Yvonne Jonsson

Immunology of preeclampsia

Preeclampsia is a placenta-dependent disorder with both local and systemic anomalies with neonatal and maternal morbidity. It is manifested late in pregnancy, but the onset is during early stages of gestation. The current hypothesis regarding the aetiology of preeclampsia is focused on maladaptation of immune responses and defective trophoblast invasion. Thus, an excessive maternal inflammatory response, perhaps directed against foreign fetal antigens, results in a chain of events including shallow trophoblast invasion, defective spiral artery remodelling, placental infarction and release of pro-inflammatory cytokines and placental fragments in the systemic circulation. During normal pregnancy, trophoblasts interact in the decidua with the unique uterine NK cells, modifying their cytokine repertoire, regulating adhesion molecules and matrix metalloproteinases. The inability of trophoblasts to accomplish these changes might be a critical factor for the onset of preeclampsia. Several cytokines, produced at the maternal-fetal interface, have an impact on trophoblast invasion. It is suggested that deficiency of interleukin-10 may contribute to enhanced inflammatory responses towards the trophoblasts elicited by e.g. tumour necrosis factor-alpha and interferon-gamma. Consequently, trophoblasts subjected to a high rate of apoptosis are hampered in their invasive capacity resulting in defective transformation of spiral arteries, hypoxia, thrombosis and infarction of the placenta. The ensuing infarction of placenta leads to leakage of increasing amounts of placental fragments and cytokines in the maternal circulation and an exaggerated systemic endothelial activation as identified in preeclampsia. So far, treatment of preeclampsia is focused on signs like hypertension, whereas attempts of modifying immune responses may be a possibility in the future.

Systemic Th1/Th2 cytokine responses to paternal and vaccination antigens in preeclampsia: No differences compared with normal pregnancy

Problem:  A Th1‐shift has been suggested to be involved in the pathogenesis of preeclampsia. This study was designed to compare Th1/Th2 related cytokine secretion in blood between women with preeclampsia (n = 15) and normal pregnancies (n = 15), using a high‐sensitivity technique for cytokine detection.

Total and allergen-specific IgE levels during and after pregnancy in relation to maternal allergy.

Type 2 T-helper cell (Th2)-skewed immunity is associated with successful pregnancy and the ability to easily direct immune responses to a Th2-polarised profile may be an evolutionary benefit. The Th2-like immunity associated with allergic disease might generate favourable effects for the maintenance of pregnancy, but could also promote development of Th2-like immune responses and allergic disease in the offspring. The aim of this study was to explore, by using IgE as a stable proxy for Th2, the Th1/Th2 balance in allergic and non-allergic women by measuring allergen-specific and total IgE antibody levels in plasma during pregnancy and after delivery. Specific and total IgE antibody levels were determined by ImmunoCAP technology at five occasions during pregnancy (gestational weeks 10-12, 15-16, 25, 35 and 39), as well as at 2 and 12 months after delivery. Thirty-six women without and 20 women with allergic symptoms were included, of whom 13 were sensitised with allergic symptoms and 30 were non-sensitised without allergic symptoms. The levels of total IgE, but not allergen-specific IgE, were increased during early pregnancy when compared to 12 months after delivery in the sensitised women with allergic symptoms, but not in the non-sensitised women without allergic symptoms (p<0.01). This increase in total IgE levels during early pregnancy only in the sensitised women with allergic symptoms indicates that allergy is associated with an enhanced Th2 deviation during pregnancy.

Increased circulating paternal antigen-specific IFN-γ-and IL-4-secreting cells during pregnancy in allergic and non-allergic women

INTRODUCTION Allergic women have been reported to give birth to more children than non-allergic women, speculatively explained by the formers predisposition for Th2 polarization, possibly favoring pregnancy. AIM The aim of this study was to test the hypothesis that allergy is associated with more Th2-deviated responses to paternal antigens throughout pregnancy. METHODS Blood samples were collected on six occasions during pregnancy and two occasions postpartum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Eleven women fulfilled the strict criteria for allergy (allergic symptoms and circulating IgE antibodies to inhalant allergens) and 23 were strictly non-allergic (non-sensitized without symptoms). The numbers of blood mononuclear cells secreting IFN-gamma and IL-4, spontaneously and in response to paternal alloantigens, were compared between the groups. RESULTS The numbers of spontaneously as well as paternal antigen-induced IFN-gamma- and IL-4-secreting cells were similar in allergic and non-allergic pregnant women on all occasions. A similar increase in the numbers of both IFN-gamma- and IL-4-secreting cells were found in allergic and non-allergic women during pregnancy, both regarding spontaneous and paternal antigen-induced secretion. CONCLUSIONS This study does not support the hypothesis of a more pronounced Th2-deviation to paternal antigens in allergic pregnant women compared with non-allergic pregnant women, as measured by number of cytokine-secreting cells. The observed increase of both IFN-gamma- and IL-4-secreting cells during normal pregnancy may be interpreted as a Th2-situation, since the effects of IL-4 predominate over the effects of IFN-gamma.

Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.

Immunological status in patients undergoing in vitro fertilisation: responses to hormone treatment and relationship to outcome

We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMCs) in response to hormone treatment in women undergoing in vitro fertilisation (IVF) and to examine the predictive value of the cytokine secretion profile in the outcome of IVF treatment, in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and four weeks after embryo transfer. The numbers of Th1-, Th2- and Th17-associated cytokine-secreting cells and cytokine levels in cell supernatants were analysed by enzyme-linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pick-up, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5- and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. A larger study is required to confirm this conclusion. Higher numbers of Th2-associated cytokine-secreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.

Cytokine profile in women with preeclampsia

Preeclampsia is a severe complication engaging 5–10% of all pregnancies. Immune mechanisms have been suggested in the etiology of this disease.