Innate Immune System Flashcards
1
Q
what are the properties of the early immune system response?
A
- starts when a microbe is encountered
- not highly specific
- fast
- resolves without creating a memory
- aim is to clear the pathogen/infected cells and alert the adaptive response
2
Q
what are the 4 general principles of the immune response?
A
- clear the microbe/inhibit its replication
- process microbes and present to cells of the adaptive immune system
- alert and attract other cells
- kill itself
3
Q
how might the microbe be cleared or its replication inhibited?
A
phagocytosis, interferon system
4
Q
what is the name of the process where microbes are presented to cells of the adaptive immune system?
A
antigen processing and presentation
5
Q
how might cells in the immune system alert and attract other cells?
A
upregulation of surface receptors, cytokines and chemokines
6
Q
how will an infected cell kill itself?
A
apoptosis
7
Q
what cells have the potential to perform the activities listed in the general principles of the immune response?
A
- all cells
- some cells are specifically made and programmed
- exceptionally good at the first 3 they are the cells of the innate immune system
8
Q
what is inflammation the result of?
A
- result of infection (a physiological process)
- damage of a tissue
9
Q
why is inflammation needed?
A
pre-requisite of a successful immune response
10
Q
what are the features of inflammation?
A
heat, redness, swelling and pain
11
Q
what are the 3 roles of inflammation?
A
- delivery of effector cells/moleucles to the site of infection; enhance microbe clearnace
- blood clotting to form a physical barrier and prevent spreading of infection to the bloodstream
- enhancement of the tissue repair process
12
Q
what changes are there in the blood vessel during inflammation?
A
- increased vessel diameter
- increased adhesion molecules to bind leukocytes
- increased vascular permeability (leaky)
13
Q
how do leukocytes move into bloodvessels?
A
attachment followed extravasation
14
Q
how fast is the innate immune response?
A
happens within hours
15
Q
what are neutrophils?
A
- form the plolymorphonuclear cell family with basophils and eosinophils
- most abundant type of white blood cells
- predominant cells in pus
- first to arrive
- quick, short lived and motile
16
Q
how do neutrophils kill?
A
- phagocytosis
- degranulation
- neutrophil extracellular traps (NETs)
17
Q
what does phagocytosis require?
A
substantial membrane rearrangement
18
Q
what are the 5 steps in phagocytosis?
A
- attachment/adhesion and engulfment
- phagosome formation
- recruitment of lysosome
- phagosome-lysosome fusion produces a phagolysosome
- microbe is killed with high concentration of reactive oxygen species, defensins, hydrolytic enzymes and the low pH
19
Q
what is degranulation?
A
release of azurophilic or specific granules containing proteases, defensins and reactive oxygen species
20
Q
what are NETs?
A
- primarily composed of DNA and anti-microbial proteins
- acts by trapping bacteria, killing them through localised and high concentrations of anti-microbial proteins
- NETs essentially releases their chromatin to create a sticky environment
21
Q
what are macrophages?
A
- myeloid lineage, mature from monocytes
- reside in tissues, already there before a threat
22
Q
what does the macrophage tissue in infected tissue?
A
-phagocytse microbes while circulating monocytes are recruited to the tissue
23
Q
how do macrophages become activated?
A
through direct interaction with pathogens or through factors secreted by T helper lymphocytes
24
Q
what are the functions of macrophages?
A
- highly phagocytic (engulf and destroy a pathogen)
- secrete cytokines (orchestrate the inflammatory response)
- present antigens to T cells
- contribute to tissue repair and formation of new blood vessels
25
what are dendritic cells?
- myeloid and plasmocytoid dendritic cell
- have long finger like processes
- migrate from the bloodstream to the tissue or are tissue resident
- are phagocytic
26
what happens to dendritic cells during maturation?
1. become less phagocytic and endocytic
2. proliferate
3. process microbial proteins to small peptides that can be recognised by T lymphocytes
4. upregulate expression of surface proteins and cytokines required for antigen presentation
5. secrete type 1 interferons that inhibit pathogen replication
6. go to the nearest lymph node to present to T cells
27
what are plasmocytoid dendritic cells?
- subset of DC's derived from CLP that look like plasma cells
- rare less than 0.5% of white blood cells
- mainly produce type 1 interferons
- very important in antiviral response
28
what are innate lymphoid cells?
- dont sense antigens directly they are activated by signal cytokines
- produce effector proteins
- dont have an antigen specific receptor
- mirror the phenotype and function of T cells
29
what are natural killer cells?
- terminally differentiated cell of the lymphoid lineage
- large
- characterised by cytoplasmic granules and cytotoxic proteins
- also secrete IFNy and kill infected cells
30
how do natural killer cells become activated?
in response to type 1 interferons secreted by other innate cells of cytokines produced by the tissue
31
how is the cytotoxic activity of natural killer cells controlled?
through inhibitory and activating receptors on the cell membrane
32
what are the main functions of the natural killer cell?
- clearance of missing self cells
| - antibody dependent cellular cytotoxicity
33
what is meant by missing self when referring to natural killer cells?
- body cells express MHC-1, how cells are recognised as self
- pathogens down-regulated MHC-1 to avoid clearance
- NKs kill any cell with no/low MHC-1 expression
- MHC-1 have a cargo (peptide) that can be self or microbial
34
what is antibody dependent cellular cytotoxicity?
- NK cells also carry receptors for the Fc region of antibodies
- microbes/cells coated with antibodies can trigger NK cells to release their cytotoxic granules
35
what is the complement system?
a system of soluble pattern recognition receptors and effector molecules that detects and initiates the response
36
what are the 3 complement system pathways?
