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The Relationship Between Thymosin β4 and Vitamin D3 in Systemic Lupus Erythmatosus Patients

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Vol. 3, Issue 9, pp 25-31, Winter 2019
ORIGINAL ARTICLE
The Relationship Between Thymosin β4 and Vitamin D3 in Systemic
Lupus Erythmatosus Patients
Noor H. Al-Hashimy 1, Hadi R. Al-Masudi 2 and Mohammed S. Mahdi 3
1 Department of Biology, College of Science, University of Karbala, Iraq.
2 Department of Clinical Laboratories, College of Applied Medical Sciences, University of Karbala, Iraq.
3 Imam Hussein Medical Hospital, The City of Karbala, Karbala Health Directorate, Karbala, Iraq.
ARTICLE INFORMATIONS
Article History:
Submitted: 29 January 2019
Revised version received:
9 February 2019
Accepted: 12 February 2019
Published online: 1 March 2019
Key words:
Systemic lupus erythematosus
Thymosin β4
Vitamin D3
Corresponding author:
Hadi R. Hasan Al-Masudi
Email: hadirassol@yahoo.com
Department of Clinical Laboratories
College of Applied Medical Sciences
University of Karbala
Karbala
Iraq
ABSTRACT
Objectives: The aim of the current study is to focus of the relationship
between thymosin β4 and vitamin D3 in systemic lupus erythmatosus
patients.
Methods: This study included sixty of systemic lupus erythematosus
patients that diagnosed by clinic specialists by using (SLEDAI) taken from
(Al-Hussein Medical City/Kerbala / IRAQ). During the period from
January 2015 to December 2016. Control group of 30 healthy persons who
matched in gender and age with patients, and haven't history for this
disease. The majority of the SLE patients were female 95% , the ratio of
female male 19:1. The age of SLE patients was ranging from (7-65)
compared with healthy control group as a seem in age.
Results: The result shows a significant decreasing in concentration of
thymosin β4, vitamin D3 and circulating complement factors (C3,C4) in
active SLE patients compare with healthy control while significant increase
in concentration of ANA and ds-DNA antibodies and disease activity
measured using the SLE disease activity index (SLEDAI).
Conclusion: Positive relationship between level thymosin β4 and
concentration vitamin D3. There is an inverse relationship between
Thymosin β4 and disease activity index of SLE.
Copyright©2019, Hadi R. Hasan Al-Masudi. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.
INTRODUCTION
Systemic lupus erythematosus is an autoimmune
inflammatory disease characterized by the presence of
incandesce of autoantibodies, particularly versus nuclear
components. Although it is believed that the etiology of
SLE is multifactorial, including immune dysfunction,
genetic, hormonal and environmental, the molecular
mechanisms implicit this systemic autoimmune response
remain largely unknown1.
Autoantibodies play an important role in the
pathogenesis of SLE, and the varied clinical
manifestations of the disease are caused by the
precipitation of antibody-containing immune complexes
in blood vessels, leading to inflammation in the kidney,
brain, and skin. Direct pathogenic effects of the
autoantibodies share in to hemolytic anemia and
thrombocytopenia2.
Available online at http://www.sjomr.org
SCIENTIFIC JOURNAL
OF MEDICAL RESEARCH
Vo. x, Issue x, pp xx - xx, Winter
2018
Citation: Al-Hashimy N.H., Al-Masudi H.R.H., and Mahdi M.S. “The relationship between thymosin β4 and vitamin D3 in systemic lupus
erythmatosus patients”. Sci. J. Med. Res. 2019; 3 (9): 25-31.
ISSN: 2520-5234
Sci. J. Med. Res., Vol. 3, Issue 9, pp 25- 31, Winter 2019 25
.
Antinuclear antibodies (ANA) positivity is usually
considered as hallmark of SLE being positive in more
than 95% of patients. Lupus nephritis has been
associated with presence of many specific antibodies
such as dsDNA which correlate with the disease
activity3.
Thymosin is a hormone concerning from thymus gland
to labeled virgin T cell when can from bone marrow.
