Decreased Circulating Level of Soluble Glycoprotein ... - EuroJournals
Decreased Circulating Level of Soluble Glycoprotein ... - EuroJournals
Decreased Circulating Level of Soluble Glycoprotein ... - EuroJournals
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American Journal <strong>of</strong> Scientific Research<br />
ISSN 1450-223X Issue 26(2011), pp.59-73<br />
© <strong>EuroJournals</strong> Publishing, Inc. 2011<br />
http://www.eurojournals.com/ajsr.htm<br />
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in<br />
Recurrent Miscarriage Patients<br />
Kambiz Bagheri<br />
Corresponding Author, Department <strong>of</strong> Immunology, Faculty <strong>of</strong> Medicine<br />
Kazerun Branch, Islamic Azad University, Kazerun, Iran<br />
E-mail: Bagheri_kbz@yahoo.com or kbz.bagheri@gmail.com<br />
Tel: 0098-711-8323702 or 0098-9173118066; Fax: 0098-711-8208671<br />
Padideh Ebadi<br />
Department <strong>of</strong> Biochemistry, Faculty <strong>of</strong> Medicine, Kazerun Branch<br />
Islamic Azad University, Kazerun, Iran<br />
Hossein Berenjeian Tabrizi<br />
Department <strong>of</strong> Physical Education and Sport Sciences<br />
Kazerun Branch, Islamic Azad University, Kazerun, Iran<br />
Aboozar Dehghan<br />
Department <strong>of</strong> Clinical Studies, School <strong>of</strong> Veterinary Medicine, Kazerun Branch<br />
Islamic Azad University, Kazerun, Iran<br />
Abstract<br />
Recurrent miscarriage occurs in 1–3% <strong>of</strong> women which approximately 50% <strong>of</strong> its<br />
cases remain unexplained. It is revealed that the immune system may be implicated in<br />
miscarriage. <strong>Soluble</strong> glycoprotein-130 (sgp130) as a natural inhibitor <strong>of</strong> interleukin-6 (IL-<br />
6) mediated responses has been shown to suppress several inflammatory responses. In this<br />
study, 50 variables containing socio-demographics, health-related habits, depression score,<br />
serum molecules and blood parameters besides the sgp130 level were evaluated in recurrent<br />
miscarriage women with at least three previous abortions and healthy women with natural<br />
childbirth (normal multigravida control) in order to evaluate sgp130 which might have a<br />
role in some abortions. We found that although there was no significant difference in their<br />
socio-demographics, physical activity, educational level, dietary habits, smoking or alcohol<br />
consumption, depression score and its prevalence in these patients was higher than controls.<br />
Our results showed that the patients had significantly lower level <strong>of</strong> sgp130 than controls<br />
which also remained significant after adjustment for other variables. Although there were<br />
no significant differences in their routine hematological parameters, our recently aborted<br />
patients had averagely higher post-abortion antinuclear-antibody (ANA) than the controls.<br />
None <strong>of</strong> studied parameters in miscarriage-patients, except the level <strong>of</strong> anti-annexin-V<br />
antibodies (Anti-AV) and depression score were correlated with sgp130 level. Moreover,<br />
there was a positive correlation between hookah consumption and depression status <strong>of</strong><br />
patients. A positive significant correlation was also found between the number <strong>of</strong> abortions<br />
and parameters such as age, partial-thromboplastin-time (PTT), C-reactive-protein (CRP)<br />
and rheumatoid-factor (RF) in patient group. The patients’ level <strong>of</strong> anti-double-stranded<br />
DNA antibodies (anti-dsDNA) as well as RF was correlated positively with depression
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 60<br />
score. Taken together, as a new result, we concluded that the changes <strong>of</strong> some blood<br />
parameters like the lower post-abortion level <strong>of</strong> sgp130 or higher level <strong>of</strong> some<br />
autoimmune markers along with a higher depression score may be associated with recurrent<br />
spontaneous miscarriage. Further studies are needed to determine whether the discussed<br />
changes in our parameters are a cause <strong>of</strong>, or merely a consequence <strong>of</strong> abortion event or<br />
even abortion-related depression. Thus we can summarize by saying that psychological<br />
problems, inflammation and autoimmune processes may be associated with each other and<br />
with recurrent miscarriage.<br />
Keywords: <strong>Soluble</strong> glycoprotein-130, Recurrent miscarriage, Autoantibody, Depression<br />
1. Introduction, Objectives and Aims<br />
Recurrent miscarriage is <strong>of</strong>ten defined as three or more consecutive miscarriages which occur in 1–3%<br />
<strong>of</strong> women. Recurrent miscarriage is a heterogeneous condition and approximately 50% <strong>of</strong> them remain<br />
unexplained. There are still many unresolved questions about its cause and treatment (Carrington,<br />
Sacks, & Regan, 2005). This recurrent loss <strong>of</strong> pregnancy is <strong>of</strong>ten distressing for the patients and<br />
