Download Cartoon of current thinking on Aicardi–Goutières syndrome (AGS

Cartoon of current thinking on
Aicardi–Goutières syndrome (AGS)
– with relevance to other type I interferonopathies
1. Throughout life, cells are in a constant battle with external viruses ...
(this happens to everyone!)
Viruses
(e.g. cold or ‘flu) enter cells and
highjack the cell’s machinery to make more
copies
of
duplicating
themselves;
this
involves
their genetic material
(which can be either DNA or RNA).
The
(e.g.
cell
has
defence
mechanisms
) that detect and
destroy this foreign DNA / RNA.
However, if the infection takes hold, the viral DNA/RNA is multiplied to produce more viruses.
This sets off an alarm
system, and signals
are sent to other cells in the body
indicating “Help - I’ve been invaded! Send in the troops!” This triggers an immune response
(e.g.
), which enables the body to fight the infection. This can include attacking
and destroying the cells that have been infected with virus.
Immune
response
Crow research group (2015)
2. Chromosomes, genes and “junk” DNA
Genes (e.g. code for proteins)
“Junk” DNA
Within chromosomes there are stretches of DNA that code for proteins, which have many different
functions; but this coding DNA (genes) accounts for a very small proportion (about 1%) of the total
DNA. A large amount of the remaining DNA (sometimes referred to as “junk” DNA, because it has no
known function) is thought to be remnants of ancient viruses, which have integrated into our
chromosomal DNA during evolution over many millions of years.
3. One probable function of the AGS proteins...
Ancient viruses, that have been integrated into our
chromosomal DNA, sometimes escape from this
‘confinement’ and highjack the cell’s mechanisms
to replicate themselves – in a similar way to
external viruses – but the body has devices to
keep these under control.
Within the cell, the same mechanisms that identify
and destroy external viruses (like cold and ‘flu)
detect these pieces of DNA as being ‘foreign’.
For example, TREX1 breaks down this ‘viral’ DNA, so that an alarm is not triggered and signals are
not sent out to “mobilise the troops” (no immune response).
Crow research group (2015)
However, in the absence of TREX1, this
‘viral’ DNA is not destroyed, so it
accumulates in the cell (like a viral
infection). The alarm is raised, and signals
are sent out to “send in the troops”.
This sets off an immune response, (like
the reaction to a viral attack). However,
since the foreign DNA is not external, but
(Auto)
Immune
response
comes from within the body’s own cells.
This can be considered to be an autoimmune response (against self).
Research has shown that all the AGS proteins are involved in either nucleic acid metabolism
(TREX1; RNase H2A, B and C; SAMHD1; ADAR) (i.e.
IFIH1) (i.e.
) or signalling (MDA5 coded by
). This might explain why AGS mimics viral infections.
4. Working towards possible future therapies for AGS …
Trex1 knock-out mice (i.e. mice that do not have a functional Trex1 enzyme), develop severe
inflammation of the heart muscle, and have a significantly shorter life-span with many dying very
young. A research group based in California has reported that treatment with certain antiretroviral drugs (Reverse Transcriptase Inhibitors RTIs)
can
significantly
reduce
the
heart
inflammation and prolong the life of these
animals.
The explanation for this is probably that antiretroviral drugs prevent the replication of DNA
from
the
integrated
‘ancient
viruses’.
Consequently, there is no accumulation of this
‘viral’ DNA in the cell, the alarm is not triggered
and an immune response is not raised.
The results from mouse models cannot necessarily be directly applied to humans .
However, these results support the idea that antiretroviral therapy is worth exploring as a
treatment for AGS patients.
Crow research group (2015)
5. Biomarkers
In addition to assessing drug-safety, one of the main aims of any clinical trial is to assess the
effectiveness of a particular treatment. This usually involves measuring biological indicators or
markers (“biomarkers”), which may be specific for each medical condition, and have to be
identified and verified beforehand. Suitable biomarkers show significantly different levels in
affected individuals (pre-treatment) compared to control ‘normal’ levels. A clinical trial would
measure these biomarkers before, during and after any treatment, to see if the levels in affected
individuals became ‘normalised’, i.e. if the levels move towards those found in healthy controls.
We have investigated potential biomarkers for AGS, and identified one that is very promising –
interferon-stimulated genes (ISGs).
6. Interferon-stimulated genes (ISGs)
Human DNA is like an encyclopaedia that contains coded information, in a number of volumes
(chromosomes), to make thousands of different proteins. If a specific protein is required, a copy is
made of that particular coding region (gene); like taking a photocopy of a specific page from one
volume of the encyclopaedia. The string of nucleic acids (RNA) is translated into a string of amino
acids which is then folded into the correct shape of the protein.
DNA (genes)
WITHOUT
Interferon
signal
Interferon is a biochemical messenger that is involved in the immune response. If the body is being
attacked by viruses (e.g. cold or ‘flu virus), interferon stimulates certain specific genes (Interferon
Stimulated Genes = ISGs) to make more anti-viral proteins
(“send in the troops”).
DNA (genes)
WITH
Interferon
signal
When the infection has cleared, the interferon signal is switched off, and those RNA and protein
levels drop back to ‘normal’ (i.e. when the body is not fighting an infection). However since AGS
mimics infection, we are trying to find out if these ISGs are activated all the time in AGS patients by
measuring the amount of certain specific chemicals (RNA) in the blood.
Crow research group (2015)
7. Measuring the relative amounts of ISGs
Initially, we focussed on fifteen interferon-stimulated genes (ISGs) that are involved in the normal
immune response. Compared with the pool of controls, all the AGS patients had significantly more
RNA of each of these ISGs (over 1,000 times in some cases). This increase in levels was found at all
ages tested (from a few months to 32 years), both genders (male and female), and with all the AGS
genes (TREX1; RNASEH2 A, B and C; ADAR1; and IFIH1). For each patient, measuring the levels of a
set of ISGs might provide a ‘signature’ or pattern which could then be used as an AGS biomarker;
the levels of several ISGs would be measured before, during and after treatment to monitor the
effectiveness of any therapy.
To explore this further, six (from the
original fifteen) ISGs were selected to form
a screening panel. The five patients shown
here all have higher levels of ISG RNA
compared to controls (relative quantity = 1
indicated by the very small blue bar on the
left-hand-side of each ISG grouping). Serial
samples from patients (e.g. samples taken
at 6-monthly intervals from the same patient) have revealed that their ISG signature is robust and
constant in most cases. This panel of six ISGs is now used routinely as a screening tool in research
practice and it identifies almost all molecularly-defined type I interferonopathy patients that we
have assayed so far (around 330 individuals). In this context, we have so-far generated interferon
signatures on over 1,000 samples which generally show remarkable consistency within individuals.
The relative amount of several ISGs has been
measured in blood samples from a number of AGS
patients and their parents, and in controls. Each dot
represents the amount of ISG from a single individual.
In general, patients have very significantly higher
levels of RNA compared to controls, with little overlap.
This work is on-going.
We are extremely grateful to the affected families for their help with this research.
Crow research group (2015)