There are two type of thymosin: alpha and beta.
thymosin alpha is labeling virgin T cell arrive from the
bone marrow and thymosin beta labeling virgin T cell
in germinal sit in secondary immune organs. Thymosin
β4 is detected outside of cells in blood plasma or in
wound fluid. Several biological effects are attributed to
thymosin β4, like induction of metallo-proteinases,
chemotaxis, angiogenesis and inhibition of inflammation
as well as the inhibition of bone marrow stem cell
proliferation4.
Vitamin D3 is the common denomination of a group of
sterols with a crucial role in phospho-calcic metabolism.
The main source of vitamin D3 is the conversion of 7-
dehydrocholesterol to pre-vitamin D3 in the skin, by
means of solar ultraviolet B radiation. Conversion to
vitamin D3, or cholecalciferol, also takes place in the
skin through a heat-mediated process5.
The major function of 1,25(OH)2D3 has a regulatory in
the calcium homeostasis, endocrine system, proliferation
of skin keratinocytes and importantly plays a significant
role in the regulation of the immune system6.
Vitamin D3 appears to act as an immunomodulator
through its actions on the regulation and differentiation
of immune cells like lymphocytes, macrophages, and
natural killer cells (NK), besides interfering with the
production of cytokines. Among the immunomodulatory
effects demonstrated :inhibition of the production of
autoantibodies by B lymphocytes and a reduction in the
secretion of interleukin-2 (IL-2), gamma interferon
(INFγ), and tumor necrosis factor (TNF); inhibition of
the scretion of IL-6 7.
MATERIALS AND METHODS
Patients and controls: This study has been performed
on 60 patients suffering from SLE including 3 males and
57 females. Age range was (9-65) years old and
apparently healthy control 30 were selected to
participate as a normal group for comparison with age
group and sex matching of patients. attending to the
Imam Hussein Medical City in Karbala governorate
during period from October 2015 to December -2016.
Sample's collection: Six milliliters of blood sample
have been drown from each patients and healthy persons
by vein puncture using disposable syringes under aseptic
technique8.
Blood of each sample has been divided to two part. one
milliliters are transferred into vacuum EDTA tubes for
measuring ESR . The remaining five milliliters has been
transferred into vacuum gel and clot tubes left at room
temperature for at least 30 minutes for clotting then
centrifuge at 4000 rpm 4 minutes.
Then separated serum has been divided into four
Eppendorff tubes and stored at -60° C until used to
avoid repeated thawing and freezing. For measuring
immunological test ANA ELISA kit (Generic
assay/Germany) normal range (0-1 IU/ml),Anti-dsDNA
ELISA kit (Generic assay/Germany) normal range (0-35
IU/ml), Complement factor (C3 , C4 ) , Thymosin beta 4
ELISA kit (Hcusaio/Japan) normal range (544-1234
ng/ml) , Vitamin D ELISA kit (Euroimmun/ Germany)
normal range(20-30 ng/ml).
Bio-statistical Analysis: Statistical analysis was
performed using statistical package for the social
sciences (SPSS) statistical software for windows. The
results are presented as means and standard deviation
(SD). Comparison of group differences on normally
distributed numerical variables were assessed by using
the students' T-test to compered between patients and
healthy control (group1 and 2) and ANOVA, one way to
compered between classes of patients (group 1,2)
depended on the least significant difference (LDS) at
level less than 0.05. P-values at levels (p<0.05) was
considered to be statically significant. Correlation
between parameter were determined using the person
correlation coefficients.
RESULTS
Sample distribution
Gender incidence: The majority of SLE patients were
57 female and 3 male, the ratio of female to male 19:1.
In the healthy control 27 female and 3 male, the ratio of
female to male 9:1.show in Figure 1.
Figure 1. Distribution of SLE patients according to gender.
Age group: The age of patient with SLE in this study
(n= 60) ranged between (7-65) years with the mean age
(36.11± 1.53) compared with healthy control (n=30)
ranged (19-61) years with the mean age (37.56±2.32) .
The age group of SLE patient from (1-15) years reported
1 (1.7%) while the age group (15-45) years reported 47
(78.3%) and 12 (20%) belong to (46-65) years age
group, show in Figure 2.
female
95%
male
5%
Figure 2. Distribution of SLE patients according to age group.