frustrating for physicians. Recurrent miscarriage causes significant psychosocial morbidity, and for<br />
many couples the label <strong>of</strong> ‘unexplained’ is unacceptable. Overall, 75% <strong>of</strong> affected women will have a<br />
successful subsequent pregnancy, but this rate falls for older mothers and with increasing number <strong>of</strong><br />
miscarriages (Duckitt & Qureshi, 2008). The immune system has long been implicated in miscarriage.<br />
It is revealed that the level <strong>of</strong> inflammatory mediators may be as factors related to pregnancy<br />
complications including recurrent miscarriage. So far, several investigations have been conducted on<br />
the relationship between the IL-6 family members or other related molecules and the natural processes<br />
associated with fertility and pregnancy (Arruvito, Billordo, Capucchio, Prada, & Fainboim, 2009;<br />
Arslan, et al., 2004; Hattori, et al., 2007). On the other hand, there are some studies which show that<br />
most women with habitual abortion <strong>of</strong> unknown etiology have a higher level <strong>of</strong> autoreactivity, which<br />
may affect the course <strong>of</strong> pregnancy. Indeed, there are several evidences which help us to confirm the<br />
association <strong>of</strong> autoimmune and psychological problems. Moreover, in the respect <strong>of</strong> inflammation,<br />
available evidence is consistent with three causal pathways: depression to inflammation, inflammation<br />
to depression, and bidirectional relationships (Howren, Lamkin, & Suls, 2009). For example, an<br />
activation <strong>of</strong> inflammatory response may occur in depression (Maes, et al., 1997; Song, et al., 1998).<br />
Thus, we can summarize by saying that inflammation and autoimmune processes may be<br />
associated with abortion and on the other hands, both processes <strong>of</strong> autoimmune and inflammation is<br />
known that can be associated with depression and psychological problems. Also, other factors such as<br />
coagulation disorders, blood sugar and homocysteine (Hcy) level related problems can also be effective<br />
in causing abortion. In this regard, some other factors related to socio-demographic information or<br />
health-related lifestyle habits are noteworthy and thus their assessment in miscarriage patients could be<br />
helpful.<br />
It will be interesting to simultaneously evaluate the relationship between three major<br />
components which mentioned above (i.e., inflammation, autoimmunity and depression) along with the<br />
socio-demographic and health-related lifestyle information in miscarriage patients.<br />
Therefore, sgp130 as a natural inhibitor <strong>of</strong> IL-6 mediated inflammatory responses was selected.<br />
CRP was also studied as another inflammatory marker. Probable abortion related autoimmune markers<br />
were including ANA, anti-dsDNA, anti-AV, anti-laminin-1, anticardiolipin antibodies (aCLA), lupus<br />
anticoagulants (LACs) and RF. Depression was assessed with the Beck's depression Inventory (BDI).<br />
Socio-demographics and health-related lifestyle habits were also comprised <strong>of</strong> 27 separate components.<br />
sgp130 as a natural inhibitor or antagonist <strong>of</strong> IL-6 / soluble IL-6 receptor (sIL-6R) complex<br />
contributes to resolution <strong>of</strong> acute inflammatory response and also transition between acute and chronic<br />
inflammatory reaction (Augustyniak, Majkowska-Skrobek, Basiewicz-Worsztynowicz, & Jankowski,
61 Kambiz Bagheri, Padideh Ebadi, Hossein Berenjeian Tabrizi and Aboozar Dehghan<br />
2006). Indeed, sgp130 selectively inhibits IL-6 trans-signaling and thus is the natural inhibitor <strong>of</strong> IL-6<br />
responses dependent on sIL-6R (Jostock, et al., 2001).<br />
The main purpose <strong>of</strong> this study was to test if recurrent miscarriage is associated with a different<br />
level <strong>of</strong> sgp130 after adjusting for other variables. As well as, in this study the relationship between<br />
many factors such as socio-demographic information, health-related lifestyle habits, history <strong>of</strong><br />
pregnancy loss or abortion, depression status, the level <strong>of</strong> several autoantibodies, some coagulation<br />
parameters, the level <strong>of</strong> Hcy, glucose challenge test (GCT), fasting blood sugar (FBS), CRP and RF<br />
with themselves and with sgp130, has been evaluated.<br />
2. Research Materials and Methods<br />
2.1. Miscarriage Patients and Control Group<br />
We studied 42 unrelated recurrent miscarriage women with at least three previous abortions which<br />
were not under therapy. Some exclusion criteria were hematological malignancies, viral infections,<br />
pulmonary disorders and documented sepsis. 42 healthy age matched women with natural childbirth<br />
(normal multigravida control) were also randomly selected as controls. The healthy controls were free<br />
<strong>of</strong> any acute and chronic disease or apparent illnesses and also any history <strong>of</strong> psychiatric diseases or<br />
pregnancy loss. Informed consent was obtained from all the participants.<br />
