MODULE 4 - Immunology I: Innate and Adaptive Sensing of Infection Flashcards
(135 cards)
1
Q
why is immune protection of a unicellular organism different to immune protection of a mammal?
A
as complexity of an organism increases so must the demands on the immune system to repel invaders
2
Q
why can’t you just have a one size fits all protective mechanism?
A
because there are multiple and diverse threats to our bodies
haematopoetic system (bone marrow system) creates ways to deal with multiple different threats
3
Q
why is plasticity in T lymphocytes (Th1, Th2, Th17 etc.) good?
A
it means they can differentiate into different pathways to deal with different types of infection
this means we can deal with multiple types of threats to our body
4
Q
give some examples of cellular specialisation?
A
neutrophils - good for bacterial, fungal, yeast infection
mast cells - good for parasite infections and interact with IgE
5
Q
what are some important innate molecules made in the liver?
A
complement (tags and destroys microbes)
mannose binding proteins (bind to mannan chains on microbes, some microbes particularly enriched in mannose, some MBPs activate complement)
haptoglobin (scavenges free iron keeping it away from microbes)
C-reactive protein (CRP) binds bacteria cell membranes, is an important clinical indicator (biomarker) of infection as high in infected people
6
Q
what are pattern recognition receptors (PRR)?
A
recognise pathogen associated molecular patterns (PAMPs) such as LPS and bacterial DNA (different to ours cause methylated)
recognise damage associated molecular patterns (DAMPs) such as uric acid (gout) and heat shock proteins
7
Q
what are DAMPs (damage associated molecular patterns)?
A
DAMPs immediately alert the immune system that something is going on there just from wounding, they are part of the damaged/stressed host response
8
Q
what are toll-like receptors (TLRs)?
A
can distinguish between different classes of bacteria (not species, classes)
9
Q
what does TLR2 bind?
A
lipoteichoic acid
10
Q
what does TLR3 bind?
A
dsDNA
11
Q
what does TLR4 bind?
A
lipopolysaccharide (LPS)
12
Q
what does TLR5 bind?
A
flagellin
13
Q
what does TLR9 bind?
A
bacterial DNA (CpG)
14
Q
what class of MHC does dendritic cells express?
A
both MHC class I and MHC class II
15
Q
what are the main differences between CD8 and CD4 T cells?
A
one expressing CD4 molecule and one expressing CD8 molecule
CD8 reacts with MHCI
CD4 reacts with MHCII
16
Q
what assists the binding of a TCR to a specific type of MHC?
A
coreceptors (e.g. CD4 and CD8)
17
Q
what does TCR signalling do?
A
switches LFA-1 to a high affinity state capable of binding ICAM-1 on the dendritic cell
these are two adhesion molecules and this switching to high affinity allows the cells to lock together enabling efficient T cell interaction with dendrictic cell
this is signal 1
18
Q
what does MHC-TCR interactions being very weak and having a high on and off rate allow for?
A
it allows serial triggering to occur which is where the TCR can jump on and off the MHC-peptide and jump onto another and multiple TCRs can become activated then (cause it can jump off then MHC-peptide free for another TCR to engage)
so serial triggering allows activation of multiple TCRs from just one MHC-peptide
19
Q
why is serial triggering beneficial?
A
it increases the efficiency of antigen presentation, especially for rare MHC/peptide complexes
20
Q
what is signal 2?
A
because signal 1 isn’t enough, we also need signal 2 which is costimulation
T cells express surface costimulator molecule called CD28
CD80 only appears on dendritic cell surface if they activated by by pamps or damps. Once they cause expression on surface costimulation between CD80 and CD28 can occur and T cell gets activated
no signal 2 = no T cell activation
21
Q
what is it that signal 2 (costimulation) allows?
A
allows additional signalling in the T cell including growth signals, anti-apoptotic signals etc. and of course T cell activation
22
Q
what does signal 2 ensure and why?
