| 1. |
- Hellberg, Sandra, 1986-
(författare)
-
Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.
|
|
| 2. |
- Hellberg, Sandra, et al.
(författare)
-
Maintained thymic output of conventional and regulatory T cells during human pregnancy
- 2019
-
Ingår i: Journal of Allergy and Clinical Immunology. - Philadelphia, United States : American Academy of Allergy, Asthma and Immunology. - 0091-6749 .- 1097-6825. ; 143:2, s. 771-775.e7
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- During pregnancy, immunological tolerance toward the semiallogeneic fetus needs to be established while at the same time an effective immune defense must be maintained.1 The pregnancy-associated thymic involution reported in rodents2 has been suggested to support maternal immune regulation by reducing the output of potentially harmful TH cells. However, the functional importance of this thymic involution remains unclear and it is not known whether it even occurs in humans.3 In fact, the role of thymus during human pregnancy and in pregnancy-associated tolerance remains largely unknown,4 albeit a role for thymic-derived regulatory T (Treg) cells in pregnancy complications has been suggested,4 supporting a role for thymus in immune regulation during human pregnancy. The aim of this study was to assess the role of thymus in TH-cell regulation during human pregnancy by analyzing the output of different TH-cell populations.
|
|
| 3. |
- Kempe, Per, et al.
(författare)
-
Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis
- 2018
-
Ingår i: Journal of Reproductive Immunology. - : Elsevier. - 0165-0378 .- 1872-7603. ; 1:26, s. 53-59
-
Tidskriftsartikel (refereegranskat)abstract
- To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity.
|
|
| 4. |
- Kempe, Per, et al.
(författare)
-
T cell subset-associated transcription factors, cytokines and chemokines in relation to the menstrual cycle and use of combined hormonal contraceptives in women with multiple sclerosis and healthy controls
- 2014
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Study question: Do peripheral blood levels of cytokines, chemokines, and transcription factors for different T helper (Th) cell subsets change in relation to high and low estrogen/progestogen states in women with multiple sclerosis (MS) and healthy controls with and without combined hormonal contraceptives (CHC)?Summary answer: Our findings indicate a general activation of peripheral blood T cells and B cells during high estrogen/progestogen phases with higher levels of transcription factors associated with both Th1 (TBX21) and Th2 (GATA3) subsets of T cells and the B cell-associated chemokine CXCL13.What is known already: There are some indications that sex steroids may positively affect MS clinically and immunologically.Study design, size, duration: A total of 60 women were included. Paired blood samples were drawn in high and low estrogen/progestogen phases during the same cycle in women using or not using CHC.Participants/materials, setting, methods: Participants were female MS patients and healthy controls with and without CHC. Concentrations of cytokines and chemokines were measured using multiplex bead technology and expression of transcription factors in blood cells was determined by qPCR. Owing to possible differences in cell composition, expression of Th-associated transcription factors were normalized to the T cell-specific transcription factor CD3E.Main results and the role of chance: Sixty women were included but 13 women dropped out, leaving 47 women to the statistical analyses. In healthy controls using CHC, both TBX21, and GATA3 expression was higher in the high estrogen/progestogen phase than in the low estrogen/progestogen phase. TBX21 expression in high estrogen/progestogen phase differed significantly between groups with the highest levels in healthy controls without CHC. In all MS patients as well as in healthy controls using CHC, the concentrations of CXCL13 was significantly higher in the high estrogen/progestogen phase compared to the low estrogen/progestogen phase.Limitations, reasons for caution: The low number of participants. A majority of the MS patients were using immunomodulatory drugs which may have interfered with the results. The study design makes it impossible to differ between estrogenic and progestogenic effects.Wider implications of the findings: Our findings show that high and low levels of estrogens and/or progestogens differently affect immune parameters related to Th cell subsets as well as B cells. The differences between high- and low estrogen/progestogen phases were most obvious in women using CHC indicating that CHC is more potent than 17β-Estradiol/progesterone in inducing immune changes in both MS patients and healthy women.Study funding/competing interest(s): This study was funded by the County Councils of Östergötland and Västernorrland, Sweden. No author have any conflicts of interest to declare.
|
|
| 5. |
- Papapavlou, Georgia, et al.
