Document Detail

Effect of pregnancy on serum cytokines in SLE patients.
Jump to Full Text
MedLine Citation:
PMID:  22417776     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: The aim of this study was to evaluate an extensive panel of cytokines involved in immune regulation during pregnancy in patients with systemic lupus erythematosus (SLE) and in healthy women.
METHODS: A total of 47 consecutive successful pregnancies in 46 SLE patients and 56 pregnancies in 56 matched healthy subjects, as controls, were prospectively studied. Serum interleukin (IL)-1-α, IL-1-β, IL-2, IL-6, IL-8, IL-10, IL-12p70, interferon (INF)-γ and tumor necrosis factor (TNF)-α were detected in sera obtained at the first and third trimester of pregnancy by a highly sensitive, multiplexed sandwich ELISA.
RESULTS: Medians (pg/ml) of serum levels of most helper T (Th)1-type cytokines were significantly lower in the third trimester compared with those observed in the first trimester of pregnancy in healthy women: INF-γ 2.0 vs 3.4, TNF-α 10.2 vs 11.5, IL-1-α 0.9 vs 1.1, IL-1-β 0.6 vs 1.0, IL-2 3.0 vs 3.5, and IL-12p70 4.9 vs 5.6 (P-values < 0.02 for all). By contrast, only the IL-1-α serum levels were lower in the third trimester compared with the first trimester in SLE patients (P = 0.006). IFN-γ/IL-6 and IFN-γ/IL-10 ratios were higher in controls than in SLE (P = 0.002, and P = 0.001, respectively); moreover, they were significantly reduced in the third compared to the first trimester of pregnancy in healthy women, but not in SLE.
CONCLUSIONS: In SLE patients, Th1/Th2 cytokine serum level ratio does not decrease during pregnancy progression as much as in healthy pregnant women. This could account for the observation of a low frequency of disease flares in the third trimester of gestation.
Authors:
Andrea Doria; Maurizio Cutolo; Anna Ghirardello; Margherita Zen; Danilo Villalta; Angela Tincani; Leonardo Punzi; Luca Iaccarino; Michelle Petri
Related Documents :
19880086 - Use of herbal preparations during pregnancy: focus group discussion among expectant mot...
23830106 - Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovu...
7200646 - Machakos project studies. agents affecting health of mother and child in a rural area o...
19235556 - Lumbopelvic pain associated with catastrophizing and fear-avoidance beliefs in early pr...
20701506 - The management of reduced fetal movements in an uncomplicated pregnancy at term: result...
19407526 - Infectious complications of pregnancy termination.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-14
Journal Detail:
Title:  Arthritis research & therapy     Volume:  14     ISSN:  1478-6362     ISO Abbreviation:  Arthritis Res. Ther.     Publication Date:  2012  
Date Detail:
Created Date:  2012-09-18     Completed Date:  2013-05-21     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101154438     Medline TA:  Arthritis Res Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  R66     Citation Subset:  IM    
Affiliation:
Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, Padova, 35128, Italy. adoria@unipd.it
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Biological Markers / blood
Cohort Studies
Cytokines / blood*
Female
Humans
Lupus Erythematosus, Systemic / epidemiology,  immunology*,  pathology
Pregnancy
Pregnancy Complications / epidemiology,  immunology*
Prospective Studies
Th1 Cells / metabolism
Th2 Cells / metabolism
Young Adult
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Cytokines
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Arthritis Res Ther
Journal ID (iso-abbrev): Arthritis Res. Ther
ISSN: 1478-6354
ISSN: 1478-6362
Publisher: BioMed Central
Article Information
Download PDF
Copyright ©2012 Doria et al.; licensee BioMed Central Ltd.
open-access:
Received Day: 2 Month: 8 Year: 2011
Revision Received Day: 7 Month: 3 Year: 2012
Accepted Day: 14 Month: 3 Year: 2012
Print publication date: Year: 2012
Electronic publication date: Day: 14 Month: 3 Year: 2012
Volume: 14 Issue: 2
First Page: R66 Last Page: R66
ID: 3446434
Publisher Id: ar3782
PubMed Id: 22417776
DOI: 10.1186/ar3782

Effect of pregnancy on serum cytokines in SLE patients
Andrea Doria1 Email: adoria@unipd.it
Maurizio Cutolo2 Email: mcutolo@unige.it
Anna Ghirardello1 Email: anna.ghirardello@unipd.it
Margherita Zen1 Email: margimeg@libero.it
Danilo Villalta3 Email: danilo.villalta@aopn.fvg.it
Angela Tincani4 Email: tincani@bresciareumatologia.it
Leonardo Punzi1 Email: leonardo.punzi@unipd.it
Luca Iaccarino1 Email: luca.iaccarino@unipd.it
Michelle Petri5 Email: mpetri@jhmi.edu
1Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani 2, Padova, 35128, Italy
2Research Laboratory and Academic Unit of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV 6, Genova, 16132, Italy
3Hospital S. Maria degli Angeli, Via Montereale 24, Pordenone, 33170, Italy
4Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Piazza Spedali Civili 1, Brescia, 25123, Italy
5Division of Rheumatology and Immunology, Johns Hopkins University School of Medicine, North Wolfe Street 600, Baltimore, MD 21287, USA

Introduction

Cytokines play an important role in the pathogenesis of systemic lupus erythematosus (SLE), and their balance seems to affect disease activity [1].