A
sometime peptides from microbes resemble our own peptides (molecular mimicry) so signal 2 ensures that dendritic cell has actually seen some microbes and been triggered before activating T cell
23
Q
what does the T helper cell (CD4) do once activated?
A
go and give cytokines to help B cells make antibodies and activate CD8 cells
24
Q
what happens when helper T cells activate CD8 T cells?
A
they become cytotoxic T lymphocytes (CTL)
25
what else is required for a CD8 T cell to be activated to a CTL?
cross-presentation of exogenous antigen onto MHC-1 by APC
interaction with APC via the MHC-1-peptide:TCR
and then the cytokine 'help' from CD4 T cell and boom you've got a CTL
26
what is the reason behind all the steps for CTL activation?
safety guards to prevent autoimmunity from occurring
27
what are the steps required for T helper cells to activate B cells?
B cell recognises native antigen (unprocessed)
B cell receives cytokine 'help' from a CD4 T cell. The B cell was developed in the bone marrow specific for antigen of whatever peptide was presented to T cell
The native antigen that the B cell recognised earlier was swallowed by the B cell and loaded onto MHCII and this interaction with TCR confirms it is the right B cell and activates CD8 T cell making it CTL
28
where are CD8 T cells/CTLs usually get stimulated?
in the lymph node or spleen and then they fuck off around the body looking for shit to kill cause they are CTLs now
29
how do CTLs kill infected cells?
perforin - make hole
granzyme - go in hole and trigger apoptosis
30
what does antibody do once released from plasma cells?
goes off and neutralises toxins or 'tags' microbes for destruction
31
what happens if an antigen specific CTL encounters a virus infected cell without MHCI and why might it be missing MHCI?
no killing of target cell
many viruses have adapted to not present MHCI or down regulated it to where its not relevant, MHCI also often not presented on cancer cells so these cancer cells can be selected for
32
what are NK cells and what do they do?
natural killer cells which detect low or absent expression of MHCI
if MHCI drops below certain threshold on cell they fucking kill it
they have activating receptor which binds random receptors on cell giving positive signal to kill and inhibitory receptor which binds MHCI giving negative signal to kill (i.e. chills it out)
if positive signal occurs and no negative signal cause inhibitory receptor can't find any MHCI then NK cell fucks up the cell using perforin/granzyme ---> apoptosis of low/no MHCI cell
33
what is neonatal tolerance?
occurs in utero and in neonates
at neonatal stage thymus produces a wave of Tregs which can hang around for life and dampen the immune system against auto reaction as they secrete immunosuppressive cytokines (IL-10, TGF-beta) via CTLA-4 which is a molecule on T cells
this also means central tolerance is especially active at neonatal stage
34
where does central tolerance occur?
T cells screened in thymus
B cells screened in bone marrow
both being screened for auto reaction
35
what is peripheral tolerance?
ultimate aim is to make cells not autoreactive
T cells that are stimulated by antigen in absence of costimulation become anergic or apoptotic
Tregs involved in this process
I have a feeling this occurs to deal with any escapees from bone marrow/thymus screening
36
how does B cell screening occur (central tolerance)?
immature B cell chilling on bone marrow stromal cell and self-antigen being run past it
if it responds and binds self-antigen it triggers apoptosis, if not it enters the blood
37
do the innate and adaptive immune systems only recognise pathogens?
no they recognise commensals too
PRR may be localised away from commensals and therefore are only triggered by invasive microbes e.g. commensals which become opportunistic pathogens in immunocompromised
for example TLR-5 (detects flagella) present on certain bottom membranes of gut epithelium
38
where are relevant PRRs located?
