1
Q
What is a cytokine?
A
soluble protein made by the cell that control teh behaviour of other cells.
rapid signaling to impact gene transcrpition
controls growth, development, dfferentaiton and death
2
Q
How big is a cytokine?
A
20-25 kDA
3
Q
What are the three main kinds of cytokine?
A
Interleukine
Lymphokines
Monokines
4
Q
What are chemokines?
A
Chemoattractant proteins that stimulate migration/activation, esp. phagocytes/lymphocytes. They play critical roles in inflammation and homeostasis
5
Q
What do all chemokines act via?
A
GPCRs
6
Q
What are the two geroups of chemokines?
A
CC
CXC
7
Q
What are the human body’s innate defences made up of?
A
Rapid response
invariant receptors used
no memory cells generated
Phagocytes, molecular pattern recognition, inflammation, acute phase proteins, Interferons, NK cells
8
Q
What are the three types of phgocyte?
A
dendritic
neutrophils
macrophage
9
Q
What is a brain mononuclear phagocyte called?
A
Microglial cell
10
Q
Describe the role of dendritic cells
A
Drink in fluid via pinocytosis
Provide link between innate and adaptive immune system
sample pathogens in tissues, then migrate to lymph nodes to present to MHC on T cells
11
Q
3 stages of phagocytosis
A
Chemotaxis
Attachmetn adn uptaake
Microbicidal activity
12
Q
What is chemotaxis triggered by?
A
bacterial components (f-met-leu-phe)
Complement (C3a and C5a)
chemokines
13
Q
List the macrophage receptors
A
dectin 1
mannose
scavenger
lipid
complement
Fc
14
Q
macrophage receptors: dectin 1
A
Binds to beta glycan receptor (eg. fungi beta1-3)
15
Q
What is the enzyme that phagoctyoses?
A
Phagolysosome
16
Q
What receptors recognise pathogen associated molecular patterns?
A
Pattern recognition recpetors
Toll like receptors
17
Q
what bacterial surface molecules do TLR2 heterodimers recognise?
A
Gram +ve lipoteichoic
18
Q
what bacterial surface molecules do TLR4 and MD2 recognise?
A
Gram -ve LPS
19
Q
How do molecular pattern recognition receptors activate NFkappa B?
A
- bactrerial proteoglycans can be recognised (TLRs at cell surface by NODs in cytosol)
- MyD88 and RICK bind to TLR2/NOD2
- leads to activation of transcription factor NF kappa B and expression of pro inflammatory genes
20
Q
What does interleukin IL-1beta do?
A
activates vasc endoth. and lymphocytes
local tissue destruction, and access to effector cells. Fever causing, and IL-6 production
21
Q
What does TNF alpha do?
A
Increase vasc perm
increase IgG entry, fluid drainage,
Fever and shock
22
Q
What does IL-6 do?
A
activates lymphocytes and antibody production
Fever, induces acute phase protein, production by hepatocytosis
23
Q
What does CXCL8 do?
A
chemotactic factor
recruits neutrophils, basophils, T cells
24
Q
What does IL-12 do?
A
activate NK cells
CDL-1 binds T h cells
25
Which cytokines activate the acute phase response?
IL-1beta
IL-6
TNF alpha
26
What are the two categories of toxic substance that lysosomes contain?
oxygen dependent
oxygeen independent
27
Describe oxygen dependent killing
1. neutrophils work better in O2 than macrophages
2. ROS
3.NADPH oxidase reduces NADPH
4. Respiratory burst
28
Describe oxygen independent killing
Acidic pH (3.5-4)
Lysozyme degrades gram +ve cell wall
Pepsin disrupts bacterial membrane/ cell wall
Defensins and cathelicidins
acid hydrolases aid post death digestion
reactive nitrogen species (inducible iNOS2, NO)
29
What are the five ROS?
Superoxide
hydrogen peroxide
single oxygen
hydroxyl radical
hypophalite
30
Describe what a superoxide O2- ion causes
K+/H+ enter phagocytic vesicles
Vesicle acidification
release of cathepsin G/ elastase
activation by lysomal proteases
31
What is the respiratory burst?
