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Immunological Evaluation of Psoriatic Patients In Erbil City/Iraq

Authors:
  • Salahaddin University College of Science, Erbil, Iraq

Abstract and Figures

Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The immunopathogenesis of this disease is complex and involve alternations in the innate and acquired immune system through cytokines that released by keratinocytes and inflammatory leukocytes contribute to the induction and persistence of inflammatory processes in psoriasis. This study was carried out to evaluate the immunological aspects in psoriasis patients attended consultation clinics of dermatology at Hawler Teaching Hospital in Erbil city/Iraq. Blood samples were obtained from 50 psoriatic patients and 30 healthy controls. Serum neopterin (NPT), tumor necrosis factor-alpha (TNF–α), interleukin-10 (IL–10), interleukin-22 (IL–22), high sensitive C-reactive protein (hsCRP), and malondialdehyde (MDA) levels were estimated in the patients. The result showed that serum TNF-α, IL-22, NPT, hsCRP, and MDA were highly significant in the psoriatic patients compared to healthy controls (p< 0.05), while serum IL-10 showed no significant difference between psoriatic patients and healthy controls. The study revealed that elevation of serum NPT, TNF-α, IL-22, hsCRP, MDA in one hand, and impaired IL-10 expression, on the other hand, are involved in the pathogenesis of psoriasis by induction and maintenance of psoriatic lesion. The dysregulation of IL-10 is associated with enhanced immunopathology and increased risk for chronic non-healing infection in psoriasis patients.
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ZANCO Journal of Pure and Applied Sciences
The official scientific journal of Salahaddin University-Erbil
ZJPAS (2017), 29 (6); 59-67
http://dx.doi.org/10.21271/ZJPAS.29.6.7
Immunological Evaluation of Psoriatic Patients In Erbil City/Iraq
Sonia Elia Ishaq, Taban Kamal Rasheed, Faraydoon A. Salih
Department of Biology, College of Science, Salahaddin University, Erbil, Kurdistan Region, Iraq.
1. INTRODUCTION
Psoriasis is a common skin disease with
extracutaneous manifestations. It is
characterized by chronic inflammation of the
skin with changes in the maturation of
keratinocytes (KCs), which manifested by the
hyperproliferation of the epidermis. It is
mediated by T lymphocytes, multigenic and
environmental factors (Scarpa et al., 2010).
The Hyper-proliferation of epidermal KCs
in psoriasis patients is driven by cytokines
secreted from activated resident immune cells,
an infiltrate of T cells, dendritic cells and other
cells of the innate immune system, as well as
the KCs themselves (Baliwag et al., 2015).
Different factors including infections, trauma,
medications and emotional stress can activate
KCs to release cytokines such as interleukin-1
(IL-1) and tumor necrosis factor-alpha (TNF-α)
which in turn initiate the activation of resident
A R T I C L E I N F O
A B S T R A C T
Article History:
Received: 03/05/2017
Accepted: 01/09/2017
Published: 23/1/2018
Psoriasis is a common inflammatory skin disease with an incompletely
understood etiology. The immunopathogenesis of this disease is complex and
involve alternations in the innate and acquired immune system through cytokines
that released by keratinocytes and inflammatory leukocytes contribute to the
induction and persistence of inflammatory processes in psoriasis. This study was
carried out to evaluate the immunological aspects in psoriasis patients attended
consultation clinics of dermatology at Hawler Teaching Hospital in Erbil
city/Iraq. Blood samples were obtained from 50 psoriatic patients and 30 healthy
controls. Serum neopterin (NPT), tumor necrosis factor-alpha (TNF–α),
interleukin-10 (IL10), interleukin-22 (IL22), high sensitive C-reactive protein
(hsCRP), and malondialdehyde (MDA) levels were estimated in the patients. The
result showed that serum TNF-α, IL-22, NPT, hsCRP, and MDA were highly
significant in the psoriatic patients compared to healthy controls (p< 0.05), while
serum IL-10 showed no significant difference between psoriatic patients and
healthy controls. The study revealed that elevation of serum NPT, TNF-α, IL-22,
hsCRP, MDA in one hand, and impaired IL-10 expression, on the other hand, are
involved in the pathogenesis of psoriasis by induction and maintenance of
psoriatic lesion. The dysregulation of IL-10 is associated with enhanced
immunopathology and increased risk for chronic non-healing infection in
psoriasis patients.