Cytokines produced by CD4+ helper T (Th) cells have been traditionally subdivided into Th1 and Th2 repertoires. The former includes interferon (IFN)-γ, interleukin (IL)-1, IL-2, IL-12, and tumor necrosis factor (TNF)-α, which stimulate cellular immunity, and the latter includes IL-4, IL-5, IL-6 and IL-10, which induce humoral immunity and antibody production [2].

The Th1/Th2 paradigm has recently been overcome by identification of novel Th families, including Th9, Th17 and Th22, with their signature cytokines [3]. In addition, some cytokines considered in the Th1 or Th2 profiles can also be produced by other immune cells. Despite this caveat, the Th1/Th2 cytokine pattern remains an effective, although over-simplistic, model of representing the intricate relationship between immune abnormalities characteristic of autoimmune rheumatic diseases and immune regulatory changes induced by pregnancy.

In SLE, an overproduction of Th2 cytokines, which results in B-cell hyperactivity, has been demonstrated [4] and SLE is thought to be mainly a Th2-driven autoimmune disease. However, abnormalities in Th1 cytokine production are also involved in the pathogenesis of SLE [5].

Pregnancy is a physiological condition during which important changes occur in the maternal immune and endocrine systems [6]. The most important change seems to be the Th2 polarization in maternal immune response, due to a progressive increase in estrogen and progesterone serum levels during pregnancy [7-9].

At high levels, as those achieved during pregnancy, estrogens and progesterone inhibit the secretion of Th1 cytokines, and stimulate the production of Th2 cytokines [6,10]. This Th2 cytokine polarization occurs both at the systemic level and at the fetal-maternal interface [9].

Since SLE is mainly a Th2-mediated disease and during pregnancy an increase in steroid hormone levels occurs, we should expect a subsequent predominance of Th2 response and an exacerbation of the disease, particularly in the third trimester during pregnancy, when estrogens and progesterone levels should be higher [1,11].

However, some studies showed an increased frequency of disease flares in the second trimester and not in the third trimester of pregnancy [1,12-14]. Notably, a lower increase of estrogens, progesterone and Th2 cytokine serum levels in the third trimester of pregnancy in SLE patients compared to that observed in healthy pregnant women has been reported [1,14].

The purpose of this study was to investigate the fluctuations of a large panel of serum cytokines during pregnancy in a considerable number of SLE patients and healthy women, as controls.


Materials and methods

We prospectively studied 47 successful pregnancies in 46 SLE patients, and 56 pregnancies in 56 healthy women, as controls. All patients fulfilled the 1997 American College of Rheumatology (ACR) classification criteria for SLE [15].

Patients were recruited from SLE cohorts followed at the Departments of Rheumatology of the University of Padova and Brescia (Italy), and at the Johns Hopkins University School of Medicine in Baltimore, Maryland (USA). All subjects declared by written informed consent their approval for study participation, according to the Declaration of Helsinki. The study was approved by the local ethics committee.

The mean age of SLE patients at the time of diagnosis was 23 ± 5.8 years, range 13 to 34 years, and at the time of conception was 30.8 ± 4.4 years, range 18 to 39 years. The mean disease duration at the time of conception was 7.48 ± 5.5 years, range 1 to 20 years. Seven patients were African-American and 39 patients and all healthy controls were Caucasian.

The mean age of healthy controls at the time of conception was 30.2 ± 4.9 years (range 21 to 40 years), matched with that of patients.

During pregnancy and the postpartum period all patients were carefully monitored with monthly rheumatologic and gynecological examinations. Moreover, each patient underwent monthly laboratory analysis as suggested for pregnancy monitoring in SLE [16].

Disease activity was assessed before pregnancy according to ECLAM (European Consensus Lupus Activity Measurement) [17] and during pregnancy with ECLAM modified for pregnancy [18]. SLE was considered active in the case of ECLAM score ≥ 2.

Determination of cytokines in sera

Serum samples for cytokine assays were collected respectively at the first (9 to 11 weeks) and third (29 to 31 weeks) trimester of gestation, and stored in aliquots at -80°C until analyses were performed.

Serum levels of IL-1-α, IL-1-β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFN-γ and TNF-α were quantitatively determined by a sandwich highly sensitive enzyme-linked immunosorbent assay (ELISA) designed with multiplex technology (SearchLight Human Inflammatory Cytokine Array by Pierce Biotechnology, Rockford, IL, USA) [19]. In 2006, this commercial kit was approved by the National Institute of Health in the United States (U.S. NIH) as a reference method for the quantitative determination of cytokines in human biological fluids.

The assay procedure was performed according to the manufacturer's instructions.

The ranges of measurability of the standard curve for each cytokine tested were: IL-1-α = 0.78 to 200 pg/ml; IL-1-β = 0.39 to 100 pg/ml; IL-2 = 0.78 to 200 pg/ml; IL-6 = 0.78 to 200 pg/ml; IL-8 = 0.78 to 200 pg/ml; IL-10 = 0.78 to 200 pg/ml; IL-12p70 = 1.2 to 300 pg/ml; IFN-γ = 0.78 to 200 pg/ml, TNF-α = 4.7 to 1,200 pg/ml.