TLRs associated with plasma membrane or endosomal membrane
cytoplasmic receptors: RIG-I and MDA-5 detect dsRNA from microbes well AIM-2 detects dsDNA
NOD-like receptors present in cytoplasm and can form large complexes called inflammasome
39
what kind of things do PRRs recognise?
things that bacteria have been unable to evolve away from despite the selection pressure e.g. LPS in gram-negs and lipoteichoic acid in gram-pos
40
how can PRRs distinguish between bacterial DNA and our DNA?
microbe DNA cytosines are under-methylated (CpG)
41
what are TLRs?
they signal via other adaptor proteins and activate transcription factors changing gene transcription patterns towards pro-inflammatory e.g. cytokines are secreted
TLR signalling important for priming the genes (pro-IL-1 and pro-IL-18) required for the inflammasome
42
why do TLRs only signal as dimers?
upon ligand (bacterial molecule) binding this induces dimerisation of TLR which causes adaptor proteins from cytoplasm will bind the TLR leading to shuttling of activated transcription factors to nucleus to induce inflammatory gene transcription
43
what is the difference between PRRs and adaptive immune system receptors (BCRs and TCRs)?
PRRs are broadly expressed i.e. a single immune cell may express multiple types of PRR
One B cell or T cell expresses one type of BCR or TCR (specific)
also unlike BCR and TCR some PRR are present and active in the cytoplasm
44
what are NOD-like receptors (NLRs)?
nucleotide oligomerization domain
subset of PRRs and are a family of 23 cytosolic proteins activated by intracellular PAMPs or DAMPs
they activate transcription factors (e.g. NFkappaB) to stimulate inflammatory gene transcription
45
what do nucleic acid sensors such as RIG-I and MDA5 do?
detect short and long dsRNA and induce a type I interferon which is released from infected cell and go activate nearby cells through interferon alpha receptor (IFNAR) which is like an alarm telling them there's a virus nearby so those cells will shut down protein transcription and translation (so virus can't exploit) and up regulate MHCI
this is an especially important response to viral infection (cause dsDNA common in viruses)
46
what do activated RIG-I or MDA5 do?
coalesce on mitochondria with MAVS (common pathway) ( allowing activation of transcription factors such as IRF and NFkappaB which shuttle to nucleus to activate antiviral response (mainly production of type I IFN such IFN-aplha and beta)
47
what common pathway do RIG-I and MDA5 act via?
MAVS
48
what is the inflammasome?
intracellular macromolecular complex that senses 'danger' to initiate an inflammatory response
required for innate and adaptive immunity and cell death via pyroptosis
exploited in vaccine design to stimulate innate sensing in APCs (in response to alum hence immediate (i.e. innate) arm swelling after vaccine)
important in auto-immune disease such as gout and IBS
49
what is the inactive form of inflammasome and what induces transcription of these molecules?
TLR-priming induces transcription of pro-IL-1beta and pro-IL-18 (inactive forms of IL-1 and IL-18 which inflammasome acts upon)
this is the priming stage (TLR activated synthesis of pro-IL-1beta and pro-IL-18)
so this question kinda wrong cause they aren't inactive form of inflammasome but the answer is useful
50
what does NEK7 do?
helps assemble the NLRP3 inflammasome and assists with detection of cell stress (indicated by things like ROS production and potassium efflux)
51
what is NLRP3?
the main type of inflammasome we focusing on
contains a PYD domain which recruits something called ASC which can then recruit caspase 1
nod-like receptor p3
52
what is caspase 1?
the thing that converts the inactive cytokines pro-IL-1beta and pro-IL-18 to active IL-1beta and IL-18
participates in processing of cytokines and also cell death
once recruited you get the big inflammasome structure (see diagram with highlights in L17)
53
how are IL-1 and IL-18 cytokines secreted?
they lack signal sequences so cannot be secreted through canonical pathway and are instead secreted through gasdermin pathway
54
what is gasdermin-D
an inactive protein which is cleaved by inflammasome (important role of inflammasome)
cleavage product of gasdermin D will go form a pore which IL-1 and IL-18 secreted through
if there are a few pores the cell survives but too many and the cell dies
so cell survival depends on how much gasdermin-D shuttled to pores or cleaved
55
inflammasomes can recognise lots of shit, which type of inflammasome is an intracellular sensor of dsDNA and what does it do?
