Peripheral monocyte expression of the chemokine receptors CCR2, CCR5 and CXCR3 is altered at parturition in healthy women and in women with systemic lupus erythematosus.

Monocytes are precursors of macrophages and recruited to the uterus throughout pregnancy to perform important immunological functions. In this study, we hypothesized that pregnant women have reduced peripheral monocyte expression of chemokine receptors and alterations in PBMC responses to microbial stimuli as an adaption to pregnancy and that these changes are less pronounced in women with autoimmunity. We therefore investigated the chemokine receptor expression, migratory behaviour and responses to microbial stimulation of peripheral monocytes from pregnant women at parturition (n = 13) and from non-pregnant women (n = 9). In addition, we compared healthy pregnant women with women suffering from SLE (n = 5), a condition with pronounced systemic inflammation increasing the risk for pregnancy complications. We demonstrate that peripheral monocytes are affected by pregnancy with reduced percentages of CCR2+, CCR5+ and CXCR3+ monocytes of both classical (CD16-) and inflammatory (CD16+) subsets and that the trophoblast-secreted chemokine CCL2/MCP-1 recruited monocytes of both subsets in vitro. Further, PBMCs from pregnant women had a divergent response to microbial stimulation with lower CCL5/RANTES and higher CCL2/MCP-1 secretion compared with non-pregnant women. In addition, pregnant women had lower basal PBMC-secretion of CCL5/RANTES and higher basal secretion of IL-10 and CCL2/MCP-1. Interestingly, the women with SLE responded similar to pregnancy as did healthy women with lower percentages of CCR2+, CCR5+ and CXCR3+ monocytes. However, they had increased expression of CCR5 on CD16+ monocytes and heightened PBMC-secretion of CCL5/RANTES. In conclusion, our data indicate that monocyte chemokine receptor expression and the chemokine milieu during pregnancy are tightly regulated to support pregnancy.

Pregnancy-associated inflammatory markers are elevated in pregnant women with systemic lupus erythematosus.

During normal pregnancy a dampening in T cell-mediated immunity is compensated by an increased pro-inflammatory activity. Likewise, the autoimmune disease systemic lupus erythematosus (SLE) is associated with inflammatory activity and pregnancy complications occur frequently in women with SLE. The aim of this study was to elucidate how SLE influences the chemokine and cytokine balance during and after pregnancy. Blood samples were taken from pregnant women with or without SLE at second and third trimester and 8-12 weeks after pregnancy. Cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, TNF, IFN-γ and IFN-α), chemokines (CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CCL2/MCP-1, CCL5/RANTES and CCL17/TARC), soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (gp130) were measured in serum using cytometric bead array (CBA) or enzyme-linked immunosorbent assay (ELISA). Women with SLE had increased serum concentrations of CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10 and IL-10 compared to controls both during and after pregnancy. Further, when dividing the patients based on disease activity, the women with active disease had the highest levels. Importantly, women with SLE seemed to respond to pregnancy in a similar way as controls, since the changes of cytokines and chemokines over the course of pregnancy were similar but with overall higher levels in the patient group. In conclusion, changes in pro- and anti-inflammatory serum components during pregnancy in women with SLE, occurring on top of already more pro-inflammatory levels, might increase their risk for pregnancy complications and flares. How their children are affected by this heightened inflammatory milieu during pregnancy needs further investigation.

Maternal country of origin, breast milk characteristics and potential influences on immunity in offspring.

Breast milk contains pro- and anti-inflammatory cytokines and chemokines with potential to influence immunological maturation in the child. We have shown previously that country of birth is associated with the cytokine/chemokine profile of breast milk. In this study we have investigated how these differences in breast milk affect the cellular response of cord blood mononuclear cells (CBMCs) and intestinal epithelial cells (IECs, cell line HT-29) to microbial challenge. Ninety-five women were included: 30 from Mali in West Africa, 32 Swedish immigrants and 33 native Swedish women. CBMCs or IECs were stimulated in vitro with breast milk, alone or in combination with lipopolysaccharide (LPS) or peptidoglycan (PGN). Breast milk in general abrogated the LPS-induced down-regulation of surface CD14 and Toll-like receptor (TLR)-4 expression on CB monocytes, while inhibiting the PGN-induced TLR-2 up-regulation. However, breast milk from immigrant women together with LPS induced a lower CBMC release of interleukin (IL)-6 (P = 0·034) and CXCL-8/IL-8 (P = 0·037) compared with breast milk from Swedish women, while breast milk from Swedish women and Mali women tended to increase the response. The same pattern of CXCL-8/IL-8 release could be seen after stimulation of IECs (HT-29). The lower CBMC and IEC (HT-29) responses to microbial compounds by breast milk from immigrant women could be explained by the fact that breast milk from the immigrant group showed a divergent pro- and anti-inflammatory content for CXCL-8/IL-8, transforming growth factor-ß1 and soluble CD14, compared to the other two groups of women. This may have implications for maturation of their children's immune responses.