The analytic sensitivity was: IL-1-α = 0.4 pg/ml; IL-1-β = 0.2 pg/ml; IL-2 = 0.4 pg/ml; IL-6 = 0.2 pg/ml; IL-8 = 0.4 pg/ml; IL-10 = 0.2 pg/ml; IL-12p70 = 0.4 pg/ml; IFN-γ = 0.2 pg/ml; TNF-α = 1.6 pg/ml.

Statistical analysis

Statistical analysis was performed with the SPSS 16.0 program (Bologna, Italy) using the Wilcoxon test for paired data and the Mann-Whitney U test.

The choice of a non-parametric statistical analysis was due to the fact that the values of cytokine serum levels did not follow normal distribution, both in healthy controls and in SLE patients.

We applied the Mann-Whitney U test to compare cytokine median levels measured in patients and in healthy women in the first and the third trimester of pregnancy. We corrected the Mann-Whitney univariate analysis by using the Bonferroni test for multiple comparisons, considering a significant P-value of 0.0056.

To analyze the longitudinal changes in cytokine levels during pregnancy, we used the Wilcoxon test for paired data. The graphical representation of the results was carried out by the so-called box plots displaying the median, the range of values between the 25th and the 75th percentiles, and the range of values obtained. We considered as significant a P-value < 0.05.


Results

As stated in the inclusion criteria, all pregnancies successfully ended with the birth of a living baby. There were no differences between the mean weight of babies born from SLE women and healthy controls. The duration of gestation was similar in SLE patients (37.5 weeks, range 27.3 to 45.7) and in controls (38.1 weeks, range 27.5 to 44.8 weeks).

The ECLAM score before pregnancy ranged from 0 to 4.5, (mean ± SD 1.86 ± 1.21, median value 2). At the time of conception the disease was in remission in 30 patients (65%), while it was still active in the remaining 16 patients (35%). In these patients, hematological and joint involvements were the most frequent manifestations. Moreover, 16 patients (34.1%) had renal involvement at the time of conception. Clinical and laboratory features of the 46 patients at the time of conception are summarized in Table 1.

During pregnancy 36 patients (76.5%) had received corticosteroid therapy at the mean dose of 10.56 ± 9.3 mg/day (range 2.5 to 40) in the first trimester of pregnancy, 10.72 ± 9.27 mg/day (range 2.5 to 40) in the second trimester, and 10.71 ± 8.8 mg/day (range 2.5 to 40) in the third trimester; in addition, 18 patients (38.3%) had received an anti-malarial (hydroxychloroquine), 11 (23.4%) azathioprine, and 5 (10.6%) were free of therapy during pregnancy.

Patients with active SLE received a median dose of prednisone higher than patients with inactive disease: 12.3 mg/day (range 5 to 40) vs. 4.6 mg/day (range 2.5 to 12.5) (P = 0.008).

We did not observe differences in treatment, disease activity and pregnancy outcome in African-American patients compared to Caucasian SLE patients.

Sixteen of the 46 SLE patients fulfilled the criteria for anti-phospholipid syndrome (APS): 14 had previous miscarriages, and 2 had previous thrombotic events. None of the patients had thrombotic events during this study.

We observed three cases of pre-eclampsia: two in patients with a history of renal involvement before pregnancy but with SLE in remission at the time of conception, treated with low dose prednisone ( < 10 mg/day), while the third case in a patient with active glomerulonephritis at the time of conception, treated with high dose prednisone ( > 10 mg/day) in combination with azathioprine and anti-malarial.

Cytokines

The cytokine median levels in the first and third trimesters of pregnancy in healthy women and in SLE patients are reported in Table 2.

In healthy women, Th1-type cytokine serum levels showed a significant reduction in the third trimester versus the first trimester of gestation while no significant changes were observed in IL-6 and IL-10 serum levels between the first and third trimester of pregnancy.

In SLE patients, IL-1-α was the only Th1 cytokine whose levels were significantly decreased in the third trimester compared to those observed in the first trimester (P = 0.006). Serum levels of all the other Th1 cytokines tested and Th2 cytokines IL-6 and IL-10 did not significantly change between the first and the third trimester of pregnancy.

IL-10 serum levels were higher in SLE patients compared to controls in the third trimester of pregnancy (P = 0.001) (Figure 1). Moreover, in the third trimester the difference in IL-10 serum levels between active SLE and controls (P = 0.004) was greater than between inactive SLE and controls (P = 0.015, which is not significant when corrected by Bonferroni test multiple comparisons).

We did not observe any difference in cytokine levels in African-American SLE patients compared to Caucasian patients.

Both in SLE patients and in healthy women cytokine, serum levels did not correlate with age at the time of conception.

In the first trimester, IL-2, IL-12, IFN-γ and IL-6 serum levels correlated with ECLAM score (IL-2 r = 0.524 P = 0.005, IL-12 r = 0.549 P = 0.007, IFN-γ r = 0.492 P = 0.017, IL-6 r = 0.515 P = 0.02) in SLE women.

The median (25th to 75th percentiles) cytokine serum levels were similar in patients with and without glomerulonephritis both in the first and in the third trimester of pregnancy (Table 3).

