5 - vaccine for T1 diabetes Flashcards
is there a vaccine that can recognise the serotypes of enterovirus found in the pancreas
no
importance of the polio virus
can recognise the 4 different serotypes of enterovirus
HOWEVER none of these are involved in diabetes
aim and thinking behind the vaccine idea
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
disadvantage of the vaccine
cannot predict whether it will have any adverse side effects in humans
insulitis
disease of the pancreas caused by infiltration of lymphocytes
key feature of T1 diabetes
autoantibodies and T1 diabetes
developed by most people with T1 diabetes
produced as a symptom
why is dsRNA produced by viruses in beta cells
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
effect of rubella virus on islets of langerhans
infects beta cells but rarely induces T1 diabetes
expression of protein kinase R
viral sensing kinase
expressed at low levels in alpha and beta cells
massively upregulated by beta cells when cell is infected
what is Mcl-1
gene that codes for myeloid leukemia cell differentiation protein
(protein is part of Bcl-2 family)
function of Mcl-1
regulates apoptosis by switching off protein synthesis
heterodimerises with Bcl-2 to protect cell
result of insulitis
inflamed pancreas by immune cells causes loss of beta cells
why do beta cells die
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
what is VP1
capsid belonging to enterovirus
how does PKR stop protein synthesis
phosphorylates elFa
role of RIG-1
PRR found in surface of membrane recognises viral PAMPs works with Mda 5 causes upregulation of interferons activates downstream signalling (NFkB)
why does RNA become double stranded
so it can replicate within cells
have vaccines already been developed
they are in phase II trials
phase III trials must be done but are very expensive
vaccine has been shown effective in animal models
example of vaccine already made
BCG vaccine (for TB in 1921)
- stimulates TNF production
- abnormal t cells cause apoptosis
is T1 diabetes hereditary
only 5-10%
importance of the media in communicating science
uses language the public will understand
reinforces beliefs
however can misinterpret information e.g. MMR/autism
which cytokines prevent viral replication
interferon alpha and beta
how do we know environmental factors are involved in type 1 diabetes?
prevalence is increasing too quickly for it too be genomic
features of group B coxsackie virus
belongs to enterovirus
non-enveloped
positive-sense single stranded RNA
viral infection of group B coxsackie virus
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.
why is phase III trial for T1 diabetes vaccine expensive
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
why is TNF produced by BCG vaccine important
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.)
strong environmental risk factors for T1 diabetes
maternal enteroviral infection
old maternal age
overweight infant
enteroviral infection
increased height velocity
pscyhological stress
environmental protective factors for T1 diabetes
high omega 3 fatty acid intake
role of Mda 5
senses virus by ssRNA
induces production of interferon alpha and beta
when do persistent infections occur
when the primary infection is not cleared by the
adaptive immune response