Keywords:
Psoriasis, Neopterin, Tumor
Necrosis Factor-α, Interleukin-
10, Interleukin-22, High
sensitive C- reactive protein,
Malondialdehyde.
*Corresponding Author:
Dr.Taban K. Rasheed
taban.rasheed@su.edu.krd
60 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
skin macrophages and dendritic cells (DCs)
(Nickoloff and Nestle, 2004). The cytokines
produced by dendritic cells and effector T-cells
stimulate KCs to proliferate and increase the
migration of inflammatory cells into the skin,
promoting epidermal hyperplasia and
inflammation (Monteleone et al., 2011). These
changes are accompanied by dermal
angiogenesis leading to an increasingly
complex underlying vascular system, giving
the plaques their deep red coloration (Liu et al.,
2007).
This increased vascularity allows for a
greater influx of inflammatory cells into the
skin, further driving the inflammation. Lesions
are rich in activated CD4+ and CD8+ T cells
that release proinflammatory cytokines and are
typically distributed symmetrically on the
scalp, elbows, knees and lumbosacral area.
Thus, psoriasis is now generally regarded as a
T cell-mediated immune disease with a mixed
Th1/Th17 cytokine environment (Baliwag et
al., 2015).
Acute phase reactants, cytokines and
growth factors are known to play an important
role in the pathogenesis of psoriasis and it is
accepted that different cells are crucial in
psoriasis at different stages (Coimbra and
Santos-Silva, 2014). Neopterin, which is a non-
specific marker for activation of cellular
immune system (Mualla et al., 2010) is
produced by human monocytes and
macrophages upon stimulation with IFN-γ,
increased levels indicate T cell activation and
IFN-γ production (Huber et al., 1984) which
plays an important role in psoriasis (Mualla et
al., 2010)
Elevation of NPT, CRP, up-regulation of
proinflammatory cytokines, may contribute to a
cumulative increase in the risk of
cardiovascular diseases (CVDs) in psoriasis
(Balta et al., 2013, Yanchun and Zhidong,
2011). It has been also suggested that
generation of reactive oxygen species (ROS)
from neutrophils (Miyachi and Niwa, 1983),
KCs (Turner et al.1998), and fibroblast
(Raynaud et al., 1997) can contribute to
neutrophil activation, which plays an important
role in the psoriatic process. Elevation in ROS
result in malondialdehyde (MDA) production
from the skin cells in the psoriatic lesion have a
significant increase in arachidonic acid, which
is the natural substrate for synthesis of
malondialdehyde (MDA), an end product of
lipid peroxidation (Kadam et al., 2010).
We aimed through this study to evaluate the
role of acute phase reactants cytokines and
growth factors, TNF-α, IL-10, IL-22, NPT,
hsCRP, and MDA, in the pathogenesis of
psoriasis to improve understanding of the
mechanisms of immunopathology of the
disease that eventually lead to developing
therapeutic strategies against the impaired
cytokine production.
2. MATERIALS AND METHODS
2.1. Patients
Patients were consented to take part in this
study. Among 90 psoriatic patients, only 50
patients were willing to participate in the study,
26 males (52%) and 24 females (48%) with a
mean of age of 30.46±14.612 years, attended
consultation clinics of dermatology at Hawler
Teaching Hospital in Erbil city-Iraq during
September 2014 to April 2015.