There were no significant differences in cytokine serum levels among the 27 patients receiving low-dose steroid therapy ( ≤ 10 mg/day) and the 9 patients taking steroids at higher dose ( > 10 mg/day) in both the first and the third trimester of gestation (Table 4).

Moreover, no differences in cytokine levels among patients treated with or without anti-malarial were observed.

No differences in cytokine serum levels in SLE patients with a history of pregnancy loss compared with those without were observed; moreover, cytokine levels did not correlate with the number of previous pregnancy losses.

The ratio between IFN-γ and IL-6 serum levels (IFN-γ/IL-6) was significantly lower in the third compared to the first trimester (median 0.43, range 0.04 to 220.20, vs 0.71, range 0.08 to 41.00, P = 0.033) in healthy controls, but not in SLE patients (median 0.34, range 0.01 to 30.00, vs 0.43, range 0.01 to 4.63, P = n.s.) (Figure 2).

The ratio between IFN-γ and IL-10 serum levels (IFN-γ/IL-10) was higher in healthy women compared to SLE patients in both the first (median 1.88, range 1.30 to 3.67, vs 0.97, range 0.44 to 1.93, P = 0.001) and the third trimester of pregnancy (median 2.00, range 0.90 to 3.10, vs 0.83, range 0.35 to 1.48, P = 0.001).


Discussion

The increase in cortisol, progesterone and estradiol concentrations observed during pregnancy in healthy women has been associated with an increase in cytokines predominantly produced by Th2 cells and a reduction in those mainly produced by Th1 cells [1,20]. It has been shown that estrogens and progesterone are able to modulate antibody production [21], by promoting Th2 polarization. In fact, estrogens at pharmacological levels seem to stimulate antibody production by increasing IL-6 and IL-10 secretion [22,23], whereas high levels of progesterone, such as those observed in the second part of gestation, seem to stimulate the production of IL-4, IL-5 and IL-10 [24] and inhibit Th1 type cytokine production [6].

IL-6 is a pleyotropic cytokine that plays an important role in the differentiation of Th0 cells toward a Th2 phenotype, inhibiting the development of a Th1-mediated response [25]. It has been shown that SLE patients have elevated IL-6 serum levels which correlate with disease activity or anti-dsDNA antibodies [26,27]. IL-6 promotes the proliferation of renal mesangial cells in mice and several studies report IL-6 as a critical mediator of tissue damage due to its ability to stimulate the production of nephritogenic antibodies [28].

In SLE patients, IL-10 is also overproduced [29-32] and IL-10 serum concentration correlates with disease activity [26,33,34]. IL-10 is a powerful stimulator of B cell proliferation, differentiation and antibody secretion [35], as well as an inhibitor of antigen presenting cell and T cell functions [4,36]. IL-10 may be also influenced by the use of glucocorticoids. However, in our study no differences in IL-10 serum levels between patients taking steroids at high or low dose were observed.

The role of Th1 cytokines in the pathogenesis of SLE is less clear and probably systemic and local effects are different. It has been demonstrated that TNF-α leads to T cell hypo-responsiveness and controls autoreactivity inducing T cell apoptosis in the peripheral blood [37]. On the other hand, TNF-α has been found in kidney and skin biopsies in SLE and is thought to be responsible for tissue damage [38,39].

Since the activation of the Th2 cytokines seems to be a relevant pathway in the pathogenesis of SLE, the gestation-induced Th2 polarization of immune response might theoretically contribute to a disease flare during pregnancy in SLE women [1,11].

In our study, IL-6 and TNF-α serum levels were similar in SLE patients and controls and only the IL-10 level was higher in patients than in controls. The most relevant feature in our study was a lower decrease of Th1 cytokine and a lower increase of Th2 cytokine serum levels in SLE pregnant women compared with healthy pregnant controls. This profile is confirmed by the lower than expected reduction of IFNγ/IL-6 ratio (Figure 2) in the third trimester of SLE pregnancy.

In our previous study, we demonstrated that IL-6 serum levels were lower in pregnant SLE patients than in healthy pregnant controls in the third trimester of pregnancy; by contrast, IL-10 serum levels in SLE pregnant patients were higher during the whole pregnancy [1].

Moreover, our data appear similar to those recently published by Torricelli et al. [40]. In their study, they also found higher levels of IL-10 in pregnant patients affected with SLE compared with healthy pregnant women. Interestingly, in SLE patients IL-10 level progressively increased during pregnancy.

Furthermore, another study [41] showed higher levels of IL-10 in pregnant patients affected with SLE than in healthy pregnant women, particularly during the third trimester of pregnancy. In this study, IL-6 was not measured.

Thus, a lower Th2 polarization was observed during pregnancy in SLE patients compared with healthy pregnant controls, especially in the third trimester of gestation. This feature may be explained by the lower than expected levels of estrogen and progesterone during the second and third trimester of pregnancy, which we have recently reported [14]. The lower Th2 polarization during pregnancy could account for the lack of differences in disease flare between pregnant and non-pregnant SLE patients reported in some controlled studies [12,42,43].

Since Th2 polarization is thought to be important for the trophoblast to invade and anchor to the deciduas, ensuring pregnancy maintenance [44] one may argue why our patients were able to successfully complete their pregnancies. A potential explanation is that cytokine patterns could be different at the feto-maternal interface compared with those measured in the systemic circulation, and the low levels of estrogen and progesterone produced by the placenta could at least be sufficient to induce a localized Th2 polarization at this level, allowing a maternal tolerance to paternal antigens and thus a successful gestation.