1. Clq - classical pathway
2. mannose binding lectin and lectin pathway
3. C3 - alternative pathway
37
what is the classical pathway?
interacts with an antibody coated pathogen surface
38
what is the lectin pathway?
recognises carbohydrates on pathogen surfaces
39
what is the alternative pathway?
undergoes spontatneous hydrolysis leading to deposition of C3 convertase on pathogen
40
what are the key steps of the complement amplification cascade?
- circulating proteins react with each other to fight infection
- complement proteins can be inactive precursor proteases
- at sites of infection the complement system is activated through a triggered enzyme cascade
41
how do complement proteins become activated?
activated by proteolytic cleavage
42
what are the steps of the complement system becoming activated through a enzyme cascade at the site of infection?
- active complement enzyme generated by cleavage of its zynogen precurosr
- cleaves its substrates to active enzymatic form
- become activated by the protease before them in the cascade
- needs strong regulatory mechanisms to prevent uncontrolled complement activation
43
how is the complement system amplified?
activation of a small number of complement and proteins
| - hugely amplified resulting in rapid generation of a disproportionately large complement response
44
what are the steps in the classical pathway?
- Clq binds directly to pathogen surfaces or indirectly to antibody bound pathogens
- this activates Clr which cleaves and activates Cls
- Cls cleaves C4 and C2
45
what are the functions of the complement system?
1. opsonisation
2. chemotaxis
3. pathogen lysis
46
what is opsonisation in the complement system?
enhancing phagocytosis
47
what is chemotaxis in the complement system?
complement proteins can acts as a chemoattractant to recruit more phagocytes to the site of complement activation
48
what is pathogen lysis in the complement system?
damage certain bacteria by creating pores in the bacterial membrane
49
what is the key event in complement activation?
- activation of the C3 convertase
- whichever pathway yo will go through C3
- in turn activates more enzymes
50
what are the 4 steps of immune complex clearance?
1. antibody antigen complexes are formed in the circulation
2. complement activation leads to deposition of C3b on the immune complex
3. complement receptor Cr1 on erythrocytes bind immune complexes through C3b
4. erythrocytes go to the spleen and liver where phagocytosis removes immune complexes from the surface of erythrocytes
51
what do innate immune cells recognise?
broad pathogen associated molecular patterns (PAMPs)
52
how do innate immune cells recognise?
recognition by a small number of pattern recognition receptors (PRRs)
53
what are are PAMPs?
- found on nearly all members of a pathogen class
- eg LPS of gram -ve
- they are essential for microbial survival
54
what are PRRs?
- a few proteins can sense millions of pathogens
- all cells express some PRRs
- dendritic and macrophages express all PRRs
55
what are the 4 families of PRRs?
1. Toll like receptors (TLR)
2. NOD like receptors (NLRs)
3. C type lectin receptors (CLRs)
4. RIG-1 like receptors (RLRs)
56
what are TLRs?
- localised at the plasma membrane and membranes of endosomes
- broad range of specification
57
what are NLRs?
- cytoplasmic proteins
| - form multiprotein complexes known as inflammasomes
58
what are CLRs?
- localised at plasma membrane
- broad range specifcity
- recognise glycans on the wall of fungi/some bacteria
59
what are RLRs?
- cytoplasmic proteins
- sense viral RNA
- signal through mitochondrial adaptor proteins
60
how are PRRs activated?
- pathogen
- receptor activation
- signalling cascade
- transcription factor activation
- transcription
61
what is transcribed as a result of PRR activation?
- amplifiers/positive feedback
- effectors/anti-virulent
- messengers/initiators of adaptive response
- negative regulators of innate immunity
62
what are TLR4s activated by?
- LPS
- leads to a signalling cascade
- involves adaptor proteins
- activation by phosphorylation of IRF3
63
in TLR4 activation what is the role of IRF3?
- starts transcription and production of type 1 interferons (IFN B)
64
what is the role of IFN B in TLR4 activation?
- IFNB is secreted through binding to its receptor
- second wave of response (amplification)
- dependent on STAT family transcriiption factors
65
what does TLR4 depend on?
- depends on where it is
66
where is TLR4 localised?
- only TLR localised on the membrane and the endosome
67
what are important adaptors of TLR4 activation?
MyD88 and TRIF are important adaptors
68
what does the NF-KB and AP1 pathways lead to?
production of inflammatory regulators
69
what does the IRF pathway lead to?
production of type 1 interferons
70
what is the NF-KB pathway?
- activation downstream of PRRs lead to induction of transcription of chemokines (attract other immune cells) and cytokines (promote inflammation)
71
what does IRF3 and IRF7 induce following PRR activation?
- induces transcription of IFNB and IFNa (type 1 interferons)
72
what is the role of type 1 interferons following PRR activation?
- they are translated
- secreted
- bind the IFNAR
- gives a positive feedback loop
- get a second wave of interferon stimulated genes (SIGs) through the action of other transcription factors of the IRF and STAT families
73
what are the functions of type 1 interferons?
- inhibition of pathogen replication
- induction of cell death (apoptosis) of infected and neighbouring cells
- activation of other innate immune cells
- activation of the antigen presentation machinery
74
what is the activation of type 1 interferon pathway driven by?
driven by the activation of the RF family transcription factors
75
what do T cells recognise?
recognise small linear peptides
76
what can APCs process?
human or microbial cells to generate peptides that can be checked by T cells
77
what do MHC-1 have?
can carry self-peptide or a microbial peptide
- T cells recognise and kill non-self
- non-self killed by NK cells
78
what negative regulators do the innate immune gene expression programme induce?
- anti-inflammatory cytokines
- phosphatases that stop the signalling cascade
- intracellular factors that inhibit inflammatory transcriptional factors
- microRNAs that supress translation of inflammatory mRNAs
79
what can a prolonged immune response lead to?
tissue damage and diseased caused by the immune system rather than the pathogen
