5 - vaccine for T1 diabetes

Question 1

is there a vaccine that can recognise the serotypes of enterovirus found in the pancreas

Answer 1

no

Question 2

importance of the polio virus

Answer 2

can recognise the 4 different serotypes of enterovirus

HOWEVER none of these are involved in diabetes

Question 3

aim and thinking behind the vaccine idea

Answer 3

if you vaccinate children soon after birth (before they encounter the virus) the immune system will be primed to stop the virus infecting any tissues

Question 4

disadvantage of the vaccine

Answer 4

cannot predict whether it will have any adverse side effects in humans

Question 5

insulitis

Answer 5

disease of the pancreas caused by infiltration of lymphocytes
key feature of T1 diabetes

Question 6

autoantibodies and T1 diabetes

Answer 6

developed by most people with T1 diabetes

produced as a symptom

Question 7

why is dsRNA produced by viruses in beta cells

Answer 7

viruses almost always make use of intracellular organelle membranes as their sites of replication
they hijack internal cellular systems

beta cells are good to hijack as they have vast amounts of intracellular membranes due to secretory granule production to produce insulin

Question 8

effect of rubella virus on islets of langerhans

Answer 8

infects beta cells but rarely induces T1 diabetes

Question 9

expression of protein kinase R

Answer 9

viral sensing kinase
expressed at low levels in alpha and beta cells
massively upregulated by beta cells when cell is infected

Question 10

what is Mcl-1

Answer 10

gene that codes for myeloid leukemia cell differentiation protein

(protein is part of Bcl-2 family)

Question 11

function of Mcl-1

Answer 11

regulates apoptosis by switching off protein synthesis

heterodimerises with Bcl-2 to protect cell

Question 12

result of insulitis

Answer 12

inflamed pancreas by immune cells causes loss of beta cells

Question 13

why do beta cells die

Answer 13

they become infected with the virus –> lots of VP1 expression

increased protein kinase R expression –> elFa gets phosphorylated

infected islets lack Mcl-1

protein synthesis stops therefore infected cells cannot recover quickly enough

Question 14

what is VP1

Answer 14

capsid belonging to enterovirus

Question 15

how does PKR stop protein synthesis

Answer 15

phosphorylates elFa

Question 16

role of RIG-1

Answer 16

PRR found in surface of membrane
recognises viral PAMPs
works with Mda 5
causes upregulation of interferons
activates downstream signalling (NFkB)

Question 17

why does RNA become double stranded

Answer 17

so it can replicate within cells

Question 18

have vaccines already been developed

Answer 18

they are in phase II trials
phase III trials must be done but are very expensive
vaccine has been shown effective in animal models

Question 19

example of vaccine already made

Answer 19

BCG vaccine (for TB in 1921)

• stimulates TNF production
• abnormal t cells cause apoptosis

Question 20

is T1 diabetes hereditary

Answer 20

only 5-10%

Question 21

importance of the media in communicating science

Answer 21

uses language the public will understand
reinforces beliefs
however can misinterpret information e.g. MMR/autism

Question 22

which cytokines prevent viral replication

Answer 22

interferon alpha and beta

Question 23

how do we know environmental factors are involved in type 1 diabetes?

Answer 23

prevalence is increasing too quickly for it too be genomic

Question 24

features of group B coxsackie virus

Answer 24

belongs to enterovirus

non-enveloped
positive-sense single stranded RNA

Question 25

viral infection of group B coxsackie virus

Answer 25

infection first spreads to the pancreatic islets causing inflammation
in some people cannot efficiently eradicate the virus or in persistent infection
it stays in beta cells in a slowly replicating form producing continuously viral RNA and proteins
which stimulate innate immune system and drives inflammation and autoimmunity.

Question 26

why is phase III trial for T1 diabetes vaccine expensive

Answer 26

due to the large number of children and long

follow-up (5-years) needed to find out the efficacy of the vaccine in the primary prevention of T1D

Question 27

why is TNF produced by BCG vaccine important

Answer 27

kills disease-causing autoimmune cells to restore insulin production

solube TNF binds to its receptors on the cells –> leads to apoptosis

(Signaling errors in insulin-autoreactive T cells make
them vulnerable to death upon exposure to TNF.)

Question 28

strong environmental risk factors for T1 diabetes

Answer 28

maternal enteroviral infection
old maternal age

overweight infant
enteroviral infection
increased height velocity
pscyhological stress

Question 29

environmental protective factors for T1 diabetes

Answer 29

high omega 3 fatty acid intake

Question 30

role of Mda 5

Answer 30

senses virus by ssRNA

induces production of interferon alpha and beta

Question 31

when do persistent infections occur

Answer 31

when the primary infection is not cleared by the

adaptive immune response