A further intriguing aspect in this field is the trimester of pregnancy which is at higher risk for a disease relapse. Data on the timing of disease flares during pregnancy are conflicting. Since during pregnancy the Th2 immune deviation is primarily due to the increase in estrogen and progesterone levels, exacerbations of disease should be expected more frequently during the third trimester, when these hormones reach their highest levels. By contrast, recent studies report a lower number of relapses in the third trimester than in the second trimester of gestation or post partum [1,12-14,43,45-48]. This variation may also be explained by the different Th1/Th2 balance observed in SLE pregnant women, compared with healthy pregnant controls caused by the lower estrogen and progesterone levels observed in SLE patients during the third trimester.


Conclusions

Our study demonstrates that the induction of a predominant Th2 cytokine milieu during pregnancy is less evident in SLE patients than in healthy pregnant women. This cytokine profile, characterized by a lower Th2 response could explain why, in some studies, SLE flares are not more common in pregnant than in non-pregnant patients and why, if they occur, they rarely take place during the third trimester of gestation.


Abbreviations

Ab: antibody; aCL: anticardiolipin antibodies; ACR: American College of Rheumatology; APS: antiphospholipid syndrome; CNS: central nervous system; dsDNA: double stranded DNA; ECLAM: European Consensus Lupus Activity Measurement; ELISA: enzyme linked immunosorbent assay; ENA: extractable nuclear antigens; IL: interleukin; INF: interferon; LAC: lupus anticoagulant; PDN: prednisone; pg/ml: pycogram/milliliter; SD: standard deviation; SLE: systemic lupus erythematosus; Th: T helper; TNF: tumor necrosis factor; U.S. NIH: National Institute of Health in the United States.


Competing interests

The authors declare that they have no competing interests.


Authors' contributions

AD conceived the study, participated in its design and coordination, helped to draft the manuscript and is responsible for the final version. MC gave helpful suggestions to the study design and critically revised the manuscript. AG and DV carried out the cytokine dosage and looked after data collection. AG also revised the manuscript. LI and MZ followed up patients, participated in the design of the study and drafted the manuscript. MP took care of patients from the United States, participated in the design of the study and revised the manuscript. AT followed up patients. LP revised the manuscript. All authors read and approved the final manuscript.


Acknowledgements

This work was supported by "Ministero dell'Istruzione, dell'Università e della Ricerca" [Grant number 60A07-1030/09], Italy.