2.2. Normal Controls
The control group consists of 30 volunteers,
17 males (56.66%) and 13 females (43.33%),
with a mean of age of 26.50 ±11.33 years and
from the same urban populations. The purpose
and nature of the study were explained to all
subjects. Exclusion criteria for the healthy
control included a family history of psoriasis,
61 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
smoking, medication, pregnancy and any
abnormalities in the body.
2.3. Blood Sampling and Storage
Seven milliliters of non-heparinized venous
blood was drawn from patients and healthy
controls using sterile disposable syringes then
the 7ml was put into a clot-activator tube for
serum separation. The serum was collected
after centrifugation at 3000 round per minute
(rpm) for 10 minutes and it was separated and
stored at -80°C.
2.4. Cytokines detection
Serum TNF-α, IL-10, IL-22 levels were
measured by quantitative enzyme-linked
immunosorbent assay (ELISA) technique. The
assay was achieved according to the
manufacturing company instruction
(Komabiotechinc Company Republic of
Korea). Sample results were calculated by
interpretation from the calibration curve that is
performed in the same assay with samples. The
standard curve was plotted using Graph Pad
Prism (Version 6.01) then the optical density
for each sample was plotted on the standard
curve to obtain the concentration in pg/ml.
2.5. Detection of High sensitive C- reactive
protein (hsCRP)
Quantitative determination was used for
detection hsCRP. The test was achieved and
data were analyzed according to manufacturer
instruction (CobasC111, Roche, USA).
Measuring range was 1-200 mg/L and 5 mg/L
was the upper limit of the normal range.
2.6. Detection of Human Neopterin (Npt)
The serum of patients and normal controls
were subjected to the levels of Human
Neopterin using quantitative enzyme-linked
immunosorbent assay (ELISA). The test was
achieved and data were analyzed according to
manufacture construction (My Biosource,
USA).
2.7. Detection of Human Malondialdehyde
(MDA)
Serum MDA was measured spectrophoto-
metrically by a modified method described by
(Muslih et al., 2002) using Trichloro Acetic
Acid (TCA) and Thiobarbituric Acid (TBA).
2.8. Statistical Analysis
Data were processed and analyzed with
Graph Pad Prism (Version 6.01). The data were
not normally distributed and since the median
is not affected by outliers like mean would do
the results were expressed as Median-
Interquartile Range and statistical differences
between psoriasis patients and controls were
determined using Mann-Whitney’s test. P-
values below 0.05 were considered to be
statistically significant.
3. RESULTS AND DISCUSSION
Psoriasis is a chronic inflammatory
cutaneous skin disease. The diseases
characterized by red, scaly and well-
demarcated skin lesions formed by the
hyperproliferation of epidermal KCs. This
hyperproliferation is driven by cytokines
secreted by activated resident immune cells, an
infiltrate of T cells, DCs and cells of the innate
immune system, as well as the KCs
themselves. (Baliwag et al., 2015).
Psoriasis can present at any age and has
been reported at birth and in older people of
advanced age. The majority of our cases, 72%
(36 patients out of 50), present before the age
of 40 years. The remaining cases, 28 % (14
patients out of 50), present after the age of 40
years. A bimodal age of onset has been
recognized in several studies. The mean age of
onset for the first presentation of psoriasis can
range from 15 to 20 years old before the age of
40 years, with a second peak occurring at 55
62 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
60 years after the age of 40 years (Griffiths and
Barker, 2007) and this was consistent with our
results.
Familial clustering in psoriasis had been
observed for many years (Naldi et al., 2001).
The present study showed that sixteen patients
(32 %) had a positive family history of
psoriasis in one or more of their relatives. This
confirmed the important role of genetics in the
etiology of psoriasis especially in those with
early onset (Ferrándiz et al., 2002).
Understanding the function of individual
cytokine in psoriatic patients is complicated
because their role can vary depending on the
cellular source, target, and phase of the
immune response. In fact, numerous cytokines
have both proinflammatory and anti-
inflammatory potential (Commins et al., 2008).
