Dr Francesca Capon, King's College London
What is already known about
the problem that the project will address?
Palmar plantar pustulosis (PPP)
is a severe form of psoriasis manifesting with the appearance of painful
pustules on the palms and soles. These lesions can be preceded or accompanied by
plaque psoriasis and/or psoriatic arthritis. PPP is a disabling condition that
has a profound effect on quality of life, as affected individuals can find it
very difficult to walk or carry out everyday tasks. At the same time, very
little is known about the causes of the disease, which as a consequence is
extremely difficult to treat.
What do you hope to find
The aim of our research is to
achieve a better understanding of the causes of PPP, as that is essential for
the development of effective treatment. Our group has already discovered two
genes that malfunction in affected individuals, causing excessive production of
an inflammatory molecule known as IL-36. Importantly, we also demonstrated that
IL-36 drives the release of a protein called IL-1, which can be blocked by
existing drugs. This was a breakthrough, which suggested that PPP could be
treated with known IL-1 inhibitors.
It is important to bear in
mind, however, that the genetic defects we have discovered are only found in
10-15% of individuals with PPP. Therefore, it is still not clear whether
abnormal release of IL-36 and IL-1 is a general feature of the disease.
With this project, we plan to
identify novel PPP genes and to establish whether they also cause excessive IL-36
and IL-1 production. If we find that the newly identified defects do not alter
IL-36/IL-1 levels, we will seek to clarify what are the alternative mechanisms
whereby they cause disease.
Latest results summary
focus of this project is on palmar plantar pustulosis (PPP), a severe variant
of psoriasis that manifests with the appearance of painful skin pustules on the
hands and feet. The hypothesis driving our study is that PPP is caused by the
excessive accumulation of two related proteins called IL-1 and IL-36. To
demonstrate that this is the case, we are examining the DNA of affected
individuals, looking for changes in genes that influence IL-1 and IL-36
the last 12 months, we have concentrated our efforts on a gene called CARD14,
which in the past has been linked to IL-36. We examined the DNA of 160 PPP
sufferers and found that 14 of them carried CARD14 defects. Of interest,
DNA changes that cause CARD14 to malfunction have previously been
observed in individuals affected by other rare and severe forms of psoriasis (erythrodermic
psoriasis and generalised pustular psoriasis). We are now investigating whether
the mutations that we have identified and those reported by others can enhance
the production of IL-1 and IL-36. This will shed new light on a common
mechanism contributing to the onset of different forms of psoriasis.