Innate Immunity Flashcards
What are the 3 traits of innate and adaptive immunity? (hint - specificity, prior, time)
Innate:
- Broad specificity
- Not affected by prior contact; No memory
- Immediate/rapid response (hours)
Adaptive:
- Highly specific
- Enhanced by prior contact; Memory
- Slow response (days-weeks)
What components make up the innate immune system? (4 things) Give examples
Barriers (physical, chemical)
Soluble proteins (complement, interferons etc.)
Local and systemic responses (inflammation, fever)
Leukocytes (Phagocytes, NK cells)
What components make up the adaptive immune system? (4 things) (hint - memory, types of immunity)
B and T lymphocytes
B cells respond by secreting soluble antibodies - Humoral immunity
T cells develop into cytotoxic T cells or helper T cells - Cell mediated immunity
Both B and T cells can develop into memory cells
What part of the immune system derives from pluripotent stem cells?
What are the 2 main lineages and what part of the immune system are they involved in? (hint - Mye, Lym)
Leukocytes
Myeloid lineage - Innate
Lymphoid lineage - Humoral
How does the body recognise function (i.e. whether a cell is innate and adaptive)?
Innate - Pattern Recognition Receptors (PRRs) that recognise Pathogen Associated Molecular Patterns (PAMPs) on cells of the innate immune system
Adaptive - B and T lymphocytes express specific antigen receptors
What do PRRs recognise?
What are the traits of these? (3 traits)
PAMPs/MAMPs
Unique to microbes
Conserved
Essential for microbe survival
What is clonal selection?
What happens to ‘self’ recognising lymphocytes?
Antigen binds antibody being presented on certain B lymphocyte
Activates B lymphocyte causing it to proliferate and produce more of that antibody
Lymphocytes that recognise ‘self’ are deleted early in development
The immune system aims to maximise host defences while minimising damage to host tissues
What are the traits of innate immunity that link to this? (hint - number, distinguishing, activation, targeting)
Innate:
- Small number of inherited PRRs recognise MAMPS unique to microbes
- Good at distinguishing between self/non-self
- Non-clonal activation
- Potential for collateral damage to self (immunopathology)
The immune system aims to maximise host defences while minimising damage to host tissues
What are the traits of adaptive immunity that link to this? (hint - number, distinguishing, activation, targeting)
Adaptive:
- ‘Infinite’ number of randomly generated antigen receptors
- Cannot reliably distinguish between self/non-self or between harmful/innocuous material
- Clonal activation
- Targets immune response specifically towards infection, sparing uninfected tissues
How are innate and adaptive immunity linked?
Innate immune system activates and directs adaptive responses
Adaptive immune system can control and focus innate immunity
What occurs in primary and secondary lymphoid tissue?
Primary - Lymphocytes reach maturity and acquire their specific receptors
Secondary - Mature ‘naïve’ lymphocytes are stimulated by antigen
How do lymphocytes meet antigen?
Dendritic cells and macorphages present antigen via uptake and MHCII expression
These then go to the secondary lymhpid tissue where they present them to lymphocytes
Adaptive immunity takes ~4-6 days to develop. Why is innate immunity then essential?
Critical in controlling infections before this
Explain microbiology as a barrier
What exposed tissues have this is a barrier?
Commensals help deter pathogenic bacteria
Almost all have commensals growing on them
What do all mechanical barriers involve?
Give examples of mechanical barriers and what they use
Epithelial cells joined by tight junctions
Lungs have cilia to move mucous
Urogenital tract has the flow of urine
How is keratinised skin a barrier?
What do keratinocytes produce and what does this do? (2 things)
How does skin shedding and commensal growth help?
Generally impermeable
Keratin; Strong and bacteria struggle to grow on this
Sebum; Contains fatty acids
Methods to get rid of and prevent bacterial growth
How do the gut and urogenital tract act as a chemical barrier?
Gut - Low pH enzymes in stomach acid to destroy bacteria
Urogenital tract - Low pH (vagina) urine
How do mucous membranes work with cilia?
Mucins are secreted in the respiratory tract to trap microbe and cilia direct mucous towards stomach acid
What are preformed mediators? (hint - broad)
Give an example; Why is it more effective against gram positive bacteria?
Proteins/peptides with broad specificity that damage pathogens, induce inflammation or help recruit and activate innate immune cells
Lysozymes present in secretions (tears, saliva, mucous etc.)
Breaks a bond in peptidoglycan; Gram +ve have more peptidoglycan and no outer membrane
Antimicrobial peptides are a type of pre-formed mediators. Give an example, where its produced and what it does
Defensins
Produced by many epithelial cells and neutrophils
Cationic, disrupt lipid bilayers in bacteria, fungi and enveloped viruses
What is complement and what does it consist of?
It is normally inert, but when is it activated and what does this trigger?
