Forum for Nordic Dermato-Venereology Nr 2, 2018 | Page 17

Charlotta Enerbäck – Ingrid Asp Psoriasis Research Center
nal differentiation in the psoriatic epidermis, which results in
the retention of granulated and cornified cells, may be a con-
sequence of massive proliferation that does not allow sufficient
time for the proper differentiation of the cells. We hypothesized
that dysregulated cell death contributes to the thickened epi-
dermal plaques in psoriasis. Using cultured KCs obtained from
skin punch biopsies, we have demonstrated higher viability and
resistance to ultraviolet (UV)-B apoptosis in the KCs derived
from both involved and uninvolved skin, compared with KCs
from healthy controls. We positioned the dysregulation up-
stream of cytochrome c release in the mitochondrial pathway
and observed a change in the expression of apoptosis-related
genes using microarray transcriptome analysis (6).
In addition, the proliferating KC sub-population, which is
twice as large compared with normal skin, is still poorly
defined. In one of our current projects, we aim to define the
level of cellular differentiation in proliferating psoriatic KCs.
We apply multicolour flow cytometry on psoriatic epidermal
KCs and control KCs. In recent preliminary data we describe an
overall more immature phenotype of psoriasis KCs compared
with normal KCs, with higher expression levels of the stem
cell-associated markers p63, CD44 and CD29. We are currently
addressing the mechanism and consequences of this decreased
cellular differentiation.
In collaboration with Professor Helleday’s team at the Kar-
olinska Institute, we evaluated the potential use of MTH1
inhibitors in the treatment of psoriasis. To counteract the
damaging effects of increased ROS production, cells upregu-
late defence mechanisms including MTH1, which detoxifies
oxidized nucleotides. MTH1 was identified as a potential
cancer therapeutic target (7) and several potent small mole-
cule inhibitors have been developed. Interestingly, we found
an increase in MTH1 expression in involved psoriatic skin
compared with normal skin, suggesting a potential beneficial
effect of MTH inhibition.
Our present project plan includes studies of selected, predict-
ed causal variants in the coding sequence that will help us
to understand the biological and mechanistic connections
between each locus and disease pathogenesis, disease onset
and severity. This could also lead to the identification of new
drug targets. We previously collected a large psoriasis patient
sample, including 1,988 individuals from 491 families, in
collaboration with the Swedish Psoriasis Association. Using
this sample, we analysed how components of the inflammas-
omes (NLRP3, NLRP1 and CARD8) contribute to psoriasis
susceptibility (9,10).
We have ongoing studies on tyrosine kinase 2 (TYK2) that
transmits signals from activated cytokine receptors. In an
in-depth analysis of the TYK2 genomic region using GWAS
and resequencing data, we found a strong genetic association
between three non-synonymous variants in the exonic regions
of the TYK2 gene. We found that individuals who carried the
protective I684S variant had significantly reduced p-STAT4
levels in CD4+CD25+CD45RO+ and CD8+CD25+CD45RO+
cells compared with controls homozygous for the ancestral
haplotype (Fig. 2). Similar reductions in p-STAT4 were also
observed in skin-homing, cutaneous lymphocyte-associated
antigen (CLA)-positive CD4 and CD8 cells from I684S carriers.
These data establish the functional significance for the TYK2
I684S variant in psoriasis susceptibility (11) DNA methylation
is the most widely studied epigenetic mechanisms regulating
gene transcription. We have used reduced representation
bisulphite sequencing (RRBS) to determine the methylome
and the associated gene expression pattern in involved (PP)
and uninvolved (PN) psoriatic epidermis. Through the RRBS
assay, we were able to compare the methylation status of ~2–3
Studies of the genetic and epigenetic predisposition
in psoriasis
Genome-wide association studies (GWAS) and more targeted
candidate gene approaches have identified more than 80 single
nucleotide polymorphisms (SNPs) associated with psoriasis.
Many of them are situated near genes that are involved in
adaptive and innate immune pathways and, more specifically,
the IL-23/Th17 axis. The work conducted by our collaborator,
Professor J. T. Elder at the University of Michigan, whom I
joined for a sabbatical period in 2013–2014, has directed many
of these genetic studies. This collaboration has led to several
publications, such as the recent international ExomeChip gen-
otyping experiment of more than 6,000 cases and controls (8).
Forum for Nord Derm Ven 2018, Vol. 23, No. 2
Fig. 1. Flow cytometry data describing IL-12-induced pSTAT4 signaling
in CD4+CD25+CD45RO+ cells in different TYK2 haplotypes. n = 5–9 in
each group.
D ermato -V enereology in the N ordic C ountries
47