2.2. Detection <strong>of</strong> ANA and Anti-dsDNA Antibody<br />
The presence <strong>of</strong> ANA and anti-dsDNA antibodies was determined by ELISA (Aesku.lab, Aesku<br />
Diagnostics, Wendelsheim,Germany).<br />
2.3. Detection <strong>of</strong> Anti-AV and Anti-Laminin-1 Antibodies<br />
<strong>Level</strong>s <strong>of</strong> circulating IgG/IgM antibodies directed against annexin V as well as IgG antibodies against<br />
laminin-1 were determined by their respective ELISA kit (Aesku.lab, Aesku Diagnostics,<br />
Wendelsheim,Germany).<br />
2.4. Total Hcy <strong>Level</strong> Measurement<br />
Fasting total plasma L-homocysteine was measured by Axis® Homocysteine enzyme Immunoassay kit<br />
(Axis-Shield Diagnostics Ltd., The Technology Park Dundee DD2 1XA. United Kingdom). All<br />
samples were run at the same time to minimize assay variability.<br />
2.5. Detection <strong>of</strong> Serum CRP and RF<br />
The acute-phase inflammatory response was assessed by determining the serum level <strong>of</strong> CRP in a highsensitive<br />
approach (HS-CRP) by photometry method (Dade Behring, Deerfield, USA). The serological<br />
status for RF was performed using a latex semi-quantitative kit (ENiSon, ENiSon Lab, Tehran, Iran).<br />
2.6. Detection <strong>of</strong> aCLA<br />
Plasma concentration <strong>of</strong> aCLA were performed using the standard aCL ELISA kit (Orgentec<br />
Diagnostika GmbH, Mainz, Germany), which recognises the sum <strong>of</strong> IgG, IgM and IgA class anti-<br />
Cardiolipin autoantibodies.<br />
2.7. Measurement <strong>of</strong> LAC<br />
All patient samples were measured with the “classic” LAC assays, notably a partial thromboplastin<br />
time – lupus anticoagulant (PTT-LA) (PTT-LA kit, Diagnostica Stago, Asnieres, France). LACs are<br />
antibodies detected based on their ability to prolong phospholipid dependent coagulation reactions.
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 62<br />
Indeed lupus anticoagulants exert an inhibitory effect on phospholipids, which are normally required in<br />
some clotting tests such as activated partial thromboplastin time (APTT). The presence in the test<br />
plasma <strong>of</strong> lupus anticoagulants prolongs the clotting time.<br />
2.8. Coagulation Tests<br />
Functional protein S and C levels were measured using the STA®-Staclot® Protein S kit and C kit<br />
(Diagnostic Stago, France) according to the manufacturer’s instructions. Antithrombin activity (AT)<br />
level in plasma was quantitated using the STA®-Stachrom® AT III kit (Diagnostic Stago, France) by a<br />
synthetic chromogenic substrate method. Prothrombin time (PT) was also measured using the<br />
NEOPLASTIN® CI kit (Diagnostic Stago, France). The result <strong>of</strong> the PT test was reported as the<br />
international normalized ratio (INR) which is the ratio <strong>of</strong> a patient’s prothrombin time to a normal<br />
control sample.<br />
2.9. Measurement <strong>of</strong> FBS and GCT Value<br />
FBS test were done on fresh samples. But GCT value was noted from medical records <strong>of</strong> patients,<br />
which had been performed between the 24th and 28th weeks <strong>of</strong> gestation.<br />
2.10. Hematological Studies<br />
A complete blood count (CBC) with differential was done on the hematology counter (Coulter Sysmex<br />
K1000 machine). ESR was also measured by Westergren method.<br />
2.11. Assessment <strong>of</strong> Depression Status<br />
Depression score was measured using the Persian translated and validated version <strong>of</strong> the BDI<br />
(Ghassemzadeh, Mojtabai, Karamghadiri, & Ebrahimkhani, 2005), the suggested cut-<strong>of</strong>f values <strong>of</strong><br />
which are classified in table 1. The BDI-(Persian) contained a full 21-item, self-report questionnaire,<br />
which the severity <strong>of</strong> each item, scores between 0 (indicating no depressive symptomatology) and 3<br />
(indicating a severe level <strong>of</strong> symptomatology), with possible total scale score ranging from o to 63.<br />
Table 1: Suggested classified cut-<strong>of</strong>f values for the BDI assessment<br />
Test scores Depression status Alphabetical grouping<br />
0-10 No depression A<br />
11-16 Mild depression B<br />
17-20<br />
Mild to moderate depression-require consultation with the<br />
C<br />
psychologist<br />
21-30 Moderate depression D<br />
31-40 Severe depression E<br />
41-63 Severe depression-require hospitalization F<br />
Information on depressed mood and the intensity <strong>of</strong> depression in the recruited subjects was<br />
obtained using the BDI-Persian. A score <strong>of</strong> 17 and more indicates a clinically significant depression.<br />
2.12. Questionnaires<br />
A team <strong>of</strong> interviewers, who received training, completed questionnaires consisting <strong>of</strong> variables, all <strong>of</strong><br />
which were defined as quantitative values (Table 2). All the discussed variables in the questionnaires<br />
along with all the measured factors and laboratory parameters were 50 variables.