The respiratory burst, or oxidative burst, is a rapid, intense production of reactive oxygen species (ROS) like superoxide and hydrogen peroxide by immune cells (phagocytes) when they encounter pathogens, serving as a powerful defense mechanism to kill bacteria and other microbes. This process involves the enzyme NADPH oxidase, which converts oxygen into these harmful ROS
32
What is chronic granulomatous?
Diseaise caused by the lack of NADPH oxidase
Causes chronic bacterial infection, and sometimes skin or liver granulomas.
33
What does X linked inactivating mutations in gp91cause?
Infant bacterial and fungal infections
34
What are NETs?
Neutrophil extracellular traps eg. salmonella
they create a sticky net to trap and kill both grams of bacteria. Triggered by CXCR2. Includes DnA, histones, neutrophil granules, cytoplasmic protiens.
35
What are the main innate responses to viral infection?
IFN
Cytotoxicity by NK
PRRs recognise biochemical characteristics
dsRNA is a coomon viral replication intermediate
unmethylated CpG DNA triggers TLR-9
36
What is TLR3 linked with?
DCs
Macrophages
GI epithelial expression in endosomes
37
What are type 1 IFN molecules?
Antiviral effector molecules produced by virally infected cells. IFN alpha and beta.
Aid resistance to viral replication, increase MHC expression, activates DCs, macrophages and NK cells.
38
What is IFN alpha specifically?
leukocyte ifn
39
What is IFN beta specifically?
fibroblast ifn
40
Where are NK cells derived from?
Common lyphoid progenitor
41
What are NK cells?
Large granular lymphocytes
activated by type 1 IFNs/ cytokines from macrophages
Early defence against some intracellular infections
eg. herpes, lishmania, listeria
42
During a viral infection, what order to T cells, IFNs and NK cells activate?
1. Production of IFNalpha, IFN beta, TNF alpha, IL-12
2. Nk cells mediated killing of infected cells
3. T cell mediated killing of infected cells
43
What do NK cells recognise?
cells lacking in MHC class 1 expression
44
What do Granules in NK cells contain?
Perforin
Serglycin
Granzymes
45
What does perforin do?
Helps delivery of granule content
46
What does serglycin do?
This proteoglycan aids scaffolding
47
What is an example of a granzyme?
serine protease
triggers host cell apoptosis
48
How does granzyme B trigger DNA degradation and thus apoptosis?
Granzyme B cleaves and activates procaspase 3
Cleaves ICAD )inhibitor of caspase activated DNase)
triggers DNA degradation via CAD
49
What is the process of B cell development like?
Cytokines cause B cell precursor antibody gene rearrangment
50
What happens in B cell activation and differentaition?
Mature B cell bouond to foreign antigen is activated.
Migration of B cells to lymphoid organs.
Activated B cells become plasma or memory cells
51
How do B cells recognise antigens?
via B Cell receptors (cell surface Ig)
then.. Ig alpha and Ig beta are nearby to initiate intracellular signalling
52
What is the precise process for B cell becoming effector B cells?
1. Ig alpha and Ig beta near to cell surface BCRs
2. ITAM (immunoreceptors tyrosine based activation motifs) are phosphorylated at key tyrosine residues to intiatiate intracellular signalling
3. Syk binds and activates
4. Lymphoblast forms
5. antibodies made by B effector cells
53
In an antibody, what is the hinge made of? and what is it's function?
Disulphide bonds
hinge provides flexibility
54
How big is the human genome compared to the human Ig repetoire?
genome= 3x10^9 base pairs
Ig= >1x10^11
55
In mature B cells, what segments rearrange during somatic recombination? how many specificities does this create?
V,D,J segments.
2x10^6 different speificities created
56
What feature about Recombination signal sequences prevents rearrnagement of V/J genes with themselves whilst ensuring D is included?
12/23 rule
(Rss with 12 base pair gap can only bind to one with 23)
Bc.. RAG can only cut DNA when one signal is long and the pther is short, to match the twists in the DNA so the enzyme can grab them both.