AIM2 is an inflammasome which recognises dsDNA via a HIN-200 domain (adaptor protein)
dsDNA shouldn't be in cytoplasm (unless nucleus ruptures) and indicates cellular destruction (e.g. gout) or DNA virus infection or bacterial DNA release
AIM2 has PYD domain which recruits ASC which recruits caspase I to form a multimeric inflammasome
everything else done same as NLRP3 (gasdermin-D and IL-1/18)
56
why is inflammasome important to vaccines?
alum is a salt of aluminium and is a common adjuvant in vaccines
signal 1 (aka priming stage provided by bacterial components of vaccine) and signal 2 (activates NEK7 provided by alum)
so basically alum helps activate inflammasome leading to production of IL1 and IL18 which help with the adaptive immune response
57
what is uric acid and how does it cause gout?
uric acid is like alum in that they are insoluble salts which can form crystals
in gout the NLRP3 inflammasome is triggered by uric acid crystals
process involves priming stage (gene transcription of NLRP3, pro-IL-1 and pro-IL-18) and triggering via NLRP3 inflammasome (this could also be caused by ROS prod by neutrophils and K+ efflux)
58
why is gout a particularly notable problem in NZ?
Māori and Pacific men have highest rates of gout in the world due to inherently higher levels of uric acid (hyperuricaemia) likely due to genetic (e.g. variations of GLUT9 gene encoding glucose transporter) and environmental reasons
59
why might genes which cause elevated levels of urate be of advantage in some circumstances?
high uric acid selective advantage during starvation (e.g. sea voyage)
hyperuricaemia helps maintain bp under low salt diet
serum urate potent antioxidant
later in life serum urate associated with increased cognitive function
60
what are cytokines?
low molecular weight glycoproteins which are active in the stimulation or suppression of the immune response
allow communication between cells and secreted by stromal and haematopoietic cells
61
how are most cytokines exported (and what are the exceptions)?
most cytokines exported via a signal sequence/peptide which is a hydrophobic sequence found in the N terminus which directs cytokine transport
the signal sequence helps a protein get locked into a membrane and allows them to get translocated through them
except IL-1 and IL-18 which are secreted via gasdermin pore
62
what do cytokines promote and what are two examples?
cytokines promote activation of immune cells
e.g. IL-2 promotes T cell proliferation and IL-4 promotes B cell antibody production
63
what does autocrine mean in terms of cytokines?
acting on the same cell e.g. the T cell producing IL-2 gets the signal
64
what does paracrine mean in terms of cytokines?
between cells via a receptor e.g. T cell giving signals to B cell
65
what does endocrine mean in terms of cytokines?
cytokines acting on distant organs e.g. IL-1 on hypothalamus to induce fever
66
why is close cell contact beneficial for cytokine production?
close cell contact ensures a high local cytokine concentration but a low systematic concentration i.e. allows cytokine secretion to be specific
67
describe the IL-2 receptor and how/why does its affinity for IL-2 change?
comprised of three distinct chains: alpha, beta and gamma
naive T cells express IL-2 receptor of intermediate affinity (beta and gamma)
activation of T cells leads to expression of alpha chain and formation of high-affinity trimeric form IL-2 receptor and also allows this T cell to start secreting IL-2 which modulates T cell differentiation and enhances proliferation
68
what is structurally similar about many cytokine receptors and what isn't and why?
most cytokine receptors have a gamma chain however they also have their own components such to allow specificity
69
what does it mean if a cell is expressing IL-2 receptors with just an alpha chain subunit?
low affinity
70
what are the only two cytokines in gamma chain family with three chains in their receptor (trimeric)?