(författare)
-
Differential effects of estradiol and progesterone on human T cell activation in vitro
- 2021
-
Ingår i: European Journal of Immunology. - : Wiley-VCH Verlagsgesellschaft. - 0014-2980 .- 1521-4141. ; 51:10, s. 2430-2440
-
Tidskriftsartikel (refereegranskat)abstract
- Estradiol (E2) and progesterone (P4) are steroid hormones important for the regulation of immune responses during pregnancy. Their increasing levels coincide with an improvement of T cell-mediated diseases such as multiple sclerosis (MS). Although immune-endocrine interactions are involved in this phenomenon, the relative contribution of hormones is not known. We here report a direct comparison of E2- and P4-mediated effects on human CD4+ T cells, key cells in immune regulation. T cells were stimulated to obtain different activation levels and exposed to a broad range of hormone concentrations. Activation level was assessed by CD69/CD25 expression by flow cytometry, and secreted proteins (n = 196) were measured in culture supernatants using proximity extension assay and electrochemiluminescence immunoassay. We found that in low activated cells, pregnancy-relevant E2 concentrations increased activation and the secretion of several immune- and inflammation-related proteins. P4, on the other hand, showed a biphasic pattern, where serum-related concentrations upregulated activation and protein secretion while placenta-relevant concentrations induced a prominent dampening irrespective of the initial activation level. Our results demonstrate the importance of P4 as a major hormone in the immune modulation of T cells during pregnancy and emphasize the need to further evaluate its potency in the treatment of diseases like MS.
|
|
| 6. |
- Almen-Christensson, Anna, et al.
(författare)
-
Prevention of menstrual migraine with perimenstrual transdermal 17-beta-estradiol: a randomized, placebo-controlled, double-blind crossover study
- 2011
-
Ingår i: Fertility and Sterility. - : Elsevier Science B.V., Amsterdam.. - 0015-0282 .- 1556-5653. ; 96:2, s. 498-500
-
Tidskriftsartikel (refereegranskat)abstract
- he effect of treatment with percutaneous E(2) (100 mu g/24 h) during 2 weeks perimenstrually on the number and severity of menstrual migraine attacks was studied in 27 women in a randomized, placebo-controlled, double-blind, crossover trial. We were not able to demonstrate any difference between E(2) supplementation and placebo on the number or severity of migraine attacks, but both regimens showed significant effects compared with before treatment.
|
|
| 7. |
- Axelsson, Daniel, et al.
(författare)
-
Maternal obesity and the risk of postpartum infections according to mode of delivery
- 2023
-
Ingår i: The Journal of Maternal-Fetal & Neonatal Medicine. - : Informa Healthcare. - 1476-7058 .- 1476-4954. ; 36:2
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the present study was to assess the impact of different maternal Body Mass Index (BMI) classes on the risk of postpartum endometritis, wound infection, and breast abscess after different modes of delivery. Secondly to estimate how the risk of postpartum infection varies with different maternal BMI groups after induction of labor and after obstetric anal sphincter injuries.Methods: A population-based observational study including women who gave birth during eight years (N = 841,780). Data were collected from three Swedish Medical Health Registers, the Swedish Medical Birth Register, the Swedish National Patient Register, and the Swedish Prescribed Drug Register. Outcomes were defined by ICD-10 codes given within eight weeks postpartum. The reference population was uninfected women. Odds ratios were determined using Mantel-Haenszel technique. Year of delivery, maternal age, parity and smoking in early pregnancy were considered as confounders.Results: There was a dose-dependent relationship between an increasing maternal BMI and a higher risk for postpartum infections. Women in obesity class II and III had an increased risk for endometritis after normal vaginal delivery aOR 1.45 (95% CI: 1.29-1.63) and for wound infections after cesarean section aOR 3.83 (95% CI: 3.39-4.32). There was no difference in how maternal BMI affected the association between cesarean section and wound infection, regardless of whether it was planned or emergent. Women in obesity class II and III had a lower risk of breast abscess compared with normal-weight women, aOR 0.47 (95% CI: 0.38-0.58). The risk of endometritis after labor induction decreased with increasing maternal BMI. The risk of wound infection among women with an obstetrical sphincter injury decreased with increasing BMI.Conclusion: This study provides new knowledge about the impact of maternal BMI on the risk of postpartum infections after different modes of delivery. There was no difference in how BMI affected the association between cesarean section and wound infections, regardless of whether it was a planned cesarean section or an emergency cesarean section.
