7. Immunity (extracellular + intracellular pathogens) Flashcards
What is the main function of innate immune system?
- To detect that there are Ag present
- To hold off pathogen infection to buy time for adaptive immune system
Explain the sequence of events in initial inflammatory response
Innate sensing:
1. Barrier break - microbe enters the host
2. Pathogen PAMPs + tissue DAMPs detected by PRRs by sentinel cells - activated
3. Sentinel cells secrete inflammatory mediators - cytokines
4. Increased vascular permeability - secreted molecules into blood
5. Complement system, Ab, macrophages, neutrophils, NK cells, anti-microbial peptides sent to infection site to kill
6. Secreted inflammatory mediators : adhesion + chemokines cause leukocyte (B / T cell) migration into tissue
7. Phagocytosis of microbes in infection site
What is the role of DCs in innate sensing?
- DCs sample the env
- If detect Ag - activated
- Activated DCs mature and travel to NL
- In LN DCs present antigens to T naive cells
- T cell activation
DC three modes:
- sampler
- traveller with cargo
- presenter
What are the types of T cells and what are their functions?
Which T cell types recognise extracellular Ags?
- Helper T cells (Th cells) - CD4+
- Regulatory T cells (Treg cells) - CD4+
Explain the whole sequence of events of T cells
- APCs present Ags to naive T cells -> T cells activated - mature
- Secrete cytokines, express receptors - TCR
- Proliferate - ‘clonal expansion’ of T cells
- T cell differentiation into one of the specific subtypes
- Differentiated T cell subtypes exhibit effector functions against specific Ag
What are the different Th cell subtypes? Which immune cells do they activate?
How is T cell subset differentiation started?
3 Signals needed:
- Signal 1: APC presents Ag by MHC - TCR (receptor) binds -> T cell activated - clonal expansion (but doesn’t know the type of infection)
- Signal 2: APC upregulates B7 - binds with CD28 on Th cell -> signals that the Ag comes from microbe
- Signal 3: APC secretes specific cytokines - tells T cell infection type -> knows into which subset to differentiate
What are the destinations of differentiated T cell subsets?
- Th cells migrate to sites of infection through bloodstream
- Tfh cells remain in LN, activate B cells produce Ab
What is the differentiation sequence of B cells?
- Naive B cells don’t produce Ab until activated
- Activated by Tfh cells - plasma cells - Ab factories
- Secrete BCRs - Ab as effector molecules
What are the functions of Abs?
Antibodies - effectors molecules - effector mechanisms
What are the types of antibodies and what are their properties?
MEGA
What are sentinel cells?
Sentinel cells - cells in body’s first line of defense - embeded in tissues - some of them also referred as APCs (but not all are APCs)
What are extracellular microbes?
Extracellular microbe pathogens - do not invade cells - replicate in extracellular environment - enriched with body fluids
What is the complement system? What are its functions?
Whar are the different pathways of the complement system?
- Alternative pathway
- Classical pathway
- Lectin pathway
What are the three main effector functions of the complement system?
- Opsonisation to enhance phagocytosis
- Stimulating inflammation by recruiting and activating immune cells
- Lysing microbes and cells
What is complement mediated opsonisation?
Opsonisation - immune process - uses opsonins to tag foreign pathogens for elimination by phagocytes
C3b bound to microbe - phagocyte receptor for C3b recognises - phagocytosis and killing
What is complement mediated inflammation?
Complement system mediates inflammation-like process: in complement activation mast cells release C3a, C4a, C5a - act similarly to cytokines - act locally to recruit cells to infection site + can activate cells
What is complement mediated cytolysis?
Complement activated - releases C5a - for inflammation and C5b - for membrane attack complex (MAC) assembly - assembles MAC in microbe plasma membrane - channel - water passes in, ions rush out - ion imbalance - bursts => killed pathogen
Can also kill host / foreign cells (ex transplant)
What is the main process for killing pathogens?
Phagocytosis
What are the main types of phagocytes?
What are the steps in phagocytosis?
How do Ab make phagocytosis more effcient?
What are NETs?
How do T cells enhance macrophage and neutrophil killing?
By releasing cytokines
What are the types of neutralisation performed by Ab?
What are granulocytes?
Granulocytes - innate immune cell that prestore effector molecules in granules (small particles) with enzymes that are released during infections / allergic reactions / asthma
- Mast cells
- Neutrophils
- Basophils
- Eosinophils
What is antibody dependent cell mediated cytotoxicity (ADCC)?
Antibody dependent cell mediated cytotoxicity (ADCC) - mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface Ag have been bound by specific Ab
Explain ADCC example: fighting helminths
Explain ADCC example: mast cell degranulation in fighting helminths
Mast cells secrete cytokines to attract more immune cells - inflammation
How to Th2 cels enhance immunity to helminths?
How do extracellular pathogens contribute to immune memory?
Extracellular - on the surface:
- more APCs can be activated by extracellular Ag
- easier to activate B / T cells - easier for memory cells to secreet effector molecules
Why is it beneficial for pathogens to be intracellular?
- Hide from immune effector mechanisms
- Host cells provide resources
- Host cells can help migrate
Which cells do intracellular pathogens invade?
