Lecture 30 - Immunopathology Flashcards Preview

MIIM30002 - Principles of Immunology > Lecture 30 - Immunopathology > Flashcards

Flashcards in Lecture 30 - Immunopathology Deck (33):

Give an overview of the hypersensitivities

Type I:
• Ab mediated
• Immediate hypersensitivities
• "Allergies"

Type II:
• Ab mediated
• Ab against cell-bound or ECM Ag
• Often linked to autoimmunity

Type III:
• Ab mediated
• Immune complex
• Often linked to autoimmunity

Type IV:
• T cell mediated
• Delayed type Hypersensitivity


What are the triggers of Type I hypersensitivity?

Harmless environmental antigens
• Pollen
• Dust-mites
• Cat dander


Describe atopy

Genetically determined tendency to produce IgE in response to environmental angitens

• High levels of IgE
• Large n° of eosinophils
• Large numbers of Th2 cells secreting IL-4


Describe exposure to allergens

Describe the outcome of this

Usually through mucosal route:
• Inhaled
• Ingested

• Highly soluble: meaning it's easy for them to get into the bodily tissues
• Very stable
• Introduced in very low doses

As a consequence, allergens induce a Th2 response


What are the different types of Type I hypersensitivity?

• Systemic anaphylaxis
• Allergy rhinitis (Hay fever)
• Asthma (acute, chronic)
• Food allergies


What are the phases of Type I hypersensitivity?

1. Sensitisation

2. Response
a. Local, immediate (common)
b. Systemic, late (uncommon)


Describe the Der p 1 story

1. Der p 1 in airway, cleaves occluding in tight junctions and crosses mucosa
2. Taken up by DCs
3. Drainage to LNs
4. Activation of naïve T cells → Th2 phenotype
5. Th2 'help' B cells in the follicle to make IgE (specific for der p 1)
6. Plasma cells travel back to mucosa
7. Secretion of IgE at the site
8. IgE bind to Mast cells via Fc(ε)R

-- re-encounter of Der p 1 antigen --

9. Der p 1 crosses mucosa again and cross links on mast cells
10. Degranulation → symptoms


Which cytokines released by Th2 cells skews B cell responses to IgE?

IL-4, IL-13


Describe the response after mast cell degranulation

Granule contents:
• Histamine

Newly formed mediators:
1. Lipid mediators
• Prostaglandin
• Leukotrienes
2. Cytokines
• IL-3
• IL-4
• IL-5
• IL-13

Physiological effects:
1. GIT
• Increased fluid secretion
• Increased peristalsis

• Diarrhoea
• Vomiting

2. Airways
• Decreased diameter
• Increased mucous secretion

• Wheezing
• Coughing
• Sputum

3. Blood vessels
• Increased blood flow
• Increased vascular permeability

• Increased cells, protein and fluid in tissue


What are the major GIT symptoms of allergy?

Diarrhoea and vomiting


Compare the immediate and the late phases in a diagnostic setting

→ Intradermal antigen skin pricks

1. Immediate:
• Redness (vasodilation)
• Soft swelling (oedema)
• Dependent on IgE
Due to:
• Preformed mediators released from mast cells

2. Late:
• Hard swelling, induration (leukocyte accumulation)
• Cellular infiltrate: neutrophils, Th2 cells, eosinophils
• Smooth muscle contraction
Due to:
Newly formed mediators:
• Chemokines
• Cytokines
• Leukotrienes


What is the 'wheal and flare' reaction?
Describe it

This is the immediate phase

Increased vascular permeability and dilation

Wheal: Localised swelling around site of challenge
Flare: Further dilation and engorgement of blood vessels in area


What is the time frame for the late stage response?

8-12 hours


Describe Type II hypersensitivity
• Outcomes

Abs bind to host antigens

1. Injury due to activation of effector mechanisms
• C' activation
• Recruitment of inflammatory cells
• Activation via Fc receptor

2. Abnormal physiological response (Graves, Myasthenia Gravis)
• Ab bind to receptors or proteins on host cells, interfering with their function:
• Activation / inhibition


Describe haemolytic disease of the newborn

Preformed maternal IgG Ab against child's Rhesus antigen on RBCs

Rh- mother, Rh+ child

-- First child --

1. Baby's RBC enter maternal circulation during delivery
2. Anti-Rh Ab produced

-- Second child --

3. Maternal anti-Rh Ab crosses placenta
4. C' activation
5. Removal of RBCs from foetus' blood


What is the treatment for haemolytic disease?

Administer mother with anti-Rh Ab within first 24hrs after delivery

Removes foetal RBC from mother before mother can make her own anti-Rh Ab


Describe Type III Hypersensitivity

When does it occur?
What does it depend on?

Formation of Ab:Ag complexes

Antigen may be self or foreign

Occurs if immune complexes are:
• Excessive produced
• Inefficiently cleared

Depends on:
• Size and amount
• Affinity and isotope of Ab

Pathology depends on:
• Where complexes deposit
e.g. SLE: kidney glomeruli


Describe normal removal of Immune complexes

1. Immune complexes comprised of high affinity IgG trigger C'

2. C3b bound to immune complexes

2. Resident macrophages in the spleen binds C3b with CR

3. Phagocytosis


Which class of Ig is needed to fix complement on immune complexes?