SLE Disease Activity Index (SLEDAI): According to
disease activity (SLEDAI), SLE patients can be divided
into three groups, mild, progressive and lupus nephritis.
The current data showed that 33 (55%) of patients has
mild ranged from (16-65), 14 (23.3%) had progressive
which ranged from (19-58) and 13 (21.6%) had lupus
nephritis ranged from (7-55) Show in Figure 3.
Figure 3. The distribution of SLE patients depended on SLEDAI.
Evolution thymosin β4 in SLE: The mean
concentration of thymosin β4 for SLE patients was
195.4±384.1 range 0.001- 1727.8 compared to average
of healthy control was 575.4±435.9 range 0.2 - 1290.1 ,
this difference was statistically high significant at
p<0.05 as shown in Table 1 and Figure 4.
Table 1: The concentration of thymosin β4 in SLE patients and
healthy control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus
nephritis
n= 13
Thymosin β4 (544-1234)ng/ml
Mean± SD
575.4±435.9
195.4±384.1
226.6±401.3
211.9±466.8
90.6±191.9
Range
0.2- 1290.1
0.001-1727.8
0.1 - 1720
0.0011727.8
0.1 683.1
P-value
0.037
0.01
P-value is significant at level 0.05 , n: number.
Figure 4. Concentration of thymosin β4 in SLE patients and
healthy control.
Evaluated of vitamin D3 levels: The mean of vitamin
D3 in the SLE patients was 14.9 ± 9.7ng/ml ranged
from 4.8 65.3ng/ml comperad with healthy control
24.8 ± 6.94 ng/ml ranged 13 -35 ng/ml. There was
significant difference between the level of vitamin D3 in
SLE patients and healthy control p< 0.05 , as shown in
Table 2 and Figure 5.
Table 2: Concentration of vitamin D3 in serum of SLE patients and
healthy control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus
nephritis
n= 13
Vitamin D3 (30 -50) ng/ml
Mean± SD
24.8±6.94
14.9 ± 9.7
16.6 ± 6.8
13.5 ± 15.6
12.2 ± 7.6
Range
13 -35
4.8 65.3
5.5 39
4.8 65
5.5 29.2
P-value
0.682
0.00
P-value is significant at level 0.05.
Figure 5. Concentration of Vitamin D3 in SLE patients and healthy
control.
<15 15-45 >45
percentage 1.7 78.3 20
0
10
20
30
40
50
60
70
80
90
percentage
mild
55%
progressive
23%
lupus
nephritis
22%
0
100
200
300
400
500
600
control mild progressive lupus
nephritis
thymosin b4 575.4 226.6 211.9 90.6
concentration ng/ml
0
5
10
15
20
25
control mild progressive lupus
nephritis
vitamin D 24.8 16.6 13.5 12.2
concentration ng/ml
Sci. J. Med. Res., Vol. 3, Issue 9, pp 25- 31, Winter 2019 27
.
Table 3: Comparison between two groups of SLE patients before and after receiving Ca+ / vitamin D 3 depend on serum level of(ANA , ds-
DNA , C3,C4 ) and ESR with serum level of 25-OH D3.
Group1
ANA
ds-DNA
ESR
C3
C4
Vitamin D3
SLE patients before receiving Ca+/ Vitamin D3
Mean±SD
6.73±2.44
480.85±310
78.5±23.74
1±0.71
0.07±0.13
12.22±7.67
Rang
4.1- 10.6
77.9-1022.5
38 - 110
0.26-2.73
0.01-0.52
5.5 29.2
P-value
0.00
0.00
0.00
0.00
0.00
0.00
Group2
SLE patients after receiving Ca+/ Vitamin D3
Mean±SD
3.35±1.44
228.23±92.7
43.23±12.81
1.14±0.44
0.12±0.09
17.77±4.93
Rang
1.8- 6
60-389
20-67
0.68-1.9
0.04- 0.4
13-28
P-value
0.00
0.00
0.00
0.00
0.00
0.00
P-value is significant at level 0.05.