63 Kambiz Bagheri, Padideh Ebadi, Hossein Berenjeian Tabrizi and Aboozar Dehghan<br />
2.13. Measurement <strong>of</strong> Sgp130 <strong>Level</strong><br />
The serum sgp130 levels were assessed in triplicate by a commercial human specific sandwich ELISA<br />
kit (Quantikine, R&D Systems Inc, Minneapolis, MN, USA), according to the manufacturer’s<br />
guidelines. The detection limit <strong>of</strong> the sgp130 ELISA was less than 0.05 ng/ml.<br />
2.14. Statistical Analysis<br />
The statistical significant <strong>of</strong> differences between cases and controls were calculated by the<br />
independent-samples T test and the differences at p values
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 64<br />
r= -0.321, p=0.038) even after controlling for their age and body weight, so that more depressed<br />
patients had a lower level <strong>of</strong> sgp130.<br />
Partial correlation analysis with the control <strong>of</strong> age and weight in our study showed that there is<br />
a positive independent correlation between hookah consumption and depression status <strong>of</strong> recently<br />
aborted women (Figure 2D, r= +0.398, p=0.009). Thus, our obtained results showed that depression <strong>of</strong><br />
these patients has a direct association with some habits like hookah consumption.<br />
A positive significant correlation was found between the number <strong>of</strong> abortions and parameters<br />
such as age (Figure 2E, r= +0.468, p=0.002), partial-thromboplastin-time (PTT) (Figure 2G, r= -0.348,<br />
p=0.024), C-reactive-protein (CRP) (r= +0.519, p=0.00) and rheumatoid-factor (RF) (r= +0.586,<br />
p=0.00) in patient group.<br />
We also found that a significant higher gestational glucose-challenge-test (GCT) value is<br />
observed in our patients recorded histories (Figure 1C, p
65 Kambiz Bagheri, Padideh Ebadi, Hossein Berenjeian Tabrizi and Aboozar Dehghan<br />
The independent samples T test and the Chi-square test were used to analyze our data in the<br />
study and to evaluate the significance <strong>of</strong> the difference between the two groups. P values >0.05 were<br />
considered as non-significant (NS) and p values
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 66<br />
Figure 2: Some <strong>of</strong> the important relationships between patient variables illustrated by scatter plots<br />
Scatter plots was drawn and overlaid with fitted regression lines (with 95% confidence<br />
intervals) to illustrate how the plotted parameters were positively or negatively correlated. All <strong>of</strong> the<br />
above significant correlations were still significant after adjustment for covariates.<br />
4. Discussion<br />
The sgp130 is the natural inhibitor <strong>of</strong> trans-signaling mediated by the soluble IL-6/IL-6R complex<br />
which has been shown to suppress several inflammatory responses.<br />
50 variables containing socio-demographics, health-related habits, depression, serum molecules<br />
and blood parameters besides the sgp130 level were evaluated in recurrent miscarriage women with at<br />
least three previous abortions and healthy women with natural childbirth in order to evaluate sgp130<br />
which might have a role in some abortions.<br />
Our results showed that patients with recurrent spontaneous miscarriage have significantly<br />
decreased plasma levels <strong>of</strong> sgp130 compared to those with normal. Correlation analysis between<br />
sgp130 level and all other variables in our patient group showed that the level <strong>of</strong> this natural inhibitor<br />
<strong>of</strong> IL-6 responses has a negative correlation with depression status and also the level <strong>of</strong> anti-AV even<br />
after controlling for their age and body weight. Some evidences suggested that anti-AV antibodies may<br />
be associated with recurrent pregnancy losses (Matsubayashi, et al., 2001).<br />
The sgp130 is a natural inhibitor <strong>of</strong> IL-6 mediated inflammatory responses. There are several<br />
studies on the relationship between the IL-6 family members and pregnancy (Arruvito, et al., 2009;<br />
Arslan, et al., 2004; Hattori, et al., 2007). The immune system contributes to the outcome <strong>of</strong> pregnancy<br />
by complex immunological interactions. For example, T helper 1 (Th1) cytokines TNF-alpha and IFNgamma<br />
could cause inflammation and together are thought to threaten the maintenance <strong>of</strong> pregnancy<br />
(Knackstedt, et al., 2003). Some evidences support a role <strong>of</strong> the immune system in the first trimester<br />
pregnancy and hypothesize that missed abortion may be associated with an enhanced Th1 reactivity,<br />
whereas threatened abortion with good outcome resembles the normal pregnancy with a non-enhanced<br />
Th1 reactivity (Paradisi, Porcu, Venturoli, Maldini-Casadei, & Boni, 2003). It is shown that IL-6<br />