Impaired Toll-like receptor 2 signalling in monocytes from 5-year-old allergic children.

The relative composition of the two major monocytic subsets CD14(+)CD16(-) and CD14(+)CD16(+) is altered in some allergic diseases. These two subsets display different patterns of Toll-like receptor levels, which could have implications for activation of innate immunity leading to reduced immunoglobulin E-specific adaptive immune responses. This study aimed to investigate if allergic status at the age of 5 years is linked to differences in monocytic subset composition and their Toll-like receptor levels, and further, to determine if Toll-like receptor regulation and cytokine production upon microbial stimuli is influenced by the allergic phenotype. Peripheral blood mononuclear cells from 5-year-old allergic and non-allergic children were stimulated in vitro with lipopolysaccharide and peptidoglycan. Cells were analysed with flow cytometry for expression of CD14, Toll-like receptors 2 and 4 and p38-mitogen-activated protein kinase (MAPK). The release of cytokines and chemokines [tumour necrosis factor, interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12p70] into culture supernatants was measured with cytometric bead array. For unstimulated cells there were no differences in frequency of the monocytic subsets or their Toll-like receptor levels between allergic and non-allergic children. However, monocytes from allergic children had a significantly lower up-regulation of Toll-like receptor 2 upon peptidoglycan stimulation. Further, monocytes from allergic children had a higher spontaneous production of IL-6, but there were no differences between the two groups regarding p38-MAPK activity or cytokine and chemokine production upon stimulation. The allergic subjects in this study have a monocytic population that seems to display a hyporesponsive state as implicated by impaired regulation of Toll-like receptor 2 upon peptidoglycan stimulation.

Noonan and cardio-facio-cutaneous syndromes: two clinically and genetically overlapping disorders.

BACKGROUND: Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFC) are related disorders associated with disrupted RAS/RAF/MEK/ERK signalling. NS, characterised by facial dysmorphism, congenital heart defects and short stature, is caused by mutations in the genes PTPN11, SOS1, KRAS and RAF1. CFC is distinguished from NS by the presence of ectodermal abnormalities and more severe mental retardation in addition to the NS phenotype. The genetic aetiology of CFC was recently assigned to four genes: BRAF, KRAS, MEK1 and MEK2. METHODS: A comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated patients without mutations in PTPN11 is presented. RESULTS: Mutations were identified in seven patients with CFC (two in BRAF, one in KRAS, one in MEK1, two in MEK2 and one in SOS1). Two mutations were novel: MEK1 E203Q and MEK2 F57L. The SOS1 E433K mutation, identified in a patient diagnosed with CFC, has previously been reported in patients with NS. In one patient with NS, we also identified a mutation, BRAF K499E, that has previously been reported in patients with CFC. We thus suggest involvement of BRAF in the pathogenesis of NS also. CONCLUSIONS: Taken together, our results indicate that the molecular and clinical overlap between CFC and NS is more complex than previously suggested and that the syndromes might even represent allelic disorders. Furthermore, we suggest that the diagnosis should be refined to, for example, NS-PTPN11-associated or CFC-BRAF-associated syndromes after the genetic defect has been established, as this may affect the prognosis and treatment of the patients.

Maternal allergy influences p38-mitogen-activated protein kinase activity upon microbial challenge in CD14+ monocytes from 2-year-old children.

BACKGROUND: The development of allergic diseases is dependent on genetic and environmental factors. It has been shown previously that cord blood mononuclear cells (CBMCs) from infants with parental allergy have altered cytokine profiles upon bacterial encounter; it might be possible that such impairment persists during the early years of childhood. OBJECTIVE: The aim of this study was to investigate anti-microbial responses with regard to p38-mitogen-activated protein kinase (MAPK) activity in CD14(+) monocytes and IL-6 release from mononuclear cells in the same group of children at birth and at 2 years of age. Methods Paired samples of CBMCs and peripheral blood mononuclear cells (PBMCs) were stimulated with either lipopolysaccharide (LPS) or peptidoglycan in vitro. CD14(+) monocytes were analysed for p38-MAPK activity by flow cytometry, and soluble IL-6 receptor, soluble glycoprotein130 and IL-6 release from PBMC cultures were quantified by ELISA. RESULTS: CBMCs from newborns with allergic mothers tended to have a lower IL-6 response following an LPS (P=0.09) challenge compared with the group without maternal allergy while p38-MAPK activation levels did not differ between the groups. PBMCs from 2-year-olds with allergic mothers released significantly less (P<0.05) IL-6 upon peptidoglycan stimuli compared with age-matched infants with non-allergic mothers. Infants with allergic mothers displayed markedly reduced CD14(+) monocyte p38-MAPK phosphorylation after LPS (P<0.05) and peptidoglycan (P<0.01) challenge. This altered anti-microbial response was attributed to maternal allergy rather than to being IgE-sensitized at 2 years of age. CONCLUSION: Monocytes from children with allergic mothers are less responsive to bacterial challenge than monocytes from children with non-allergic mothers, and this impairment persists during the first 2 years of infancy.

