?

IL-33, which recruits basophils, which then release IL-4

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How do DCs bias to Th2?

Indirectly, through recruiting basophils with IL-33.

Basophils then release IL-4, which biases Th2 differentiation

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Locations of mast cells

Mucosal, epithelial tissues, near blood vessels

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Effects of mast cell IgE crosslinking
1)
2)

1) Degranulation

2) Synthesis of inflammatory lipid mediators, cytokines and chemokines

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Preformed mediators in mast cells

Histamine

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Lipid mediators synthesised by mast cells

Leukotrienes, prostaglandins

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Cytokines synthesised and secreted by mast cells

IL-3, IL-4, IL-5, IL-13 (Th2-type cytokines)

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Immediate phase of allergy
1)
2)
3)

1) Redness - vasodilation
2) Soft swelling - oedema
3) Dependent upon IgE
Soluble mediator phase

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Late phase of allergy
1)
2)

1) Hard swelling - accumulation of leukocytes
2) Neutrophil, Th2, eosinophil infiltration
Cellular phase

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Wheal

Localised swelling around allergic challenge

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How long after challenge does late phase occur?

8-12 hours

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Effect of allergy on GIT

1) Increased fluid secretion
2) Increased peristalsis
3) Leads to diarrhoea, vomiting

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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.