IL-2 and IL-15
they have alpha chains as well as beta and gamma and most others are dimeric
71
what is sever combined immunodeficiency (SCID)?
loss of IL-2 gamma chain
72
what is tumour necrosis factor (TNF)?
a family of cytokines critical for cell death and T and B cell survival
ligands (e.g. TNF) and receptors (TNFR) are trimeric
73
what is TNF-alpha?
one of the main fever inducing cytokines (along with IL-1 and 6)
has pathological effects at high levels (cytokine storm in sepsis)
74
what are interferons (IFN)?
another class of cytokines
antiviral
up regulate antigen processing and the levels of MHCI and II
inhibit viral replication through inhibiting protein translation
75
what are colony stimulating factors (CSF)?
induce proliferation and differentiation of bone marrow cells
e.g. granulocyte-macrophage-CSF (GM-CSF) which supports the growth of dendritic cells and macrophages
76
what does GM-CSF promote and what does G-CSF promote?
GM-CSF promotes formation of dendritic cell from pluripotent stem cell
G-CSF promotes formation of a neutrophil from a pluripotent stem cell
so different CSFs help differentiate bone marrow cells
77
what are some uses for cytokines in the clinic?
cytokines may be administered to boost immune response to cancer (e.g. IFN-alpha or IL-2 used to treat kidney and skin cancer)
drugs may be used to target inflammatory cytokines to treat autoimmunity (e.g. treat gout with an IL-1 receptor antagonist that inhibits activity of IL-1)
78
what are chemokines?
chemoattractant cytokines
signal via 7-membrane structures (G-protein coupled receptors; GCPR)
GPCR are largest group of receptors in mammals
79
how do chemokines cause cell migration?
they bind to GPCR and trigger activation of the receptor and this leads to cell migration to the highest level of the chemokine as they are chemoattractant
80
how are chemokines involved in HIV infection?
HIV target macrophages as they have a bit of CD4 on them
macrophages also have chemokine receptor CCR5 which HIV has exploited as co-receptor
so during initial infection HIV preferentially infects macrophages using CCR5 as co-receptor then sometimes mutates and targets T cells through different chemokine receptor called CXCR4
81
what is the IL-8 (chemokine) receptor?
CXCR1
82
how do IL-8 (chemokine) induce neutrophil migration to inflamed tissues in gout?
neutrophil normally rolling around through capillaries and when an infection happens the endothelium gets sticky so neutrophils begin to adhere
IL-8 (also being produced during infection) sign posted on endothelium (bound to carb rich areas) and neutrophils can sense these and undergo trans endothelial migration moving towards highest density of IL-8 as they can sense which side of neutrophil has highest conc. of IL-8 (intracellular chemokine gradient)
83
where are chemokines usually highest in concentration?
around areas of inflammation
84
what is anti-TNFalpha therapy important for?
treating rheumatoid arthritis
85
what is the major histocompatibility complex (MHC)?
MHC is called HLA (human leukocyte antigen) in humans
exists in many alternative (allelic) forms and are the most polymorphic genes found in our genome
MHCI expressed by all nucleated cells
MHCII expressed by antigen presenting cells (APCs): DC, B cells, monocytes and macrophages
86
what are the three isotypes of MHCI and the three isotypes of MHCII expressed by humans?
MHCI: HLA-A, B and C
MHCII: HLA-DR, HLA-DP, HLA-DQ
87
what does polygeny mean?
means we co-dominantly express all the genes at one time
i.e. you express the whole collection of MHC genes you inherited
so you express six forms of MHCI and six forms of MHCII (cause one on each chromosome) and they will all be on an APC
88
since its too difficult to match all 12 MHC alleles in an organ donor, what do we do instead, and what provides further complications with this?
hardly ever can match all 12 so look for critical ones to match
critical MHC alleles for transplant rejection are HLA-A, HLA-B and HLA-DR. So if you should try get donors as close as poss for these three genes (any xtra matching great too but these most important)
these important alleles differ between ethnic groups (e.g. HLA-A24 critical for Māori)
problem is most donors European
89
what is the structure of MHCI?
heterodimer
alpha-chain and beta2-microglobulin (non-covalently associated)
one transmembrane region
polymorphisms on alpha 1 and alpha 2 subunits (peptide binding groove)
alpha 1 and 2 subunits contain alpha-helices (sides) and beta sheet (bottom) which creates groove for peptide to lie in
anchors short peptides (8-9 amino acids)
90
what is the structure of MHCII?