High affinity IgG


When might immune complexes not be cleared?
Describe what happens then

• Ag excess
• Low affinity Ab
• Inefficient C' activation

1. Deposition on vessel walls
2. Increase in concentration over time
3. Eventual C' activation:
→ Anaphylatoxin production (C3a, C5a)
→ Inflammatory cell recruitment: neurophil, mast cell degranulation
→ Macrophage cytokine release
→ Immune complexes directly activate platelets
→ Vasoactive amines; increased vascular permeability


What are the clinical syndromes due to immune complex mediated damage?

Describe where the immune complexes are being deposited in each

• Deposited on vessel walls

• Deposited on basement membrane in glomerulus

• Arthritis
• Deposition in joint synovium and vessels


Describe Type IV hypersensitivity

What can elicit it?

"Late type hypersensitivity" - DTH

"When the organism, or stimulating agen persists, T cells and macrophages accumulate at the antigen site in large numbers and result in pathology"

T Cell mediated
• + some macrophages
• Classically Th1, but also CTLs

Elicited by:
• Microbial infections: M. tuberculosis
• Intradermal injection of protein antigens
• Contact with chemicals absorbed through skin


Describe the stages of the DTH reaction

1. Antigen injected into subcutaneous tissue
2. Processing and presentation by local APCs
3. Th1 effectors cells recruited to site and recognise Ag
4. Cytokine release, some act on vascular endothelium
5. Cellular infiltrate: phagocytes
6. Visible lesions on skin


Why is Type IV called delayed type?

Because it involves recruitment of cells to the tissue where Ag is located

This takes up to 72 hours


Describe the roles of the various cytokines release by Th1 in the DTH reaction

1. Chemokines
• Recruitment of macrophages

2. IFN-γ
• Expression of vascular adhesion molecules
• Macrophage activation

3. TNF-α and LT (TNF-β)
• Expression of vascular adhesion molecules
• Local tissue destruction

4. IL-3/GM-CSF
• Monocyte production in BM from stem cells


Describe how contact sensitising agents can elicit a DTH reaction

1. Contact sensitising agent penetrates the skin and binds to self proteins (aka haptenated self proteins)

2. Complex taken up by Langerhans cells or DCs

3. DC presentation of contact sensitising agents

4. Th1 cell activation: IFN-gamma and other cytokine secretion

6. Activated keratinocytes secrete cytokines and chemokines:
• IL-1
• TNF-alpha
• CXCL11

7. All these mediators activate macrophages to secrete mediators of inflammation


List some pathogens and antigens that induce DTH

• M. tuberculosis
• M. leprae

• Actinomyces
• Leishmania sp
• Schistosoma sp


• Picrylchloride
• Hair dyes
• Nickel salts
• Poison ivy: Pentadecacatechol
• Thiomersol


What are the subtypes of Type IV hypersensitivities?

1. Contact sensitivities
• e.g. Poison ivy, Adhesives, TB test
• Previous sensitisation
• Upon re-exposure central and effector memory cells are triggered

2. M. tuberculosis
• Intracellular pathogen that resides in macrophages and resists killing
• CD4+ T cells stimulate macrophages to kill M. tuberculosis through IFN-gamma production


Describe the mechanism of DTH with a regular antigen

-- Sensitisation --

1. Uptake of Ag in skin into DCs

2. DCs draining to LNs

3. Antigens presented to T cells in paracortex

4. Th1 drain out of LNs into circulation, migrate back to site of Ag exposure

5. Clearance of antigen

-- Re-exposure --

6. Reactivation of effector and memory T cells against Ag

7. Cytokine, IFN-gamma, production

8. Large numbers of macrophages recruited

9. Excessive inflammation


Describe the Mantoux test
• Procedure
• What it tells us

Test for reveal M. tuberculosis exposure that utilises the DTH reaction

1. Purified protein deviated (tuberculin) from M. tuberculosis
2. Intradermal injection

-- if there has been previous exposure --

3. 48-72 hrs later, activated, memory T cells have migrated to injection site: inflammation, induration

Mantoux test measures exposure to Mtb, not immunity!
• May have been infected, and bacterium is cleared
• May have been infected, and are still chronically infected


What pathological feature is observed in M. tuberculosis infection?

• Multinucleated giant cells
• Formed from frustrated activated macrophages


Describe the process of M. tuberculosis infection

1. Inhalation of tuberculosis laden droplet nuclei

2. Multiplication in resident alveolar MF

3. Activation of MF:
• cytokine and chemokine prodn: IL-12, TNFalpha, IL-1
• Monocyte influx

4. Limited killing / degradation of bacterium

5. DCs take up Ag from bacterium

6. DCs migrate to LNs

7. Presentation of Mtb Ag to T cells, IL-12 signalling

8. Skewing to Th1 response

9. Activated CD8+ T cells and Th1 migrate back to site

10. Further activation of macrophages by these IFN-gamma producing cells that have just migrated (Th1, CTLs)

11. Bacterium still isn't killed

12. Formation of granulomas
• Limits spread of bacteria


Which cytokine is important for Th skewing to Th1 in DTH?