|
|
| 8. |
- Axelsson, Daniel, et al.
(författare)
-
Postpartum infection in relation to maternal characteristics, obstetric interventions and complications
- 2018
-
Ingår i: Journal of Perinatal Medicine. - : Walter de Gruyter. - 0300-5577 .- 1619-3997. ; 46:3, s. 271-278
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose was to evaluate the association between maternal characteristics, obstetrical interventions/complications and postpartum wound infections (WI), urinary tract infection (UTI) and endometritis. Furthermore, this study aimed to determine the time from delivery to onset of infections after discharge from the hospital. Three large Swedish Medical Health Registers were scrutinized for the period 2005-2012. A total of 582,576 women had 795,072 deliveries. Women with diagnosis codes for WIs, UTIs or endometritis, from delivery to 8 weeks postpartum, were compared to non-infected women. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. Increasing age and body mass index (BMI) were both associated with increasing prevalence of postpartum infections. WIs were most strongly associated with cesarean section (CS) (OR 17.2; 95% CI 16.1-18.3), 3rd and 4th degree tears (OR 10.7%; 95% CI 9.80-11.9) and episiotomy (OR 10.2; 95% CI 8.94-11.5). Endometritis was associated with anemia (OR 3.16; 95% CI 3.01-3.31) and manual placental removal (OR 2.72; 95% CI 2.51-2.95). UTI was associated with emergency CS (OR 3.46; 95% CI 3.07-3.89) and instrumental delivery (OR 3.70; 95% CI 3.29-4.16). For women discharged from the delivery hospital the peak occurrence of UTI was 6 days postpartum, while for WIs and endometritis it was 7 days postpartum.
|
|
| 9. |
- Axelsson, Daniel, 1974-
(författare)
-
Postpartum infections; prevalence, associated obstetric factors and the role of vitamin D
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Postpartum infections are a major cause of maternal mortality and morbidity worldwide. Breast infection, endometritis, urinary tract infection and wound infections are the most common postpartum infections and together they affect almost 20% of women after childbirth. Some risk factors for postpartum infections, for example cesarean section, have been relatively well studied, but other presumable risk factors are yet to be confirmed.The proportion of pregnant women who are overweight or obese is increasing in most parts of the world. Increased maternal body mass index (BMI) is associated with maternal and infant morbidity. The association between overweight / obesity and postpartum infections is incompletely understood. Vitamin D deficiency has in epidemiological studies been shown to increase the risk of various infections. Furthermore, vitamin D is an important factor in the human immune system. Concomitantly, vitamin D supplementation seems protective against some types of infections. Whether vitamin D deficiency is a risk factor for postpartum infections has not been studied.Material and Methods: In a population-based observational study using questionnaires, the prevalences of postpartum wound infections, endometritis, urinary tract infections and mastitis in the southeast region of Sweden were estimated (Paper I). All women giving birth in the region during one year (n=11 124) were asked to participate. Papers II and III were cohort studies based on all deliveries in Sweden during eight years (2005-2012). Data sources were the Swedish Medical Birth Register, the Swedish National Patient Register and the Swedish Prescribed Drugs Register. In paper II all term deliveries were included (n=795 072). Risk factors for postpartum wound infections, endometritis and urinary tract infection were evaluated. Paper III included all deliveries (n=841 780) and examined the impact of BMI on the risk of postpartum wound infections, endometritis and breast abscess after different modes of delivery. Infections were defined as the presence of applicable ICD-10 codes. The Mantel-Haenszel technique was used to calculate adjusted odds ratios. In paper IV the association between vitamin D deficiency and overall postpartum infectious morbidity was analyzed. Serum samples from the Pregnancy Biobank in Linköping, drawn at the time of delivery, were used to determine concentrations of 25-hydroxyvitamin D in 1397 