Heat-sensitive substance that “complements” antibodies in killing bacteria
- >20 soluble proteins found in blood and other body fluids
“Activated” by presence of pathogens or antibody bound to pathogen
This triggers an activation cascade
What does complement activation do early in infection?
Provides protection early in infection in the absence of antibodies
Which part of complement is essential for all pathways of activation and why?
- What is this executed by?
C3
Central event of complement activation is cleavage of C3; Executed by C3 convertase in all pathways
Why is C3 –> C3b (larger) + C3a important in complement activation? (hint - protease)
Cleavage of C3 exposes a reactive thioester (protease) in C3b; This binds covalently to adjacent proteins/carbohydrates e.g. on pathogen surface
What are the 3 pathways of complement activation?
Classical pathway – Antibody binding
Alternative pathway
Mannose-binding lectin (MBL) pathway – MBL binds mannose on pathogen surface
- Lectin – Binds tightly to carbohydrates
How do the classical and MBL pathway produce C3 convertase?
C3 convertase = C4b-C2a complex
Cleavage of C4 and C2 by C1 and MASP2, respectively
How does alternative pathway produce C3 convertase? (hint - LPS, factor B, D and P)
- There are more steps to this pathway
C3 convertase = C3b-Bb complex
Some C3b is generated spontaneously in body fluids by a “tickover” mechanism
If C3b generated binds to LPS on a pathogen surface, factor B binds
Factor B is then cleaved by factor D to produce C3b-Bb complex
C3b-Bb convertase is stabilised by factor P
How can classical/MBL pathway link with alternative pathway?
C3b generated by the classical or MBL pathway can also bind factor B
What do C5a and C3a do and what can they be called?
Give more detail (hint - receptors, blood vessels, mast cells)
Recruit phagocytes and induce inflammation
- a.k.a Chemoattractants, anaphylatoxins
Phagocytes have C5a and C3a receptors and undergo chemotaxis in response to C5a/C3a peptide
C5a/C3a act on local blood vessels, increasing blood flow, permeability and phagocyte adhesion
C5a/C3a binding to C5a/C3a receptors on mast cells induces release of inflammatory mediators
What does C3b promote and what does this facilitate?
C3b coats pathogens (opsonisation), causing them to be recognised by phagocytes with C3b receptors
This facilitates binding and phagocytosis
What does C5b - C9 form and lead to? (hint - MAC)
How?
What organisms is this important in killing?
Forms the membrane attack complex which leads to lysis
This causes C9 polymerisation which forms a pore in the membrane
Important for killing gram -ve bacteria
Why is complement referred to as a double-edged sword?
How is regulation achieved? (2 ways)
Regulation needed to prevent damage to host
Components rapidly hydrolysed in fluid phase to deactivate them
Soluble and membrane bound regulatory proteins to help regulate
Give 4 examples of regulatory proteins that regulate complement
Give 2 examples of where deficiencies in these inhibitors increase risk of disease
Factor H competes with factor B
Factor I protease cleaves C3b
CD59 on host cells binds C9, preventing MAC formation
Decay-accelerating factor (on host cells) interferes with the formation of C3 and C5 convertases
Age-related macular degeneration (lack Factor H)
Increased risk of some infections and autoimmune diseases (Factor I deficiency)
What infections are complement activation particularly important in?
Extracellular bacterial and fungal infections
How does complement interact with adaptive immune system?
Classical Pathway
Aids clearance of immune complexes (antigen:antibody)
Role in activating B and T cells
What are polymorphonuclear granulocytes?
Give examples (hint - very common white blood cells)
Immune cell that has granules (small particles) with enzymes that are released during infections, allergic reactions, and asthma
- Basophils
- Eosinophils
- Neutrophils
What are neutrophils and what receptors do they have?
What is a NET and what does it allow?
Most common leukocyte
Receptors for C3b, IgG and IgA
NET (neutrophil extracellular trap) consists of DNA and antimicrobials
Allows neutrophils to kill extracellular pathogens while minimizing damage to the host cells
What are eosinophils and what receptors do they have? (hint - allergy)
What do they release and defend against?
Leukocytes that are few in number in the blood
Receptors for C3b, IgG, IgA
- IgE with role in allergy (especially asthma)
Release toxic proteins and free radicals
Defence against multicellular parasites
What are basophils and what receptors do they have?
What do they release and defend against?
Leukocytes very few in number in the blood
Receptors for C3a, C5a, IgE
Release heparin and histamine
Defence against parasites, role in allergy (IgE)
Where are mast cells restricted to and what receptors do they have?
What do they release and defend against? (hint - sentinel)
Restricted to tissues – protect mucosal surfaces.
Receptors for C3a, C5a, IgE
Release histamine
“Sentinel” cells, defence against parasites, role in allergy
Difference between monocytes and macrophages?
