case 4 - immunology of the gut

Question 1

what type of surface does the GI tract have

Answer 1

an undulating surface, which increases surface area for absorption and secretion

Question 2

what is mucus secreted by

Answer 2

goblet cells

Question 3

what does this mucus do

Answer 3

lubricant
Prevents mechanical stress on epithelium
Thick layer provided stable microenvironment
Prevents invasion
Essential environment for microflora

Question 4

what helps to maintain the acidic environment in the stomach

Answer 4

the gastric glands and gastric pits

Question 5

what is the protection of the gastric epithelium carried out by

Answer 5

mucus and secretion of neutralising bicarbonate by specialised epithelial cells

Question 6

what does the mucus provide

Answer 6

a pH gradient - lumen pH is around 1-2 and the mucus pH is around 7

Question 7

what is this pH gradient due to

Answer 7

the bicarbonate

Question 8

what is the strongest known risk for gastric cancer

Answer 8

h pylori

Question 9

what is the upper layer of mucus colonised by

Answer 9

bacteria

Question 10

what does the absence of gut bacteria affect

Answer 10

behaviour
Gut homeostasis
Immune response under stress
Body weight
Brain development and gene expression

Question 11

what is the clostridium difficile infection

Answer 11

a spore forming gram positive bacillus which is part of normal healthy flora in 4% of healthy indivudals

Question 12

what does this infection lead to

Answer 12

pseudomembranous ulcerative colitis

Question 13

what can it result in and what is the mortaility rate

Answer 13

can result in organ failure and the mortality rate it 35-80%

Question 14

how does one fix this infection

Answer 14

infusion of donor faeces

Question 15

how do we maintain a healthy microbiome

Answer 15

antimicrobial peptides
Alpha and beta defensins that are secreted by the paneth cells
there is good experimental evidence that gut bacteria actually stimulate secretion of antimicrobial peptides maintaining homeostasis

Question 16

what is the specific antibody responsible for the primary defence against bacteria

Answer 16

IgA

Question 17

what coats colitogenic bacteria with high affinity

Answer 17

SIgA

Question 18

what do the paneth cells do to the crypt

Answer 18

keep it sterile

Question 19

what happens in coeliac disease

Answer 19

the villi get smaller and no epithelium

Question 20

what is in the sub epithelial layer

Answer 20

antigen specific responses
Macrophages and dendritic cells
T cells and innate lymphoid cells

Question 21

features of dendritic cells

Answer 21

distinct yet complimentary function
Migratory
Excellent primers of T cells via antigen presentation
Discrete subsets with different function
CD11b+/-CD103+/-
Derive from a committed progenitor

Question 22

features of macrophages

Answer 22

Non-migratory
Express CD64, CD11b, CD11c, CX3CR1
Replenished by blood monocytes
phagocytes

Question 23

what are resident macrophages

Answer 23

in mice, CX3CR1 macrophages control translocation of luminal bacteria to the draining lymph ode

front line cells that clean up any bacteria that gets though

Question 24

what does Th1 do

Answer 24

defence against intracellular parasites

Question 25

what does Th2 do

Answer 25

allergy, asthma, controls parasite and extracellular pathogens

Question 26

what does Th17 do

Answer 26

defence against pathogens, autoimmunity, transplantation rejection and cancer

Question 27

what does Treg do

Answer 27

immune homeostasis and maintains tolerance

Question 28

what does Tfh do

Answer 28

help germinal centre B cells to make antibodies, affinity maturation and antibody class switching

Question 29

what are innate lymphoid cells and some features of them

Answer 29

derived from common lymphoid progenitor Rely on IL2R signalling (as do T cells) INNATE lymphocytes i.e no T cell receptor Stimulated by cytokines or microbes - probably directly Present at very low number in steady state Characterised as ILC1,2, or 3

Question 30

what is ILC1, what does it produce and what does it expres

Answer 30

produces IFN gamma includes natural killer cells it expresses T-bet

Question 31

what is ILC2, what does it express and what does it produce

Answer 31

IL5/IL13 producers Express RORalpha and GATA3 Seen in allergy Respond to IL25 and IL33 Also called nuocytes, natural helper cells

Question 32

what is ILC3 and what does it express and produce

Answer 32

contribute to mucosal homeostasis IL17A&F and IL22 producers Express RORgammaT Respond to IL23 Important in fetal lymphoid organogenesis Important for GALT formation Important in mucosal homeostasis Loss of ILC3 has been associated with HIV+ progression in aids

Question 33

what can all ILCs be

Answer 33

both pro and anti tumorgenic

Question 34

what happens in cancer with ILC2 and ILC3

Answer 34

ILC3s are lost and ILC2 go up and ILC3 can potentially help with anti tumour response and if they are lost they lose the help it provides to keep the barrier in tact

Question 35

what is Treg, what are the key factors

Answer 35

the two key factors are TGFbeta and IL10 T cell populations contribute to homeostasis Helps to keep everything happen particularly the ILC3s If the dendritic cells pick up something pathogenic, it triggers the production of inflammatory cytokines which drive inflammation To resolve the inflammation you need to produce more Treg

Question 36

what cell surface receptors also put a break on inflammation

Answer 36

PD-1/PD-L1 CTLA4/B71 or 2

Question 37

what interaction stops T cell activation

Answer 37

CTLA4/B7 interaction between T cell and antigen presenting cell stops T cell activation

Question 38

what activates T cells

Answer 38

CD28 on T cell binds to B7 on dendritic cells to activate T cell

Question 39

what is engaged to stop T cells working

Answer 39

By engaging CTLA4, it binds to B7 and stops T cells working

Question 40

what is PT1

Answer 40

an off switch

Question 41

what interaction reduces T cell activation

Answer 41

PD1/PD-L1 interaction

Question 42

features of PD1/PD-L1

Answer 42

PD1 is an immune suppressive molecule to avoid over activation Expressed by infected cells - prevents efficient immunity to virally infected cells Expressed on APCs and tissue - prevents immune recognition of self Expressed on tumour cells - tumour evasion mechanism

Question 43

what is sporadic colorectal cancer

Answer 43

in non-IBD patients, it usually begins as a non-cancerous polyp

Question 44

what are the chancers of developing it

Answer 44

Man has a 1 in 17 chance Woman has a 1 in 18 chance

Question 45

what is the main thing about Crohn's disease

Answer 45

dysregulation of host flora contributes to disease

Question 46

what are the paneth cell defects in Crohn's disease

Answer 46

reduced secretion of HD5

Question 47

what are the other paneth cell defects

Answer 47

NOD2 polymorphisms potentially affecting microbiome and response to commensal flora

Question 48

that is the cancer inflammation parafgm

Answer 48

Intrinsic pathway to inflammation (in tumour cells) And balanced with: Extrinsic pathway driven by chronic inflammation e.g IBD, dysbiosis

Question 49

what is the intrinsic pathway to inflammation

Answer 49

normal tissue homeostasis disrupted sequential mutations epigenetic alterations oxidative stress - Bcl2, p53 proliferation / apoptosis dysregulation

Question 50

what is the extrinsic pathway driven by chronic inflammation

Answer 50

inflammatory tumour microenvironment inflammatory cytokines (TNF alpha, IFN gamma, IL1) reduced regulatory cytokines - IL10, TGF disrupted homeostasis proliferation and apoptosis disregulation