produced not only by immunocompetent cells such as macrophages and mast cells, but also by<br />
trophoblasts and decidua cells, is directly involved in the pathology <strong>of</strong> abortion (Zenclussen, et al.,<br />
2003). It has been proposed that serum TNF-alpha and IL-6 could be related to the pregnancy loss
67 Kambiz Bagheri, Padideh Ebadi, Hossein Berenjeian Tabrizi and Aboozar Dehghan<br />
(Arslan, et al., 2004). Some other authors found significant differences between IL-6 levels in nonpregnant<br />
recurrent spontaneous miscarriage women before and after lymphocyte immunotherapy and<br />
showed that the alloimmunization with paternal white cells leads the serum IL-6 and sIL-6R levels to<br />
the values observed in the course <strong>of</strong> normal pregnancy (Zenclussen, Kortebani, Mazzolli, Margni, &<br />
Malan Borel, 2000). Moreover it has been revealed that both IL-6 and IL-8 in cervical mucus collected<br />
at 4-5 weeks' gestation are significantly higher in patients who have a history <strong>of</strong> two or more<br />
unexplained consecutive first trimester miscarriages and aborted subsequently than in those who had a<br />
live birth and thus might have predictive value for cases <strong>of</strong> recurrent miscarriage (Hattori, et al., 2007).<br />
It is also reported that in comparison with fertile women, those with recurrent spontaneous abortion<br />
show significantly increased levels <strong>of</strong> sIL-6R and IL-6 (Arruvito, et al., 2009). In addition to abortion<br />
process, theses cytokines may also involve in infertility or some other reproductive failures. For<br />
example, altered secretion <strong>of</strong> sgp130 may be observed in patients with primary unexplained infertility.<br />
The sgp130 secretion is greatly increased during a normal menstrual cycle and infertile patients show<br />
reduced secretion <strong>of</strong> sgp130 compared with fertile controls (Sherwin, Smith, Wilson, & Sharkey,<br />
2002). Other results suggest that the balance between sgp130 and its membrane-bound form may play<br />
an important role in regulating cytokine action necessary for blastocyst implantation (Classen-Linke,<br />
Muller-Newen, Heinrich, Beier, & von Rango, 2004). IL-6 and sIL-6R may also contribute to the<br />
pathogenesis <strong>of</strong> endometriosis-associated infertility (Yoshida, et al., 2004). Polycystic Ovary<br />
Syndrome (PCOS) as other cause <strong>of</strong> female infertility, are characterized by an increased sgp130<br />
(Nikolajuk, et al.). It is also reported that serum sIL-6R and sgp130 levels could be related to the<br />
development <strong>of</strong> pregnancy induced hypertension (Y. Li, Wang, & Qi, 2001). According to another<br />
study, IL-2 and IL-6 levels are significantly higher in women with pre-eclampsia as compared to those<br />
<strong>of</strong> healthy pregnant women (Dimitrakova, Milchev, Batashki, & Karumanchi, 2007).<br />
All the above reports, confirmed our observations about the lower post-abortion level <strong>of</strong> sgp130<br />
in recurrent miscarriage women. Indeed, the reduced levels <strong>of</strong> sgp130 as a natural inhibitor <strong>of</strong> IL-6<br />
responses cause changing the balance <strong>of</strong> IL-6 related network in these women and thereby could be<br />
related to spontaneous abortion and might have predictive value for some cases <strong>of</strong> recurrent<br />
miscarriage. Our reported serum values for sgp130 in patients and controls in this study are consistent<br />
with those reported by other researchers for some people with relatively similar conditions (Giuliani, et<br />
al., 2001; Y. Li, et al., 2001).<br />
There are some reports that the sgp130 level was not significantly different in the blood <strong>of</strong><br />
pregnant and non-pregnant women. On the other hand, matching the time sampling <strong>of</strong> all pregnant<br />
women was a problem for us. Also, it is clear that the final outcome <strong>of</strong> a pregnancy is not known until<br />
the end <strong>of</strong> period. Thus we decided that examine the levels <strong>of</strong> sgp130 in recurrent miscarriage women<br />
with at least three previous abortions and healthy women with natural childbirth.<br />
Our study about the several autoantibodies in miscarriage patients lead also to some interesting<br />
results. We found that beside the higher level <strong>of</strong> ANA in these women, more depressed patients had<br />
higher level <strong>of</strong> anti-dsDNA and RF. We also found that women who had greater frequency <strong>of</strong> abortions<br />
had higher level <strong>of</strong> CRP and RF.<br />
There are some studies which show that most women with unexplained habitual abortion have a<br />
higher level <strong>of</strong> autoreactivity. For example, the incidence <strong>of</strong> anti-smooth muscle antibody in women<br />