57
Which enzyme complex carries out somatic VDJ recombination?
VDJ recombinase
58
What does VDJ recombinase include?
1. lymphocyte specific RAG1 and RAG2
2. Ku70:Ku80, artemis:DNA-PK, DNA ligase IV: XRCC4
59
Where is RAG made and what does she do?
Made in T/B cells
DNA shuffler
60
Define ds Break repair?
imprecise repair results in junctiional diversity
61
what is the mechanism of ds Break repair?
1. Ku70:Ku80 binds DNA ends
2. DNA-PK: artemis has nuclease activity
3. Tat randomly adds nucleotides
4. Gap filling and ligation
61
How is diversity in the Ig repetoire generated in the bone marrow?
1. combinatorial diversity (VDJ recob + heavy/light chain)
2. Junctional diversity (imprecise addition or removal of nucleotides)
62
How is diversity in the Ig repetoire generated in the secondary lymphoid organs?
SOmatic hypermutation and affinity maturation
63
How can B cells continue to refine themselves post antigen encounter?
1. Somatic hypermutation introduces point mutations into IgV region genes.
2. AID generates different affinities for antigen
64
What does AID stand for?
Activation induced cytidine deaminase
65
How does affinity maturation generate higher antibody to antigen affinity?
Detrimental mutations eliminates B cells as they do not have functional BCRs
Good mutations cause selctive expansion of B cells. T follicular helperswithin germinal centres, via CD40L and IL21 send B cells survival signals
66
How do thymus dependent antigens work?
Moajority of antigens...
1. surface Ig and BCR binding
2. CD40L on CD4 T helper binds to CD40 on B cells
3. allows somatic hyperm, affinity maturation, memory B cells and class switching
67
How do thymus independent antigens work?
bacterial cell walls etc
1. sIg and BCR bind
2. LPS and TLR4 bind
rapid but short lived... mostly IgM made
68
What are the two sections of an antibody called?
Fab and Fc
69
What does the Fc region determine?
Creates isotpoes- determines functional specialization
eg. IgM, IgD, IgG, IgE,IgA
70
What are the functions of antibodies?
neutralisarion
opsonization
antibody dependent cellular cytotoxicity
triggering mast cell activation
activation of complement
71
Where does IgM mainly operate?
heart
72
Where does IgG mainly operate?
most places
73
Where does IgA (dimeric) mainly operate?
mouth, nose, lungs, GI
74
Where does IgE mainly operate?
mucosal surfaces, skin
75
How can we class Igs in terms of where they come from?
IgM+IgD= derived from the same premRNA
IgG, IgA, IgE= expressed as a result of class switching, in germinal centres, AID and ds break repair
76
If someone has a mutation in AID what does this cause?
Hyper IgM type 2 immunodeficiencies
so more susceptible to bacterial infections
77
Describe the dynamics of the antibody response to antigens
1. Class switching means IgM dominates initially, but replaced by IgG
2. Somatic hypermutation means as response develops affinity of antibodies increases
3. Clonal expanison/ B cell memory mean that the memory response is bigger
78
Describe how an antibody performs neutralisation
Mainly via IgA and IgG
1. antibody binds to virus receptor, bacterial toxin or adhesin.
2. stops them binding from host cell
79
Describe how an antibody performs opsonization
mainly via IgG1, IgG3, IgG4, IgA
Blocks receptors and engulfs pathogen
80
Describe how an antibody performs sensitisation fro killing via NK cells
mainly by IgG1 and IgG3
Antibody dependent cellular cytotoxicity (ADCC)
bind to target cell and NK bind to Fc portion then kill target cell
81
Describe how an antibody performs sensitization of mast cells
mainly IgE
1. mast cells are present in vascularized connective tisssue
2. Fcepsilon RI binds to monomeric with very high affinity
3. antigen cross linking to bound IgE triggers rapid degranulation and inflammatory inhibitors
82
Describe how an antibody perform activation of the complement?
mainly via IgG1, IgG3, IgM
1. C1q binds to antibodies bound to target cells
2. activates classical pathway
INF Year 2 TB1
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