- Phagocytes: survive within phagolysosomes
- Non-phagocyte cells, ex: somatic - IECs
What are the killing mechanisms used to kill intracellular pathogens?
Diff. intracell. pathogens - diff. effector mechanisms (match with extracellular killing mechanisms):
- phagocytosis
- Type 1 IFNs
- NK cells
How does the immunity detect intracellular microbes?
Use intracellular PRRs - as extracellular - just PRRs inside the cells rather than outside - different PRRs:
- endosomes: TLRs
- cytosol: NOD-like receptors recognise bacteria, RIG-like receptors recognise viral RNA
How do intracellular pathogens avoid phagocytosis?
- Prevent lysosome fusion with phagosome -> microbe ends up in rER-like vesicle - can proliferate until lyses the vesicle -> lyses the cell to spread => ex: Legionella pheumophila, Salmonella
- Break phagosome - use listeriolysin O (LLO) - use host actin to move around -> lives + replicates in cytosol intracellularly => ex: Listeria monocytogenes, Shigella
What other cells work in combination with macrophages to fight intracellular microbes?
Macrophages rarely work on their own - are fully activated by IFN-γ from:
- NK cells
- T cells (Th1 / CTL)
What is the importance of T cell help in macrophage activation for intracellular microbe killing?
Naive T cells have to differentiate - differentiate into Th1 to produce IFN-γ to activate macrophages
- if incorrect differentiation - not suitable signalling - could inhibit macrophage activation for successful killing
How are Tuberculosis bacteria adapted to evade phagocytosis?
TB - good at evading phagocytosis - causes granuloma formation - immune cell agreggates - replicate inside them -> continual production of IFN-γ -> continual macrophage activation -> lung tissue damage -> chronic infection
What is the anti-viral state?
Anti-viral state - result of signaling pathway - type 1 interferon production (antiviral genes) - IFN-α / IFN-β induce ant-viral state:
cell signals surrounding cells to enter anti-viral state - protect themselves from viral infection
Infection not fought directly - spread prevented to surrounding cells
What are the functions of type 1 interferons in viral-state?
Type 1 interferons (IFN-α / IFN-β):
- inhibit viral gene expression
- induce apoptosis of infected cell
- promote T cell and NK activation
What are the functions of NK cells in fighting intracellular pathogens?
NK cells kill intracellularly infected cells - need interferon (IFN-γ) from Th1 + CTL for full activation:
- faster than CTL but less precise
- important if pathogen adapted to evade CTLs
- act as source of IFN-γ for macrophage activation
How do NK cells and CTL kill pathogens?
NK cells + CTL kill infected host cells - induce apoptosis - apoptotic cells cleared by phagocytosis - non-inflammatory
Explain NK cell activation
NK cells need to be activated: NK cells express activating + inhibitory receptors:
- bind activating ligand on infected / injured cells
- bind inhibiting ligand on healthy cells - presented on MHC I - engaged
- bind inhibiting ligand on tumour cells without MHC I - non-engaged - downregulated MHC class 1 -> ‘missing’self’
NK activation depends on balance of activating / inhibitory signals received from the cell => more inhibitory - not kill / more activating and/or ‘missing self’ -> kill
For killing use same mechanism as CTL (perforin/granzyme or FASL)
How can Ab enhance NK killing?
Ab can enhance NK killing by ADCC - when microbe Ag remains on cell surface (ex: microbe leaves Ag behind while invading cell) - not when Ag presented via MHC I / II
How can adaptive immunity clear intracellular infections?
- Directly
- Indirectly
How do Th1 and CTL cooperate to kill intracellular pathogens?
How do Th1 cells induce CTL differentiation?
Th1 cells enhance CD8 activation -> CTL differentiation:
- Th1 cells produce cytokines - IFN-gamma - stimulates CTL differentiation
- Th1 cells enhance APC ability to stimulate CTL differentiation by cytokines release
How do CTL cells recognise intracellularly infected host cells?
CTL recognise intracellular Ag presented by MHC I - more specific, accurate, efficient than NK
MHC I are expressed by all nucleate cells - any cell can present intracellular Ag - be identified as infected by CTL
How do CTL cells kill infected cells?
CTL cells form synapse with infected cell - all interactions occur through the synapse - precise control which cell is killed - induce apoptosis - must be precise because killing mechanisms could damage healthy cells
What are the two killing mechanisms employed by NK cells and CTLs?
- Perforin / granzyme mediated killing
- Fas/FasL mediated killing
How are naive CTL cells activated?
Naive CTL cells have to be activated by professional APCs -** if DC not infected intracellularly** - cross-presentation:
allows specialised DCs to take up Ag from infected cells-> present on MHC I instead of MHC II => CTL can be activated without DC infection
What is the mechanism of viral evasion of NK cells and CTLs?
Viruses evade NK cells and CTLs by disrupting Ag presentation by MHC I -> reason why NK cells detect MHC I downregulation
How can Ab contribute to intracellular pathogen neutralisation?
Ab can target intracellular pathogens in their extracellular stages (ex moving between cells)
- ex: SARS-CoV-2 vaccine targets viral spike protein which is used to invade host cells - Ab binding prevents invasion