Various cytokines released by KCs and
inflammatory leukocytes could contribute to
the induction or persistence of inflammatory
processes in psoriasis (Ragab et al., 2010).
Serum TNF-α level was significantly
elevated in patients with psoriasis when
compared to healthy controls (figure1).Tumor
Necrosis Factor-alpha is a somewhat enigmatic
cytokine with respect to psoriasis pathogenesis;
although it is produced by most activated T
cells and antigen presenting cell (APC), TNF-α
alone does not evoke significant responses
from KCs; however, in combination with
another cytokine IL-17A (Chiricozzi et al.,
2011), IL-17C (Johnston et al., 2013) it forms
strong synergies and amplifying responses
which play a major role in the pathogenesis of
the disease through stimulating a cytokine
storm in psoriasis.
T N F - (p g/m l )
C o n tr ol s P a tie n t s
0
200
400
600 ** *
P - va l u e= 0. 0 00 1
Figure 1. Serum levels of TNF-α in patients with
psoriasis compared to healthy controls.
Furthermore, our results indicated a
significant elevation of serum IL-22 levels in
patients when compared with healthy controls
(figure 2). The over expressions in IL-22
disrupt the normal differentiation of KCs.
Boniface and his colleagues (2005 and 2007)
show that treatment of in-vitro reconstituted
human epidermis with an IL-22 result in
epidermal hyperplasia accompanied by
hypogranulosis and parakeratosis that result in
disruption of normal terminal differentiation of
KCs.
IL -22 (p g/ m l)
C o n t r o ls P a t ie n t s
0
50
100
150
200
250 *P -v alu e = 0 .0 3
Figure 2. Serum levels of IL-22 in patients with
psoriasis compared to healthy controls.
Interleukin-22 is remarkably over-
expressed most probably as a result of
upregulated IL-23 (Nograles et al., 2010,
Boniface et al., 2007, Zheng et al., 2007) and
IL-6 levels. IL-6 is reported to be important for
Th-22 differentiation (Duhen et al., 2009), and
its expression is also elevated in psoriatic skin.
63 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
Thus, the psoriatic skin provides an
environment that favors the
expansion/generation of IL-22-producing Th-
22 cells as well as the enhanced response of
keratinocytes to IL-22.
Few data have been available to reveal the
serum levels of IL-10 in patients with psoriasis
and the results are contradictory. Our results
show no significant difference in the serum IL-
10 concentrations between the psoriatic
patients and control group (figure 3). The
possible point that might be involved is a total
lack of IL-10R expression on KCs in psoriatic
lesions, and this phenomenon inevitably results
in the lack of IL-10 activity (Seifert et al.,
2003) in psoriatic plaques and thus activation
of Th1 cells (Asadullah et al., 1998)
The immunological pathogenesis of
psoriasis is a complex interaction, however, our
result was came up compatible with Mussi et
al. (1993) and Nickoloff et al. (1994) results
which indicate the key role of IL-10 in
psoriatic disease. The low level of serum IL-10
or the same levels as controls will not affect
stimulated DCs, macrophages, and T-helper
cells while continuous stimulation of these
cells leads to increase TNF- levels which lead
to activation of endothelial cells for
inflammation and coagulation and neutrophil
activation (Abbas et al. 2014) thereby
producing proinflammatory environment.
Figure 3. Serum levels of IL-10 in patients with
psoriasis compared to healthy controls.
Moreover, normal level of IL-10 will not
inhibit stimulated Th-1, Th-22, and Th-
17which lead in turn to an increased IL-22
level which has a direct effect on disruption of
KCs differentiation.(Wolk and Sabat, 2006)
Furthermore, the therapeutic trials done by
Asadullah and his colleague (1998) confirm the
key role of IL-10 through the injection of
recombinant human IL-10 (rhIL-10)
subcutaneously three time weekly decrease Th-
1type cytokines and induced remission of
psoriasis however, recombinant IL-10 therapy
doesn’t show strong therapeutic potential in all
psoriatic patents, as systemic administration of
rhIL-10 will not be sufficient to deliver IL-10
to inflammatory sites to exert its function as
anti-inflammatory and the blocked IL-10R will
not be solved based on systemic administration
(Murai et al., 2009) Thus, the potential
therapeutic role will be through gene therapy
that targets the impaired IL-10 gene expression
and signaling.