References
Doria A,Ghirardello A,Iaccarino L,Zampieri S,Punzi L,Tarricone E,Ruffatti A,Sulli A,Sarzi-Puttini PC,Gambari PF,Cutolo M,Pregnancy, cytokines, and disease activity in systemic lupus erythematosusArthritis RheumYear: 20045198999510.1002/art.2083715593367
Romagnani S,The Th1/Th2 paradigmImmunol TodayYear: 1997182632669190109
Saito S,Nakashima A,Shima T,Ito M,Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancyAm J Reprod ImmunolYear: 20106360161010.1111/j.1600-0897.2010.00852.x20455873
Funauchi M,Ikoma S,Enomoto H,Horiuchi A,Decreased Th1-like and increased Th2-like cells in systemic lupus erythematosusScand J RheumatolYear: 19982721922410.1080/0300974984408599645418
Rousset F,Garcia E,Defrance T,Peronne C,Vezzio N,Hsu DH,Kastelein R,Moore KW,Banchereau J,Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytesProc Natl Acad Sci USAYear: 1992891890189310.1073/pnas.89.5.18901371884
Cutolo M,Sulli A,Seriolo B,Accardo S,Masi AT,Estrogens, the immune response and autoimmunityClin Exp RheumatolYear: 1995132172267656468
Branch DW,Physiologic adaptations of pregnancyAm J Reprod ImmunolYear: 1992281201221285859
Doria A,Iaccarino L,Arienti S,Ghirardello A,Zampieri S,Rampudda ME,Cutolo M,Tincani A,Todesco S,Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseasesReprod ToxicolYear: 20062223424110.1016/j.reprotox.2006.04.00116704920
Lin H,Mosmann TR,Guilbert L,Mosmann TR,Guilbert L,Tuntipopipat S,Wegmann TG,Synthesis of T helper 2-type cytokines at the maternal-fetal interfaceJ ImmunolYear: 1993151456245738409418
Rodriguez E,Guevara J,Paez A,Zapata E,Collados MT,Fortoul TI,Lopez-Marure R,Masso F,Montaño LF,The altered expression of inflammation-related molecules and secretion of IL-6 and IL-8 by HUVEC from newborns with maternal inactive systemic lupus erythematosus is modified by estrogensLupusYear: 2008171086109510.1177/096120330809382719029276
Ostensen M,Forger F,Villiger PM,Cytokines and pregnancy in rheumatic diseaseAnn N Y Acad SciYear: 2006106935336310.1196/annals.1351.03316855162
Petri M,Howard D,Repke J,Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experienceArthritis RheumYear: 199134153815451670196
Tincani A,Bompane D,Danieli E,Doria A,Pregnancy, lupus and antiphospholipid syndrome (Hughes syndrome)LupusYear: 20061515616010.1191/0961203306lu2279rr16634369
Doria A,Cutolo M,Ghirardello A,Zampieri S,Vescovi F,Sulli A,Giusti M,Piccoli A,Grella P,Gambari PF,Steroid hormones and disease activity during pregnancy in systemic lupus erythematosusArthritis RheumYear: 20024720220910.1002/art.1024811954015
Hochberg MC,Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosusArthritis RheumYear: 19974017259324032
Witter FR,Management of the high-risk lupus pregnant patientRheum Dis Clin North AmYear: 20073325326510.1016/j.rdc.2007.02.00217499706
Griffiths B,Mosca M,Gordon C,Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indicesBest Pract Res Clin RheumatolYear: 20051968570810.1016/j.berh.2005.03.01016150398
Olesinska M,Wiesik-Szewczyk E,Chwalinska-Sadowska H,Evaluation of systemic lupus erythematosus activity during pregnancyPol Arch Med WewnYear: 200711731231617966597
Toedeter G,Hayden K,Wagner C,Brodmerkel C,Simultaneous detection of eight analytes in human serum by two commercially available platforms for multiplex cytokine analysisClin Vaccine ImmunolYear: 200815424810.1128/CVI.00211-0718003817
Zen M,Ghirardello A,Iaccarino L,Tonon M,Campana C,Arienti S,Rampudda M,Canova M,Doria A,Hormones, immune response, and pregnancy in healthy women and SLE patientsSwiss Med WklyYear: 201014018720120175004
Canellada A,Blois S,Gentile T,Margni Idehu RA,In vitro modulation of protective antibody responses by estrogen, progesterone and interleukin-6Am J Reprod ImmunolYear: 20024833434310.1034/j.1600-0897.2002.01141.x12516657
Peeva E,Zouali M,Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytesImmunol LettYear: 200510112314310.1016/j.imlet.2005.05.01416061292
Cohen-Solal JF,Jeganathan V,Grimaldi CM,Peeva E,Diamond B,Sex hormones and SLE: influencing the fate of autoreactive B cellsCurr Top Microbiol ImmunolYear: 2006305678810.1007/3-540-29714-6_416724801
Piccinni MP,Giudizi MG,Biagiotti R,Beloni L,Giannarini L,Sampognaro S,Parronchi P,Manetti R,Annunziato F,Livi C,Romagnani S,Maggi E,Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clonesJ ImmunolYear: 19951551281337541410
Diehl S,Rincon M,The two faces of IL-6 on Th1/Th2 differentiationMol ImmunolYear: 20023953153610.1016/S0161-5890(02)00210-912431386
Chun HY,Chung JW,Kim HA,Yun JM,Jeon JY,Ye YM,Kim SH,Park HS,Suh CH,Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosusJ Clin ImmunolYear: 20072746146610.1007/s10875-007-9104-017587156
Stuart RA,Littlewood AJ,Maddison PJ,Hall ND,Elevated serum interleukin-6 levels associated with active disease in systemic connective tissue disordersClin Exp RheumatolYear: 19951317227774098
Richards HB,Satoh M,Shaw M,Libert C,Poli V,Reeves WH,Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupusJ Exp MedYear: 199818898599010.1084/jem.188.5.9859730900
Llorente L,Richaud-Patin Y,Fior R,Alcocer-Varela J,Wijdenes J,Fourrier BM,Galanaud P,Emilie D,In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. A potential mechanism of B lymphocyte hyperactivity and autoimmunityArthritis RheumYear: 1994371647165510.1002/art.17803711147980676
Hagiwara E,Gourley MF,Lee S,Klinman DK,Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral bloodArthritis RheumYear: 19963937938510.1002/art.17803903058607886
Horwitz DA,Gray JD,Behrendsen SC,Kubin M,Rengaraju M,Ohtsuka K,Trinchieri G,Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosusArthritis RheumYear: 19984183884410.1002/1529-0131(199805)41:5<838::AID-ART10>3.0.CO;2-S9588735
Lacki JK,Samborski W,Mackiewicz SH,Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteinsClin RheumatolYear: 19971627527810.1007/BF022389639184265
Houssiau FA,Lefebvre C,Vanden Berghe M,Lambert M,Devogelaer JP,Renauld JC,Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activityLupusYear: 1995439339510.1177/0961203395004005108563734
Park YB,Lee SK,Kim DS,Lee J,Lee CH,Song CH,Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosusClin Exp RheumatolYear: 1998162832889631750
Llorente L,Zou W,Levy Y,Richard-Patin Y,Wijdenes J,Alcocer-Varela J,Morel-Fourrier B,Brouet JC,Alarcon-Segovia D,Galanaud P,Emilie D,Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosusJ Exp MedYear: 199518183984410.1084/jem.181.3.8397869046
de Waal Malefyt R,Yssel H,de Vries JE,Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferationJ ImmunolYear: 1993150475447657684412
McDevitt H,Munson S,Ettinger R,Wu A,Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunityArthritis ResYear: 20024Suppl 3S14115210.1186/ar57012110133
Atzeni F,Turiel M,Capsoni F,Doria A,Meroni P,Sarzi-Puttini P,Autoimmunity and anti-TNF-alpha agentsAnn N Y Acad SciYear: 2005105155956910.1196/annals.1361.10016126996
Aringer M,Smolen JS,SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosusArthritis Res TherYear: 2003517217712823847
Torricelli M,Bellisai F,Novembri R,Galeazzi LR,Iuliano A,Voltolini C,Spreafico A,Galeazzi M,Petraglia F,High levels of maternal serum IL-17 and activin A in pregnant women affected by systemic lupus erythematosusAm J Reprod ImmunolYear: 201166848910.1111/j.1600-0897.2011.00978.x21736662
Munoz-Valle JF,Vazquez-Del Mercado M,Garcia-Iglesias T,Orozco-Barocio G,Bernard-Medina G,Martinez-Bonilla G,Bastidas-Ramirez BE,Navarro AD,Bueno M,Martinez-Lopez E,Best-Aguilera CR,Kamachi M,Armendariz-Borunda J,T(H)1/T(H)2 cytokine profile, metalloprotease-9 activity and hormonal status in pregnant rheumatoid arthritis and systemic lupus erythematosus patientsClin Exp ImmunolYear: 200313137738410.1046/j.1365-2249.2003.02059.x12562402
Ruiz-Irastorza G,Lima F,Alves J,Khamashta MA,Simpson J,Hughes GR,Buchanan NM,Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnanciesBr J RheumatolYear: 19963513313810.1093/rheumatology/35.2.1338612024
Clowse ME,Magder LS,Witter F,Petri M,The impact of increased lupus activity on obstetric outcomesArthritis RheumYear: 20055251452110.1002/art.2086415692988
Wegmann TG,Lin H,Guilbert L,Mosmann TR,Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?Immunol TodayYear: 19931435335610.1016/0167-5699(93)90235-D8363725
Urowitz MB,Gladman DD,Farewell VT,Stewart J,McDonald J,Lupus and pregnancy studiesArthritis RheumYear: 1993361392139710.1002/art.17803610118216399
Tandon A,Ibanez D,Gladman DD,Urowitz MB,The effect of pregnancy on lupus nephritisArthritis RheumYear: 2004503941394610.1002/art.2063815593212
Meehan RT,Dorsey JK,Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapyJ RheumatolYear: 1987142522583598995
Lockshin MD,Pregnancy does not cause systemic lupus erythematosus to worsenArthritis RheumYear: 19893266567010.1002/anr.17803206022638570