Monocytes are in blood; Macrophages are tissue resident
Macrophages derive from monocytes during infection (when monocytes move from blood to tissue)
What do different tissues have? (hint - macrophages)
Give traits for lung and brain macrophages (hint - sentinel)
Different tissues have different resident macrophages
e.g. alveolar macrophages (lung), microglia (brain)
- Long-lived
- Act as “sentinel” cells – Often the first to detect infections
- Can present antigen to T lymphocytes
What do dendritic cells do?
What are they specialised for and what do they express highly?
Digest foreign material and display fragments on their cell surface
Specialised for presenting antigen to T cells
Constitutively express high levels of Major Histocompatibility Type II (MHCII) proteins
What 4 cell types perform phagocytosis?
How do healthy self-cells prevent phagocytosis by these cells?
Neutrophils
Monocytes
Macrophages
Dendritic cells
Healthy self-cells express CD47 protein which is recognised by phagocytes
What is the sequence of events during phagocytosis? (4 steps)
- Bacterium binds surface of phagocytic cell; Antibody or complement can aid binding
- Phagocyte pseudopods extend and engulf the organism
- Invagination of phagocyte membrane traps the organism within a phagosome
- A lysosome fuses and deposits enzymes into the phagosome; Enzymes cleave macromolecules and generate reactive O2 species, destroying the organism
What bactericidal agents exist in the phagosome?
Acidic (low) pH; Can also be bacteriostatic
Toxic O2-derived products
Toxic nitrogen oxides
Antimicrobial peptides
Enzymes e.g. lysozymes
Competitors e.g. lactoferrin binds Fe, depriving bacteria of Fe
What happens in O2-dependent killing when phagosomes come into contact with pathogen? (hint - 3 enzymes)
NADPH oxidase in the phagosome membrane is activated, converting O2 to superoxide ion O2(1-)
Superoxide dismutase converts the superoxide to hydrogen peroxide
Peroxidase enzymes and iron convert hydrogen peroxide to hypochlorite ion and hydroxyl radicals
All these damage bacterial DNA, proteins and membrane
What do Natural Killer (NK) cells recognise and kill? (hint - MHC)
What types of infections are they important in and what receptors do they have? (hint - until adaptive)
Recognise “altered self”, specifically self Major histocompatibility Type I (MHCI) proteins
Kill infected cells
Important in viral and some intracellular bacterial infections, until adaptive immunity is triggered
Receptors for IgG
Pattern Recognition Receptors (PRR) recognise relatively invariant structures like MAMPs and DAMPs. What are these?
MAMPs
- Critical for survival/function of pathogens
- Conserved
Damage-associated molecular patterns (DAMPs)
- Host components released during injury and cell damage
Give examples of MAMPs for bacteria (+ve and -ve), virus, fungi and protozoa
Bacteria
- Gram +ve; Lipoteichoic acids
- Gram -ve; Lipopolysaccharides (LPS)
Fungi
- Chitin
Viruses
- dsRNA
Protozoa
- Mannose-rich glycans
Give 2 examples of DAMPs and where they come from
Uric acid - Sign of kidney damage
Phosphatidylserine - Normally intracellular but is exposed during apoptosis
Give an example for each class of PRR (soluble, membrane and cytoplasmic receptor)
Soluble
- Mannose-binding lectin
Membrane
- Lectin receptor
- Toll-like receptor
Cytoplasmic
- NOD-like receptor (NLR)
How does PRR binding to MAMPs initiate macrophage phagocytosis?
Give 2 binding examples
PRR recognises relevant MAMP
- e.g. Macrophage mannose receptor recognises mannose
- e.g. CD14 recognises LPS
Macrophage then engulfs MAMP (and pathogen) and releases chemokines and cytokines
How does PRR binding to MAMP initiate chemotaxis or signalling?
Give 1 example for each
Chemoattractants released which are recognised by chemotactic receptors
Toll-like receptors (TLRs) signal the presence of microbial components
How many human TLRs are there recognising distinct MAMPs and where can they be?
How does TLR activation and signalling work? (hint - dim…)
TLR structure?
10 TLRs either on cell-surface or endosome
Ligand bind and induced dimerisation of TLR which induces signalling
Extracellular domain of TLR3 has horseshoe shape with inner surface β-sheet structure forming ligand binding domain
What are NOD-like receptors (NLR)?
What do they signal and trigger? (hint - inflam)
Large group of cytoplasmic receptors that recognise bacterial components e.g. peptidoglycan
Signal expression of pro-inflammatory cytokines
Trigger assembly of inflammasomes
What is the inflammasome and its main purpose?
What is the process?
Multi subunit complex that cleaves inactive cytokine precursors in order to limit inflammation
Active NLRs signal either cytokine transcription or inflammasome formation
Inflammasome binds protease to cleave procytokines into active cytokines for release
What is inflammation and why is it a critical local response to infection?