Our results showed the mean values of
serum NPT levels were significantly higher
p=0.0006 in the patient group compared to
healthy controls (figure 4). Sepp et al. (1993)
have reported that only a minority of patients
had elevated NPT levels either in urine or
serum. These inconsistent results may be due to
the different cytokine response, different
environmental factors, genetic factors, or
infections.
N P T (n g/m l )
C o n t r o ls P a ti e n t s
0.0
0.1
0.2
0.3
0.4
0.5 ***
P -v a l u e= 0 . 00 0 6
Figure 4. Serum levels of NPT in patients with psoriasis
compared to healthy controls.
64 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
Increasing concentrations of CRP have
been widely reported in mild, moderate and
severe forms of active psoriasis (Chodorowska
et al., 2004, Arias-Santiago et al., 2012, Balta
et al., 2013, Zhao et al., 2014). Our result
revealed that hsCRP levels were significantly
elevated p=0.001 in psoriasis patients when
compared to healthy control (figure 5).
h sC R P ( m g/L )
C o n tr ol s P atie n ts
0
5
10
15
20 **
P -v alu e = 0 .0 01
Figure 5. Serum levels of hsCRP in patients with
psoriasis compared to healthy controls.
However, Few studies did not observe
significantly increased values (Laurent et al.,
1981, Romaní et al., 2012), most likely
because the patients that were not at the active
phase of psoriasis, or were under treatment
with anti-psoriatic therapies.IL-17 is known to
play an important role in the pathogenesis of
psoriasis(Lin et al., 2011). It stimulates CRP
expression in hepatocytes, coronary artery, and
smooth muscle cells, independently of IL-1 and
IL-6 (Patel et al., 2007) and this is the possible
mechanism, which may lead to up-regulation
of CRP levels in psoriasis patients.
Plasma membranes of the skin cells in the
psoriatic lesion have a significant increase in
arachidonic acid, which is the natural substrate
for synthesis of MDA, an end product of lipid
peroxidation (Kadam et al., 2010). The present
study shows that serum MDA levels were
significantly increased p=0.025 in psoriasis
patients when compared to healthy persons
(figure 6). A rise in MDA could be due to
increased generation ROS due to the excessive
oxidative damage generated in these patients.
These oxygen species, in turn, can oxidize
many other important biomolecules including
membrane lipids (Kadam et al., 2010).
M D A (µ m ol/L )
c o n tr o l s p a ti e n t s
0
2
4
6
8
*
P - va l u e = 0 .0 2 5
Figure 6. Serum levels of MDA in patients with
psoriasis compared to healthy controls.
On the other hand, TNF-α, which is the
major proinflammatory cytokine in psoriasis,
may activate cells in a positive feedback loop
producing other inflammatory mediators,
including ROS and various other cytokines
(Gottlieb et al., 2005, Lowes et al., 2005, Pelle
et al., 2005). Thus it is thought that an
insufficient antioxidant system, together with
increased levels of ROS, contributes to the
pathogenesis of psoriasis (Antille et al., 2002,
Baz et al., 2003, Bickers and Athar, 2006).
4- CONCLUSIONS
The elevation of serum NPT, TNF-α, IL-
22, hsCRP, MDA in one hand, and impaired
IL-10 expression, on the other hand, are
involved in the pathogenesis of psoriasis by
induction and maintenance of psoriatic lesion.
The dis-regulation of IL-10 is associated with
enhanced immunopathology and increased risk
for chronic non-healing infection in psoriasis
patients.
65 Ishaq S. et al. /ZJPAS: 2017, 29(6): 59-67
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