Anti- Nuclear Antibodies (ANA): The mean of ANA
for SLE patients 2.65 ± 0.33 was statistically highly
significant at p < 0.05 when compared to the mean of
healthy controls (0.3 ± 0.02, Table 4 and Figure 6.
Table 4: The concentration of ANA in SLE patients and healthy
control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus
nephritis
n= 13
ANA (0-1)IU/ml
Mean± SD
0.3 ± 0.14
2.65 ± 2.56
1.02 ± 0.56
2.73 ± 0.49
6.7 ± 2.4
Range
0.12 0.76
0.17 10.6
0.17 1.9
2.1 3.8
4.1 10.6
P-value
0.00
0.00
P-value is significant at level 0.05 , n: number.
Figure 6. The concentration of ANA in SLE patients and healthy
control.
Anti-double strand deoxyribonucleic acid (anti-
dsDNA): The mean concentration of anti-dsDNA for
SLE patients was 229.9 ± 243.4 IU/ml ranged 2.5 - 1020
IU/ml compared to the mean of healthy control was
10.2 ± 5.3 IU/ml ranged 2.4 -24.1 IU/ml. This
difference was statistically significant at p ≤ 0.005 as
shown in Table 5 and Figure 7.
Table 5: The concentration of anti-dsDNA in SLE patients and
healthy control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus nephritis
n= 13
Anti dsDNA ( 0-30 IU/ml)
Mean± SD
10.2 ± 5.3
229.9 ± 243.4
107.39 ± 156.57
285.90 ± 124.03
480.85±310.01
Range
2.60 -24.1
2.5 - 1020
2.50 - 876
101.40 - 580
77.90 1022.5
P-value
0.00
0.00
P-value is significant at level 0.05 , n: number.
Figure 7. Concentration of ds-DNA in SLE patients and healthy
control.
The Complements ( C3, C4 ): The result of C3 and C4
concentration in SLE patient's sera showed significant
reduction comparing to healthy control. The mean
concentration of C3 for SLE patients were 1.5 ± 0.72 g/l
ranged 0.26 3.13 while the mean concentration of C4
for SLE patients was 0.22 ± 0.24 g/l ranged 0.01- 1.5, in
compared to the mean concentration of healthy controls
were 1.65 ± 0.6 ; 0.36 ± 0.25 g/l ranged 0.4 2.64 ; o.12
1.4 respectively. This difference was high significant
p≤ 0.05; Table 6 , Figure 8 and Figure 9.
0
1
2
3
4
5
6
7
control mild progressive lupus
nephritis
ANA 0.3 1.02 2.73 6.7
concentration IU/ml
0
50
100
150
200
250
300
350
400
450
500
control mild progressive lupus
nephritis
ds-DNA 10.2 107.39 285.9 480.85
concentration IU/ml
28 Al-Hashimy N.H., Al-Masudi H.R.H., and Mahdi M.S., 2019
.
Table 6: The concentration of complements in serum of SLE
patients and healthy control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus
nephritis
n= 13
C3 (1.85 0.83) g/l
Mean±SD
1.65±0.6
1.5±0.72
1.75±0.6
1.39±0.74
1±0.71
Range
0.4-2.64
0.26-3.13
0.49-3.13
0.59-2.9
0.26-2.73
P-value
0.31
0.004
C4 (0.45 0.15) g/l
Mean±SD
0.36±0.25
0.22±0.24
0.32±0.26
0.13±0.11
0.07±0.13
Range
0.12-1.4
0.01-1.5
0.1-1.5
0.01-0.38
0.01-0.52
P-value
0.014
0.000
P-value is significant at level 0.05 , n: number.
Figure 8. Concentration of complement system (C3) in SLE
patients and healthy control .
Figure 9. Concentration of complement system (C4) in SLE
patients and healthy control .
Erythrocytes Sedimentation Rate: This study showed
that SLE disease was associated with raised ESR and the
mean was 61.75 ± 29.07 mm/h that range 20 -120 mm/h
in SLE patients when compared to healthy controls 13.8
± 5.76 mm/h range 5-30 mm/h the difference was
statically significant p ≤ 0.05 , Table 7 and Figure 10.