with habitual abortion <strong>of</strong> unknown etiology is increased compared with normal multigravida control<br />
(Q. Li, Li, & Tian, 1998). In a previous study using western blotting the women with primary<br />
unexplained infertility and those with secondary unexplained recurrent miscarriage had a significantly<br />
higher prevalence <strong>of</strong> autoantibodies (el-Borai, et al., 1988). A first early pregnancy loss may be<br />
associated with increased levels <strong>of</strong> several autoantibodies (Gris, et al., 2003). It is also reported that in<br />
women with autoimmune disorders, a history <strong>of</strong> recurrent pregnancy loss is independently associated<br />
with reactivity against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) and also with the<br />
presence <strong>of</strong> antithyroglobulin antibodies, suggesting that cumulative autoimmune responses against<br />
these non-organ-specific and organ-specific antigens correlate with the risk <strong>of</strong> stillbirth and<br />
spontaneous abortion (Mavragani, Ioannidis, Tzioufas, Hantoumi, & Moutsopoulos, 1999). Some other
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 68<br />
evidences indicate that antiphospholipid antibodies which are a family <strong>of</strong> autoantibodies including<br />
lupus anticoagulant and anticardiolipin, induce thrombosis and pregnancy complications including<br />
recurrent stillbirth, recurrent miscarriage, pre-eclampsia and intra-uterine growth retardation (Chamley,<br />
1997). The results <strong>of</strong> previous studies indicate that human aCL IgG that are beta2-GPI independent can<br />
induce placental necrosis and fetal loss in BALB/c mice (Ikematsu, et al., 1998). Recent evidence<br />
shows that anti-AV and anti-beta2-GPI antibodies should be regarded as independent risk markers<br />
(Zammiti, et al., 2006). Recently, it is reported that the presence <strong>of</strong> IgG anti-laminin-1 antibodies in the<br />
blood is significantly associated with recurrent first-trimester miscarriages and subsequent negative<br />
pregnancy outcomes. Thus, anti-laminin-1 antibodies may be important in the development <strong>of</strong><br />
autoimmune-mediated reproductive failures (Inagaki, Kondo, Lopez, Shoenfeld, & Matsuura, 2005).<br />
Some results have been shown that women with recurrent spontaneous abortion <strong>of</strong> unknown etiology<br />
are differed in some parameters <strong>of</strong> immune response such as higher incidence <strong>of</strong> antinuclear antibodies<br />
in comparison with nonpregnant normal multigravidas (Malinowski, et al., 1997). There are some<br />
reports about the presence <strong>of</strong> ANA+ serum in abortion cases (Kano, Shimizu, & Kanda; Ticconi, et<br />
al.). Based on a previous study, the frequency <strong>of</strong> positive tests for ANA was significantly higher in<br />
Kuwaiti patients with unexplained recurrent spontaneous abortions (13.6%) than in controls (1.2%).<br />
No difference was found between first and second trimester aborters in the frequency <strong>of</strong> ANA positive<br />
tests. However, secondary aborters had significantly higher frequency <strong>of</strong> ANA (Bahar, Alkarmi,<br />
Kamel, & Sljivic, 1993). In other study on the prevalence <strong>of</strong> ANA in healthy women with first<br />
trimester recurrent spontaneous abortion, it was reported that only 13.2% <strong>of</strong> them had low levels <strong>of</strong><br />
antinuclear antibodies, none <strong>of</strong> which were specific. Thus the reported prevalence <strong>of</strong> ANA in these<br />
group was low (Eroglu & Scopelitis, 1994). But another study reported a high prevalence <strong>of</strong> ANA in<br />
the patients with habitual abortion (30%) as compared with the control group (6.6%) (Garcia-De La<br />
Torre, Hernandez-Vazquez, Angulo-Vazquez, & Romero-Ornelas, 1984). One recent study in 2010<br />
reported that ANA could be <strong>of</strong> some value in identifying women with recurrent pregnancy loss (RPL)<br />
with potential, although still not fully defined, immune abnormalities. It was reported that antinuclear<br />
antibodies at titers >/= 1:80 were detected in 50% women with RPL and in 16% control women.<br />
Elevated ANA titers (>/=1:180) were detected only in RPL women, whereas all control women had<br />
ANA titers no greater than 1:80. No differences in ANA positivity could be detected according to the<br />
type (primary or secondary) or number (>2 versus >/=3) <strong>of</strong> losses (Ticconi, et al.). According to a<br />
study about the outcome <strong>of</strong> pregnancy in ANA positive women, the perinatal mortality rate in the<br />
ANA-positive group was 18.6%, while there were no perinatal deaths in the ANA-negative control<br />
group. But ANA titer did not also correlate with the outcome <strong>of</strong> the pregnancy (Kiuttu, Hartikainen,<br />