women. ICD-10 codes were extracted from the women’s medical records. The prevalence of vitamin D deficiency was calculated and adjusted odds ratios for postpartum infections were estimated with multivariable logistic regression analysis.Results: More than one out of ten women in southeast Sweden reported wound infections; endometritis, urinary tract infection or mastitis postpartum and 7.5% reported antibiotic treatment for infection. Cesarean section was the strongest risk factor for wound infection, followed by obstetric anal sphincter injuries and episiotomy. For endometritis, the strongest risk factors were anemia, manual placental removal and emergency cesarean section. Urinary tract infection was associated with anemia, instrumental vaginal delivery and emergency cesarean section. There was a dose-dependent increased risk of postpartum infection with higher BMI. For morbidly obese women the risk of infection was over 50% higher than for normal weight women. The risk of endometritis after normal vaginal delivery increased the higher the BMI, as did the risk of wound infection after cesarean section, regardless of the type of cesarean section. For breast abscess, there was an inverse association with BMI.Vitamin D deficiency was present among almost 60% of pregnant women at the time of delivery. No association between vitamin D deficiency and postpartum infections was found.Conclusions: Every tenth Swedish woman acquired an infection postpartum and three quarters of them received antibiotics for infection. Anemia was an important risk factor for postpartum infection, and the strongest risk factor for endometritis and urinary tract infection. Strong efforts should be made to reduce blood loss during and after childbirth. This thesis confirmed cesarean section as a major risk factor for postpartum infection, especially wound infection. The risk increased if the woman was overweight or obese, regardless of whether it was a planned or an emergency cesarean section.Vitamin D deficiency was common among Swedish pregnant women, but it was not found to be associated with postpartum infections.
|
|
| 10. |
- Axelsson, Daniel, et al.
(författare)
-
Vitamin D deficiency at the time of delivery : Prevalence and risk of postpartum infections
- 2019
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Postpartum infections are a common cause of morbidity after childbirth. Vitamin D deficiency has been shown to increase the risk for several infections in a non-pregnant population. Vitamin D deficiency has been described as common in pregnant women.Objective: To investigate whether vitamin D deficiency in pregnant women in labor was associated with an increased risk of overall postpartum infectious morbidity within eight weeks of delivery. A secondary aim was to estimate the prevalence of vitamin D deficiency among pregnant women in Linkoping, Sweden at the time of delivery.Material and methods: Serum vitamin D levels in labor were analyzed for 1397 women. Vitamin D deficiency was defined as serum levels <50 nmol/L. All ICD-10 codes given to the women eight weeks postpartum were reviewed and postpartum infections were defined as the presence of an ICD-10 code suggestive of infection. The prevalence of postpartum infections among women with sufficient vitamin D levels was compared with women with vitamin D deficiency. Adjusted Odds Ratios and 95% confidence intervals for postpartum infections were calculated using multivariate logistic regression analysis.Results: Fifty eight per cent of the women had serum vitamin D levels <50 nmol/L. The proportion of women with vitamin D deficiency varied, as expected, with season. No association between vitamin D deficiency and postpartum infections was found. For vitamin D 25-50 nmol/L the adjusted Odds Ratio was 0.85 (95% confidence interval 0.56-1.29) and for vitamin D <25 nmol/L the adjusted Odds Ratio was 1.15 (95% confidence interval 0.66-2.03). Women who smoked or who had a cesarean section had an increased risk of postpartum infections.Conclusions: Vitamin D deficiency was more common than previously reported in Swedish pregnant women. No association between vitamin D deficiency and postpartum infections was found. Other well-known risk factors for postpartum infection were identified.
|
|