heterodimer
alpha-chain and beta-chain
two transmembrane regions (both chains embedded in APC membrane)
polymorphisms on beta-1 subunit
alpha-1 and beta-1 subunits contain alpha-helices (sides) and beta-sheet (bottom) which creates a groove for peptide to lie in
anchors peptides (15-25 amino acids) (MHCII structure slightly more open to allow longer peptides)
91
what are anchor residues?
critical amino acids in the peptide which bind to the MHC molecules
some bind better than others so some peptides bind better
bind non-covalently so weak electrostatic forces but enough to make sure peptide stays in long enough for antigen presentation
92
what do T cell receptors (TCRs) recognise and what does this mean regarding polymorphisms?
recognise MHC and peptide as an entire complex
therefore polymorphisms determine how a TCR binds to a MHC-peptide complex (as they affect ability of T cells to recognise MHC-peptide complex not just the peptide)
93
what does MHC class I display?
displays endogenous (intracellular) antigen
recognised by TCRs expressed on CD8 T cells (allowing them to visualise what is happening inside cell)
self-peptide almost exclusively displayed (to keep MHCI stable)
94
describe the MHCI antigen presentation pathway (cytoplasmic pathway)?
materials produced in cytoplasm (e.g. virus degraded into peptides) which are then transported through peptide transporter (TAP) into ER where MHCI synthesised and loaded with peptide
peptide MHC complexes transported to cell surface, chaperone molecule binds groove while MHCI being loaded because it would otherwise be unstable and thus degraded. Chaperone falls away once peptide loaded and complex transported to cell surface
95
what is cross-presentation of exogenous antigen?
where exogenous antigen becomes endogenous
if getting antigen from outside cross-presentation allows both MHCI and II to be loaded up
this is cause phagolysosome is a bit leaky and shit gets into cytoplasm
so a dendritic cell can load antigen from extracellular enviro onto MHCII via standard pathway and also onto MHCI via cross presentation/priming
96
what ideally happens after an APC presents endogenous viral peptides on MHCI?
a cytotoxic T lymphocyte (activated in the lymph node or spleen) which is specific for the viral peptide being presented will come along and kill it with perforin/granzyme
97
why is it important that the cytotoxic T lymphocyte is specific for the presented peptide on MHCI of the target cell?
so that it will only kill the infected cell
98
describe the MHCII antigen presentation pathway?
MHCII synthesised in ER and then transported to phagolysosome where it is loaded with peptide
chaperone molecule called invariant chain keeps it folded properly well MHCII waiting for peptide and then is degraded as loading occurring
MHCII-peptide complex then sent to cell surface
99
what are the main differences between loading pathways of MHCI and MHCII?
MHCI components synthesised in cytoplasm then transported through TAP
MHCI and MHCII synth in ER but MHCI loaded in ER well MHCII loaded in phagolysosome
MHCII chaperone called invariant chain
100
what are superantigens (sAg)?
proteins produced by gram-positive bacteria that interact with MHCII and the TCR (bridging them) to induce mass T cell activation
results in expansion of whole TCR families of both CD4 and CD8 T cells
101
what are two bacteria which secrete super antigens?
staphylococcus aureus
streptococcus pyogenes
102
what do superantigens bind to?
binds to MHCII with high affinity and to certain V-beta sequences on TCR
the V-beta region of TCR differs between T cells depending on which V-beta mini gene is spliced into the mature TCR gene during the generation of diversity
there are about 30 V-beta gene families in humans
103
how many T cells activated by superantigen?
stimulate 30% of CD4 and CD8 T cells causing them to release cytokines
104
what does the vascular leakage caused by superantigen allow the microbe to do?
disseminate into tissues
105
what things does superantigen induce in low quantities?