Makitalo, & Ruuska, 1994). In other study results demonstrated a high prevalence <strong>of</strong> low-titer ANApositive<br />
serum in patients with both explained (34.3%) and unexplained (51.5%) pregnancy losses in<br />
compare with healthy pregnant (6.8%) and nonpregnant women (5.6%) (Malinowski, et al., 1994). A<br />
review <strong>of</strong> pregnancy outcome by another study indicated that maternal antinuclear antibodies are not,<br />
in general, associated with abnormalities <strong>of</strong> the pregnancy or <strong>of</strong> the <strong>of</strong>fspring (Rosenberg, Bingham, &<br />
Fong, 1986). In a more recent study on the Argentine women, there was also no significant difference<br />
between the prevalence <strong>of</strong> ANA in fertile controls and patients with recurrent pregnancy loss with<br />
ANA (Bustos, et al., 2006). In other report it was demonstrate that women with recurrent spontaneous<br />
abortions showed significantly higher incidence <strong>of</strong> antibodies to phospholipids than normal<br />
multigravida controls. In contrast, the incidence <strong>of</strong> antibodies to polynucleotides and histones was not<br />
different between these two groups (Kwak, Gilman-Sachs, Beaman, & Beer, 1992).<br />
All these mentioned evidences could help us to confirm the higher level <strong>of</strong> autoreactivity in our<br />
miscarriage patients.<br />
There are some evidences which help to confirm our results regarding to higher score and<br />
prevalence <strong>of</strong> depression in miscarriage patients. For example it is reported that abortion may be a risk<br />
factor for subsequent depression in the period <strong>of</strong> 8 years after the pregnancy event (Cougle, Reardon,<br />
& Coleman, 2003). A number <strong>of</strong> studies have discussed about the relationship between abortion and<br />
depression (Rees & Sabia, 2007). For example in one report, the depression score for recurrent
69 Kambiz Bagheri, Padideh Ebadi, Hossein Berenjeian Tabrizi and Aboozar Dehghan<br />
miscaririag women and non-miscarriage group was 27.6+/-8.8 and 19.4+/-7.1 respectively (Andalib,<br />
Rezaie, Oreizy, Shafiei, & Baluchi, 2006).<br />
Our study about the depression status <strong>of</strong> miscarriage patients lead to some interesting results.<br />
We found that beside the higher average <strong>of</strong> depression score in these women, more depressed patients<br />
had higher level <strong>of</strong> anti-dsDNA and RF but lower level <strong>of</strong> sgp130. Also surprising that, more depressed<br />
patients, averagely more smoke hookah but had not more abortion number.<br />
Taken together these results showed that the lower post-abortion level <strong>of</strong> sgp130 or higher level<br />
<strong>of</strong> some autoimmune markers may become simply a consequence <strong>of</strong> higher depression which in turn<br />
may be related to unpleasant abortive occurrence or some habits like hookah consumption.<br />
Indeed high level <strong>of</strong> several autoantibodies like ANA or anti-dsDNA as well as CRP or RF in<br />
some miscarriage cases may be an outcome <strong>of</strong> depression which resulting from recurrent miscarriage<br />
as one <strong>of</strong> the most horrible event <strong>of</strong> women's life.<br />
There are several reports about the association <strong>of</strong> psychological disorders and autoimmune<br />
processes. For example it is reported that Immune dysregulation is common in depressive patients and<br />
also depressive symptoms have been found at a high prevalence in autoimmune disease. Recent studies<br />
have found that autoantibodies play an important role in the pathogenesis <strong>of</strong> depression both in animal<br />
models and human. It is suggested that depression can be regarded as autoimmune disease caused by<br />
various autoantibodies (Chen, Jiang, Ouyang, & Chen, 2009). For example it is believed that<br />
postpartum depression may have an autoimmune etiology (Gleicher, 2007). Major depression may be<br />
also accompanied by systemic immune activation or an inflammatory response with higher<br />
autoantibody (antinuclear, antiphospholipid) titers (Maes, 1995). Some groups had also reported higher<br />
titers <strong>of</strong> autoantibodies in depressed subjects than in normal controls. Meanwhile those observations<br />
pointed towards a higher expression <strong>of</strong> antiphospholipid antibodies during depression but a much<br />
lower incidence <strong>of</strong> positive patients than in classical autoimmune disorders, such as SLE (Maes, et al.,<br />
1993). It is also reported that in the patients with major depression, the frequency <strong>of</strong> some elevated<br />
autoantibodies like ANA are significantly higher than in the control group. In addition, in the<br />
schizophrenic patients significantly more <strong>of</strong>ten showed increased levels <strong>of</strong> ANA. These results point<br />