Figures

[Figure ID: F1]
Figure 1 

IL-10 levels in the first and third trimesters of pregnancy in controls and SLE patients.



[Figure ID: F2]
Figure 2 

IFNγ/IL-6 ratio in controls and SLE patients: comparison between first and third trimesters of pregnancy.



Tables
[TableWrap ID: T1] Table 1 

Clinical and laboratory features at conception and treatment in 46 SLE patients during 47 pregnancies.


No. of patients (%)
Skin manifestations 16 (35)
Arthralgias and/or arthritis 26 (56)
Serositis 4 (8.7)
Glomerulonephritis 16 (34)
CNS involvement 2 (4.3)
Hematological involvement 26 (56)
Anti-dsDNA Ab 33 (71.7)
Anti-Sm Ab 6 (13)
Anti-U1RNP Ab 10 (21.7)
Anti-Ro/SSA Ab 17 (37)
Anticardiolipin Ab 20 (43.5)
LAC 7 (15.2)
Double LAC + aCL positivity 6 (13)
Prednisone 36 (78)
Antimalarials 18 (39)
Azathioprine 11 (24)
No therapy 5 (11)

Hematological involvement, excluding hemolytic anemia. Ab, anti-extractable nuclear antigens antibodies (anti-ENA); aCL, anticardiolipin antibodies Anti-dsDNA Ab, anti-double-stranded-DNA antibodies; anti-Sm, anti-U1RNP, anti-Ro/SSA; CNS, central nervous system; LAC, lupus anticoagulant


[TableWrap ID: T2] Table 2 

Th1 and Th2 cytokine levels during pregnancy in 56 healthy women and 46 SLE patients


Healthy women SLE patients
1st trimester 3rd trimester P = 1st trimester 3rd trimester P =
TNF-α 11.5 (1.4 to 104.6) 10.2 (0.7 to 72.9) 0.001 13.5 (0 to 210.5) 11.0 (0 to 174.5) n.s.
IFN-γ 3.4 (0 to 29.0) 2.0 (0.1 to 55.5) 0.001 2.8 (0 to 75.0) 3.0 (0 to 38.2) n.s.
IL-1α 1.1 (0 to 13.2) 0.9 (0 to 12.8) 0.003 1.0 (0 to 56.6) 1.0 (0 to 27.5) 0.006
IL-1β 1.0 (0 to 10.3) 0.6 (0 to 70.8) 0.018 0.8 (0 to 35.2) 0.5 (0 to 18.4) n.s.
IL-2 3.5 (0 to 39.8) 3.0 (0 to 206) 0.018 4.5 (0 to 122.4) 4.1 (0 to 40.3) n.s.
IL-8 5.2 (0.9 to 112.6) 4.4 (0.9 to 145.9) 0.053 7.4 (0 to 910.9) 4.6 (0 to 717.1) n.s.
IL-12 5.6 (0.1 to 70.6) 4.9 (0 to 29.4) 0.018 6.0 (0 to 186.5) 4.2 (0 to 105.7) n.s.
IL-10 1.3 (0 to 45.0) 1.1 (0 to 19.1) n.s. 2.9 (0 to 124.1) 3.1 (0 to 73.6) n.s.
IL-6 5.5 (1.8 to 10.4) 4.8 (2.2 to 9.2) n.s. 6.3 (3.5 to 22.6) 7.3 (3.7 to 23.1) n.s.