monocyte/macrophage activation
endothelial cell activation
complement activation
these lead to local inflammation
106
what things does superantigen induce in moderate quantities?
fever
acute-phase reactants
these have systemic effects
107
what things does superantigen induce in high quantities?
blood vessel injury
thrombosis
DIC
ARDS
low cardiac output and low peripheral resistance
108
explain the cytokine cascade caused by superantigens?
superantigen can induce sepsis-like syndrome with excessive production of T cell derived IL-2 and IFN-gamma
these two cytokines then trigger a bunch of other cytokines such as IL-1 and IL-6/8 which are associated w fever and sepsis
109
what is TSST-1 and why can it activate both CD4 and CD8 T cells despite CD8 T cells not binding MHCII?
toxic shock syndrome toxin-1 binds V-beta2
superantigen can activate CD8 T cells (despite binding MHCII when CD8 only bind MHCI) because CD8 T cells have V-beta sequences present (the thing on TCR that superantigen binds)
110
what is Paul Ehrlich's side chain theory?
immune cells are multi-reactive
this means they express multiple immune molecules (antibodies) of different specificities (wrongish)
binding of antigen stimulates production of antibodies (true (in context of correct T cell help))
111
what is wrong about Paul Ehrlich's model?
clonal cells produce one type of receptor (antibody or TCR). Each cell makes thousands of copies of just one membrane bound receptor (one specificity)
Paul reckoned one cell express multiple of differing specificities
112
what are CDRs?
highly variable loops on variable part of antibodies which bridge the gap during antibody-antigen binding
contain the most variation on antibody molecule as during generation diversity they are subject to messy joining of genes creating a great variety of aa sequences that differ a lot between antibodies
CDRs poke up, three from heavy chain and three from light chain. So set of three per chain called CDR1, 2 and 3
rest of antibody also variable but not as much as CDR regions
113
what kind of forces are involved in antibody binding antigen?
non-covalent forces (electrostatic, hydrogen, van der weals and hydrophobic)
these are the main type of force between immune cells and also important for peptide bind, adhesion etc.
not necessarily weak e.g. hydrogen
this important cause antibodies need to be very flexible in what they bind since everything can be an antigen
114
what are antibodies shaped like and why is this important?
variety of shapes of antibodies
not very constrained unlike T cells which are very constrained due to their being screened in thymus
this ensures antibodies are very diverse and flexible and can interact with all kinds of antigens
115
how are T cells positively selected in the thymus?
undergoes rearranging of TCR during generation of diversity to create receptor which interacts w antigen
however this receptor has to interact with the self-MHC complex moderately not strongly
so TCR must interact productively with MHC. Too weak and it is negatively selected as no interaction occurs, too strong and it will be autoreactive so is deleted
moderate interaction and it'll be safe as
116
why are TCRs more constrained in their shape than antibodies?
antibody must be able to recognise almost an infinite variety of shapes
TCR confined to recognising MHC plus peptide
therefore following thymic selection, TCR are less variable in shape than antibody
117
what is the structure of a TCR?
comprised of two chains (alpha and beta) which interact with MHC-peptide via CDR regions
CDR1 and 2 (of both alpha and beta chain) contact mainly the MHC structure
CDR3 (of both chains) contacts the peptide
so there is some regional specialisation in the CDR regions
this is true for MHC I and II and for both CD4 and CD8 T cells
118
what CDR regions dictate positive selection?
the low affinity interactions required for thymic positive selection are explained by interaction of V-alpha CDR1 and 2 and V-beta CDR1 and 2 with MHC
since during thymic selection self peptide will be being presented so there should only be very weak or no interaction between CDR3 and the self-peptide
119
what is molecular mimicry?
when host and microbe share sequences of homology, anti-microbial immune responses may accidentally target host structures
could occur between identical structures e.g. peptide sequences or between epitopes on dissimilar molecules e.g. peptide and DNA (so different building blocks but the shape just looks the same)
120
what are two examples of molecular mimicry?
