Lecture 30 - Immunopathology Flashcards
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 etc.
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
Allergens:
• 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?
- Sensitisation
- Response
a. Local, immediate (common)
b. Systemic, late (uncommon)
Describe the Der p 1 story
- Der p 1 in airway, cleaves occluding in tight junctions and crosses mucosa
- Taken up by DCs
- Drainage to LNs
- Activation of naïve T cells → Th2 phenotype
- Th2 ‘help’ B cells in the follicle to make IgE (specific for der p 1)
- Plasma cells travel back to mucosa
- Secretion of IgE at the site
- IgE bind to Mast cells via Fc(ε)R
– re-encounter of Der p 1 antigen –
- Der p 1 crosses mucosa again and cross links on mast cells
- 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
Outcomes: 1. Injury due to activation of effector mechanisms • C' activation • Recruitment of inflammatory cells • Activation via Fc receptor
- 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 –
- Baby’s RBC enter maternal circulation during delivery
- Anti-Rh Ab produced
– Second child –
- Maternal anti-Rh Ab crosses placenta
- C’ activation
- 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
- Immune complexes comprised of high affinity IgG trigger C’
- C3b bound to immune complexes
- Resident macrophages in the spleen binds C3b with CR
- 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
- Deposition on vessel walls
- Increase in concentration over time
- 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
Vasculitis
• Deposited on vessel walls
Glomerulonephritis
• 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
- Antigen injected into subcutaneous tissue
- Processing and presentation by local APCs
- Th1 effectors cells recruited to site and recognise Ag
- Cytokine release, some act on vascular endothelium
- Cellular infiltrate: phagocytes
- 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
- Chemokines
• Recruitment of macrophages - IFN-γ
• Expression of vascular adhesion molecules
• Macrophage activation - TNF-α and LT (TNF-β)
• Expression of vascular adhesion molecules
• Local tissue destruction - IL-3/GM-CSF
• Monocyte production in BM from stem cells
Describe how contact sensitising agents can elicit a DTH reaction
- Contact sensitising agent penetrates the skin and binds to self proteins (aka haptenated self proteins)
- Complex taken up by Langerhans cells or DCs
- DC presentation of contact sensitising agents
- Th1 cell activation: IFN-gamma and other cytokine secretion
6. Activated keratinocytes secrete cytokines and chemokines: • IL-1 • TNF-alpha • CXCL8 • CXCL11 • CXCL9
- All these mediators activate macrophages to secrete mediators of inflammation
List some pathogens and antigens that induce DTH
Bacteria:
• M. tuberculosis
• M. leprae
Pathogens:
• Actinomyces
• Leishmania sp
• Schistosoma sp
Viruses:
• HBV
• HCV
Antigens: • Picrylchloride • Hair dyes • Nickel salts • Poison ivy: Pentadecacatechol • Thiomersol
What are the subtypes of Type IV hypersensitivities?
- Contact sensitivities
• e.g. Poison ivy, Adhesives, TB test
• Previous sensitisation
• Upon re-exposure central and effector memory cells are triggered - 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 –
- Uptake of Ag in skin into DCs
- DCs draining to LNs
- Antigens presented to T cells in paracortex
- Th1 drain out of LNs into circulation, migrate back to site of Ag exposure
- Clearance of antigen
– Re-exposure –
- Reactivation of effector and memory T cells against Ag
- Cytokine, IFN-gamma, production
- Large numbers of macrophages recruited
- Excessive inflammation
Describe the Mantoux test
• Procedure
• What it tells us
Test for reveal M. tuberculosis exposure that utilises the DTH reaction
- Purified protein deviated (tuberculin) from M. tuberculosis
- Intradermal injection
– if there has been previous exposure –
- 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?
Granulomas
• Multinucleated giant cells
• Formed from frustrated activated macrophages
Describe the process of M. tuberculosis infection
- Inhalation of tuberculosis laden droplet nuclei
- Multiplication in resident alveolar MF
- Activation of MF:
• cytokine and chemokine prodn: IL-12, TNFalpha, IL-1
• Monocyte influx - Limited killing / degradation of bacterium
- DCs take up Ag from bacterium
- DCs migrate to LNs
- Presentation of Mtb Ag to T cells, IL-12 signalling
- Skewing to Th1 response
- Activated CD8+ T cells and Th1 migrate back to site
- Further activation of macrophages by these IFN-gamma producing cells that have just migrated (Th1, CTLs)
- Bacterium still isn’t killed
- Formation of granulomas
• Limits spread of bacteria
Which cytokine is important for Th skewing to Th1 in DTH?
IL-12