towards the existence <strong>of</strong> an unspecific autoimmune disposition or reaction in at least a subgroup <strong>of</strong><br />
patients with major depression and schizophrenia (Laske, et al., 2008).<br />
Our results about the lower post-abortion level <strong>of</strong> sgp130 as a probable consequence <strong>of</strong> their<br />
higher depression are along with the previous evidences.<br />
For example, it is showed that elevated circulating pro-inflammatory cytokines are associated<br />
with symptoms <strong>of</strong> depression, and disorders involving chronic inflammation are <strong>of</strong>ten co-morbid with<br />
major depression (Dhabhar, et al., 2009). Some evidence also indicates that an immune response with<br />
an increased production <strong>of</strong> proinflammatory cytokines <strong>of</strong>ten accompanies major depression.<br />
Indeed, depression and IL-6 are positively associated in clinical and community samples<br />
(Howren, et al., 2009). Some other evidences suggest that there is an activation <strong>of</strong> the immuneinflammatory<br />
response system in depression. For example it is reported that serum IL-6 are<br />
significantly higher in subjects with major depression than in normal controls (Maes, et al., 1997;<br />
Song, et al., 1998). It was hypothesized that the elevated IL-6 levels during the acute state <strong>of</strong><br />
depression or schizophrenia may reflect an unspecific stress response (Frommberger, et al., 1997).<br />
Although, other study showed that IL-6 and the sIL-6R are decreased in cerebrospinal fluid <strong>of</strong> geriatric<br />
patients with major depression. In this study, the level <strong>of</strong> sgp130 had no statistically significant<br />
difference between patients and controls (Stubner, et al., 1999). Other new study indicates an<br />
association between increased levels <strong>of</strong> IL-6 with depressive symptomatology in elderly individuals<br />
(Dimopoulos, Piperi, Psarra, Lea, & Kal<strong>of</strong>outis, 2008). New evidences suggest that higher plasma IL-6<br />
activity is associated with the refractoriness <strong>of</strong> depression (Yoshimura, et al., 2009). Recently, It has<br />
been also revealed that depression in cancer is associated with increased plasma IL-6 concentrations<br />
(Jehn, et al.). Moreover, a direct correlation between BDI (symptoms <strong>of</strong> depression) and IL-6 levels<br />
has been found in other patients such as those on maintenance haemodialysis (Hung, et al.).
<strong>Decreased</strong> <strong>Circulating</strong> <strong>Level</strong> <strong>of</strong> <strong>Soluble</strong> <strong>Glycoprotein</strong>-130 in Recurrent Miscarriage Patients 70<br />
Thus, all these evidences could confirm which lower sgp130 in patients may be a probable<br />
consequence <strong>of</strong> their higher depression.<br />
5. Summary and Concluding Remarks<br />
Taken together, indeed, as a new result, we found that the changes <strong>of</strong> some blood parameters like the<br />
lower post-abortion level <strong>of</strong> sgp130 or higher level <strong>of</strong> some autoimmune markers along with a higher<br />
depression score may be associated with recurrent spontaneous abortion. To our knowledge, this study<br />
is also relatively novel in that it simultaneously examines the relationship between serum sgp130 levels<br />
in recurrent miscarriage patients and their autoantibody titers, some coagulation parameters, the level<br />
<strong>of</strong> Hcy, GCT, FBS, CRP and RF as well as the socio-demographic, psychological, environmental,<br />
dietary, laboratory, smoking and lifestyle parameters all <strong>of</strong> which were intelligently defined as<br />
quantitative values.<br />
Further studies are needed to determine whether the discussed changes in our parameters are a<br />
cause <strong>of</strong>, or merely a consequence <strong>of</strong> their abortion event or even abortion-related depression. Further<br />
studies are also required to justify the role <strong>of</strong> sgp130 in recurrent miscarriage.<br />
Thus we can summarize by saying that psychological problems, inflammation and autoimmune<br />
processes may be associated with each other and with recurrent abortion.<br />
Hopefully, these additional information and knowledge provided will, before long, lead to more<br />
successful treatment and improved outcome in miscarriage women.<br />
Acknowledgments<br />
The authors would like to thank Islamic Azad University, Kazerun Branch for their financial and other<br />
support as well as Dr. Parvin Javad Baghdasar (from Molavi clinical Laboratory, Shiraz, Iran), for her<br />
assistance with data collection and patient referrals.<br />
Conflict <strong>of</strong> interest: None declared.<br />
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