Table 7: The concentration of ESR in serum of SLE patients and
healthy control.
Parameter
Healthy
control
n= 30
SLE total
n= 60
Mild
n= 33
Progressive
n=14
Lupus
nephritis
n= 13
ESR (0 20) mm/h
Mean± SD
13.8±5.76
61.75±29.07
50.94±26.47
73.77±29.51
78.50±23.74
Range
5-30
20 -120
20 - 120
32 -120
38 -110
P-value
0.00
0.00
P-value is significant at level 0.05 , n: number.
Figure 10. Level of ESR in SLE patients and healthy control.
Discussion
It has been found that female of all mammalian species
have an increased incidence of
autoimmune/inflammatory disease compared to males,
and the presence of estrogen increases the severity of
autoimmune disease9.
In the current study, the demographic distribution of
data showed that SLE was teenager and old age women
less than women of fertile age (> 15 & < 45) year. This
result agreement with the results published by many
studies in Iraq and other countries10,11,12.
Calculation of SLEDAI depended mainly on the initial
primary symptom presentation that varied widely from
patient to patient and essential diagnoses test to
recognize active and inactive of SLE disease13 and the
third group is sub division from active group which
lupus nephritis .
This result show that the level of thymosin β4
significantly decrease in SLE patients compared with
healthy control, and more related with lupus nephritis.
Other study suggested that thymosin β4 decrease with
flare-up, this result agreed to other study14.
The result exhibited that low vitamin D3 level was
frequent in SLE patients, and indicated that SLE patients
had higher risk of insufficient vitamin D3. The high
prevalence of SLE patients who have vitamin D3 level
below normal was similar with most studies in the
world15.
The low level of vitamin D3 causes impaired
immunological response that is thought to increase
disease activity in SLE16. Vitamin D3 deficiency is
worldwide problem with serious health effects such as
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
control mild progressive lupus
nephritis
C3 1.65 1.75 1.39 1
concentration g/l
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
control mild progressive lupus
nephritis
C4 0.36 0.32 0.13 0.07
concentration g/l
0
10
20
30
40
50
60
70
80
control mild progressive lupus
nephritis
ESR 13.8 50.94 73.77 78.5
concentration mm/h
Sci. J. Med. Res., Vol. 3, Issue 9, pp 25- 31, Winter 2019 29
.
SLE disease and one of the most important risk factors
for immune system17.
This result show significantly decrease in SLE patients
compared with healthy control, and more related with
lupus nephritis18. After treatment receiving Ca+/Vitamin
D3 the result show increase the level of vitamin D3 and
this increasing depend on level dose, but stay the level
of vitamin D3 less than normal value19.
This study demonstrated that high titers of ANA are
most often associated with active SLE20 said this test is a
one of the most common tests used by physicians to help
diagnosis lupus is the anti-nuclear antibody (ANA) are
heterogeneous group of antibodies produced against
variety of antigens within the cell nucleus .
Antibodies to dsDNA in serum of patients are elevated
compared with the control. These results are consistent
with Ter Borg et al.21 who have found that increase in
anti-dsDNA antibody concentration prior to disease
exacerbations of SLE are part of a restricted immune
response or merely the consequence of polyclonal B cell
activation. Moreover Giasuddin et al.,22 have mentioned
that the anti dsDNA antibodies are present in 85.3% of
SLE patients .
In this result show that the level of complement (C3 and
C4) in SLE patients was significantly decreased
compared to the healthy control , and C4 level more
related with lupus nephritis ,this result is in agreement
with other reported studies23. In this studies have found a
relationship between C3 or C4 serum levels and renal
flares have discovered that C4 is critical for starting a
renal flare, while C3 activation is implicated in the
actual tissue damage24.
This result showed that increased of ESR in SLE
patients compared with healthy control, this elevation
due to inflammation causes an increase in the ESR, this
result match with25.
Conclusions
Low concentration vitamin D3 in all patients with
systemic lupus erythematosus, especially in lupus
nephritis. Positive relationship between level thymosin
b4 and concentration vitamin D3. There is an inverse
relationship between Thymosin β 4 and disease activity
index of SLE.
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