Release of Chemoattractants to attract phagocytes, and inflammatory mediators to increase blood flow and vascular permeability so phagocytes can gain access to microbes in tissues
Inflammation ensures that immune cells, defence molecules, coagulation factors etc. reach the site of infection or tissue damage
What are the 5 signs of inflammation?
Redness, swelling, heat and pain
Release of inflammatory mediators
Dilation of local blood vessels
Increased permeability and blood flow
Immune cell migration into inflammatory site
Inflammatory mediators are produced by sentinel cells, tissue damage and microbes. What are the 5 types?
Give 1 example for each
Lipid mediators
- Prostaglandins
Vasoactive amines
- Histamine
Chemoattractants
- fmet-leu-phe
Complement proteins
- C5a
Cytokines
-TNF
What is acute inflammation?
Movement of white blood cells from blood vessels into the tissues; Also known as “extravasation”
What are the “hormones” of the immune response?
What do they do? (hint - regulate)
What do they act on and how tightly are they regulated?
Cytokines
Regulate immune responses by changing cell behaviour of gene expression
Act on cells bearing specific cytokine receptors
Expression of cytokines and their receptors is tightly regulated
What are the 4 families of cytokine and their function?
IL-1 family - Most produced as inactive precursors that must be cleaved by inflammasomes; Important in inflammation
Interferons - Involved in responses to viruses
TNF family - Many are TM proteins but can be shed; Important in inflammation
Chemokines - Involved in cell movement
Similarities within a cytokine family?
Cytokine receptors for the various subfamilies tend to have similar structure and to signal in a similar way
Give an example of a local and systemic effect induced by any cytokine released during macrophage activation (hint - TNFα)
TNFα
Local
- Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes
Systemic
- Fever
- Mobilisation of metabolites
- Shock
- Toxic
Why is TNF and TNFR expression tightly regulated?
How is TNF made and what stimuli are potent?
How is TNFR activated and what are its 2 pathways?
Toxic unless in very low doses
Made by macrophages and LPS is a potent stimulus
TNF trimer cross-links 3 receptors, inducing signalling
Cell stimulation and apoptosis pathways
What are TNFs local effects and why? (3 effects)
Increased blood flow, capillary permeability
- Influx of fluid, cells and proteins into infected tissue
Influx of platelets
- Clotting in capillaries helps prevent spread of infection
Fluid from the capillaries enters tissues
- Increased drainage to lymph nodes
- Stimulation of adaptive immunity
What are TNFs systemic effects (low conc.)? (hint - temperature)
When cause TNF cause damage?
Causes fever by acting on hypothalamus to raise temperature to inhibit bacterial/viral growth and for optimum T and B lymphocyte activation
Inappropriate production of TNF e.g. in autoimmune disease, can cause tissue damage through chronic inflammation
What are TNFs systemic effects (high conc.)? (3 effects)
Hypotension (low blood pressure)
Disseminated (widespread) clot formation which can cause organ damage
Consumption of clotting factors can cause greater spread of infection
- Septic shock
What was the first cytokine used to treat rheumatoid arthritis?
Drugs which target this are the most successful in treating what?
TNF
Treating chronic inflammation and autoimmune disease
Viral infection induces production of interferons. What do they do?
Interfere with viral replication and alert immune system
What do Type I interferons do? (3 main things) (hint - translation, MHCI, recruit)
Induce expression of endoribonuclease that degrades viral RNA and protein kinase that phosphorylates eukaryotic initiation factor 2, inhibiting protein translation
Increases MHCI expression for greater antigen presentation to cytotoxic T cells, so infected cells are more easily recognised and killed
Induce chemokines to recruit lymphocytes
Give an example of 2 Type I interferons and a cell type specialised for their production
IFNα, IFNβ
Dendritic cells - Express high levels of interferons
- Normal cells also produce interferons just not as many
What do Type II interferons do?
Give an example of one and a cell that makes it?
Primary role in modulating adaptive immunity by increasing expression of MHCI and MHCII
IFN-γ made by T helper cells activates macrophages in responses to intracellular pathogens
What is a cytokine storm?
When may this occur?
Treatments?
An exaggerated immune response to infection with highly elevated levels of pro-inflammatory cytokines e.g. TNF, IL-1β, IL-6
May occur in sepsis, toxic shock syndrome, severe burns
Cytokine/Cytokine receptor inhibitors
Corticosteroids
How do innate and adaptive immunity interact?
Innate responses initiate adaptive responses (antigen presentation) and different cytokines steer adaptive responses by activating different T cell subsets, promoting the production of different antibody classes
Adaptive responses use elements of innate immunity to eliminate pathogens e.g. classical pathway of complement, activation of macrophages by T cell cytokines, antibodies can help NK cells recognise infected cells, mast cells to respond to parasites