rheumatic fever caused by strep group A
carbohydrate epitope on microbe mimics cardiac myosin
121
why can microbes be important triggers of autoimmunity?
due to molecular mimicry
122
how can campylobacter jejuni trigger Guillain-Barre syndrome?
ganglioside-like epitopes (LOS) in LPS layer of C. jejuni mimic ganglioside structures (GM1) in peripheral nerves of infected person
they are not identical but similar enough to generate auto reactive B cells
this re-directs immune attack towards nerve sheathes (where gangliosides located) causing paralysis due to autoimmune disorder Guillan-Barre syndrome
immune tolerance usually prevents this from happening but that was overcame by a substance that causes molecular mimicry i.e. ganglioside-like epitopes
123
how does our body get antigen into the right place so that B cells and T cells can best respond to it?
your body covered in lymph nodes with lymph flowing through them
blood being pumped through capillaries also and some fluid is squeezed out into lymphatic channels which flow into bigger channels which drain into lymph nodes (this process helped by pressure from capillaries and muscular tension)
once lymph filtered by lymph node its recycled back into blood
so basically it concentrates antigen from peripheral tissues in lymph nodes
124
why is it good to have antigen concentrated in lymph nodes?
there are lots of cells here which will capture antigen e.g. dendritic cells and macrophages
there are also lots of T and B cells which will recognise captured antigen and begin the adaptive immune response
so basically concentrating it in lymph nodes maximises the benefit of these immune cells
125
what are lymphocytes?
a type of white blood cell which includes T cells, B cells and NK cells
126
what are lymphoid follicles?
smaller and less organised versions of lymph nodes which contain lots of lymphocytes (T, B and NK cells) and dendritic cells
still important for immune response tho
127
what is fluid called when it is incoming to lymph node and when it is leaving?
afferent when incoming
efferent when leaving
128
what is the high endothelial venule (HEV)?
part of lymph node which is stacked endothelium and specialised to allow lymphocytes to come into lymph node from the blood
so naive T and B cells constantly coming into lymph node, circulating around it and then also constantly leaving
129
what are germinal centres?
where B cells start to make antibody if activated to become plasma cells
surrounded by T cell zone
130
outline the important components of the lymph node?
afferent lymphatic vessel - where afferent enters lymph node
efferent lymphatic vessel - where efferent leaves lymph node
artery vein - cells entering and leaving through this (prob via HEV)
primary lymphoid follicles - packed with B cells
germinal centre - where B cells start to make antibody
T cell zone - generally surround areas rich in B cells e.g. germinal centre, primary lymphoid follicles
131
what is the structure of the spleen?
more lymphocytes pass through spleen than through all lymphatics combined
captures stuff coming in from blood e.g. when u get a cut
spleen has a white pulp where periarteriolar lymphoid sheath (PALS) forms sheath around arterioles
PALS rich in T and B cells and the B cells can form lymphoid follicles that develop into secondary follicles containing germinal centres
there is a marginal zone where fluid flows through and this is a site of specialised DC, macrophages and B cells. This zone surrounds PALS and seperates it from red pulp
132
what is the marginal sinus?
part of marginal zone, flow of blood slows here so capturing antigen by DCs and macrophages very efficient here
133
what happens if antigen detected in marginal zone?
some of the DCs and macrophages begin to migrate inwards into the white pulp (PALS also called T cell zone) to present antigen and initiate immune response
134
what are the macrophages and B cells particularly important for in the marginal zone of the spleen?
trapping blood-borne pathogens
this is why people who have had a splenectomy vulnerable to systemic bacterial infection (sepsis) from S. pneumonia, N. meningitis and H. influenzae (cause spleen v good at removing capsulated bacteria)
135
what are the macrophages and B cells particularly important for in the marginal zone of the spleen?
trapping blood-borne pathogens
this is why people who have had a splenectomy vulnerable to systemic bacterial infection (sepsis) from S. pneumonia, N. meningitis and H. influenzae (cause spleen v good at removing capsulated bacteria)