IFN-γ, interferon gamma; IL, interleukin; n.s., not significant; TNF-α, tumor necrosis factor alpha. The median values (25th to 75th percentile) are expressed in pg/ml. Differences between the median cytokine serum levels in the first and third trimester were statistically evaluated by Wilcoxon test for paired data (significant P-value < 0.05).


[TableWrap ID: T3] Table 3 

Cytokine levels during the first and third trimester in SLE patients with/without glomerulonephritis before pregnancy


1st trimester 3rd trimester
SLE patients with glomerulonephritis SLE patients without glomerulonephritis P SLE patients with glomerulonephritis SLE patients without glomerulonephritis P
TNF-α 14.90 (6.50 to 41.00) 10.90 (5.30 to 25.82) n.s. 25.90 (8.20 to 38.80) 10.10 (5.97 to 30.25) n.s.
INF-γ 4.40 (2.20 to 13.00) 3.20 (0.25 to 4.67) n.s. 5.60 (1.50 to 15.80) 2.95 (1.52 to 6.95) n.s.
IL-1α 3.00 (0.50 to 10.00) 0.85 (0.27 to 1.37) n.s. 1.50 (0.40 to 6.60) 1.10 (0.12 to 2.20) n.s.
IL-1β 1.10 (0.37 to 10.025) 1.95 (1.15 to 4.30) n.s. 0.70 (0.32 to 3.37 1.80 (0.60 to 9.30) n.s.
IL-2 6.20 (1.50 to 15.20) 2.15 (1.57 to 4.05) n.s. 6.50 (1.10 to 12.80) 2.50 (1.35 to 6.12) n.s.
IL-8 8.75 (6.70 to 40.75) 27.15 (8.72 to 52.37) n.s. 7.40 (4.70 to 29.30) 24.85 (4.22 to 197.40) n.s.
IL-12 6.40 (2.00 to 22.70) 4.05 (1.77 to 18.02) n.s. 4.20 (1.70 to 25.50) 3.30 (2.02 to 20.65) n.s.
IL-10 3.25 (0.90 to 12.12) 2.50 (1.95 to 4.40) n.s. 4.20 (1.55 to 11.65) 4.60 (2.50 to 5.80) n.s.
IL-6 8.10 (3.50 to 38.10) 5.50 (2.90 to 6.50) n.s. 11.25 (1.55 to 25.57) 9.40 (5.20 to 12.90) n.s.

SLE patients with glomerulonephritis: n = 16; SLE patient without glomerulonephritis: n = 30. The median values (25th to 75th percentile) are expressed in pg/ml.


[TableWrap ID: T4] Table 4 

Cytokine levels in SLE patients according to steroids intake during the first and third trimester.


1st trimester 3rd trimester
High dose PDN Low dose PDN P High dose PDN Low dose PDN P
TNF-α 21.70 (5.75 to 64.75) 10.70 (6.50 to 38.32) n.s. 18.50 (5.25 to 34.75) 10.25 (5.05 to 25.45) n.s.
INF-γ 4.80 (1.15 to 15.30) 3.75 (1.32 to 11.62) n.s. 8.20 (0.40 to 14.05) 3.40 (1.12 to 10.00) n.s.
IL-1α 0.50 (0.15 to 5.70) 1.90 (0.50 to 7.90) n.s. 1.20 (0.0 to 2.85) 1.30 (0.25 to 5.95) n.s.
IL-1β 0.80 (0.25 to 2.05) 1.30 (0.45 to 4.20) n.s. 0.10 (0.0 to 5.80) 0.90 (0.15 to 2.40) n.s.
IL-2 6.00 (3.10 to 14.00) 3.55 (1.50 to 13.92) n.s. 4.80 (1.90 to 13.45) 4.40 (1.50 to 11.90) n.s.
IL-8 8.70 (2.55 to 25.65) 8.65 (4.62 to 33.70) n.s. 3.90 (0.50 to 6.40) 4.70 (2.10 to 19.80) n.s.
IL-12 6.40 (3.85 to 20.05) 8.35 (1.87 to 31.60) n.s. 3.20 (0.50 to 21.30) 4.45 (2.12 to 24.97) n.s.
IL-10 2.10 (1.20 to 8.45) 3.60 (1.22 to 13.57) n.s. 2.00 (1.35 to 9.50) 3.90 (1.37 to 9.67) n.s.
IL-6 6.50 (4.45 to 17.75) 8.20 (3.87 to 34.55) n.s. 6.30 (4.05 to 29.90) 7.70 (3.90 to 25.50) n.s.

SLE patients who have taken high steroids dose: n = 27; SLE patients who have taken low steroids dose: 9. The median values (25th to 75th percentile) are expressed in pg/ml.



Article Categories:
  • Research Article


Previous Document:  Tricks of the trade: How to avoid histological Pitfalls in celiac disease.
Next Document:  Fragrance material review on p-anisyl acetate.