On the velocity maximization in downhill skiing.

The dynamics of a skier performing downhill are considered. The equations of motion are utilized in a dimensionless form revealing the most important physical and physiological parameters controlling the skier speed. Several analytical results for the straight hill case are derived. The optimal shape of a hill in a vertical plane to produce maximal velocity increase between two given points is sought. The effect of the four dimensionless parameters appearing in the problem, accounting for air drag and lift, air density, ski friction, skier mass, and length and steepness of the hill, on the optimal hill shape and the final optimal velocity is studied. A comparison with the corresponding straight slope is made showing that the optimal shape may typically lead to a 50% increase in the final velocity. The variational procedure employed also yields the hill shape for minimal velocity increase between two points. The results may be used in speed prediction and hill design.

Handshaking, personality, and psychopathology in psychiatric patients, a reliability and correlational study.

A study of 29 psychiatric inpatients was performed to investigate the relation of handshaking variables (anatomical and physiological variables) with demographic data, personality traits, psychosocial functioning, and clinical diagnoses. Two psychologists rated patients' handshaking independently of each other according to four variables on an ordinal scale of five steps. The interrater reliability was satisfactory. Analysis showed that the handshaking procedure may in fact give some information about the personality make-up of the patients, most clearly through the relationship between low temperature and humidity of the palmar skin and social introversion, depression, and tendency towards symptom enhancement mainly in women. The handshaking procedure did not seem informative about psychosocial functioning and clinical diagnoses.

Presence of IgE cells in human placenta is independent of malaria infection or chorioamnionitis.

We have shown previously that numerous IgE(+) macrophage-like cells are present in the villous stroma of full term placenta and that there was no difference in the amount of IgE(+) cells between allergic and non-allergic mothers. The presence of such an abundant number of IgE(+) cells in the placenta in allergic as well as non-allergic women suggests that the IgE is of some importance for a successful pregnancy outcome. Here we have investigated the IgE-pattern in 59 placentas from second and third trimesters from Sweden with different degrees of chorioamnionitis and 27 full term placentas from Ghana with and without malaria parasites. The immunohistochemical staining pattern for IgE looked similar to our previous study, with the IgE located on Hofbauer-like cells. We could not find any difference in the amount or distribution of IgE(+) cells between malaria-infected and non-infected placentas, nor between different degrees of chorioamnionitis. The IgE score in the placenta did not correlate with the levels of IgE in maternal serum or plasma. However, the IgE score was significantly higher in second- compared to third-trimester placentas (P = 0.03). This might reflect a maturation time-point in the fetus and in the intrauterine environment during the second trimester, or it might be associated with the increased number of intrauterine fetal deaths in the second trimester.

The experience of dysmenorrhea and its relationship to personality variables.

The aims of this study were: to relate women's subjective experience of primary dysmenorrhea to psychogenic needs assessed longitudinally at the age of 15 and at the age of 25 in a nonclinical sample; to compare the psychogenic needs of women with severe primary dysmenorrhea with those of other women who never have experienced dysmenorrhea; and to examine whether women with severe dysmenorrhea were less conventionally feminine than women who never have experienced dysmenorrhea. At 25 years, 42% of the women experienced dysmenorrhea and 15% experienced pain that limited their daily activity. Differences in psychogenic needs according to the Cesarec Marke Personality Schedule and in psychological masculinity and femininity according to the Attitude Interest Schedule were found in women with severe primary dysmenorrhea compared with women who never experienced dysmenorrhea. The results indicate that women with severe dysmenorrhea have less self-esteem at 15 years, but compensate for this at 25 years by being more achievement-oriented and aggressive than women who never experienced dysmenorrhea. Further, women with severe dysmenorrhea are more conventionally feminine than women who never have experienced dysmenorrhea.

Psychogenic needs and psychiatric symptoms in young Swedish women.

In a longitudinal study of personality, 66 women completed the Cesarec Marke Personality Schedule, a Swedish personality inventory, in order to asses their psychogenic needs at the age of 15 and 25. Psychiatric symptoms and a number of background variables were assessed independently after the completion of the Cesarec Marke Personality Schedule, with the aim of examining whether traits and background variables were related to psychiatric symptoms. The psychogenic needs Defence of Status and Guilt Feelings at the age of 15 were positively and significantly related to depressive and anxiety symptoms and high score on psychiatric morbidity in general. The psychogenic needs Defence of Status, Guilt Feelings and Succourance at the age of 25 were significantly related to the symptom constructs Somatization, Interpersonal-sensitivity, Depression, Anxiety-phobia, and General Morbidity. Subjects with a low score of psychiatric symptoms differed from high scoring subjects by having been raised by older parents, experienced a secure childhood, better relationships with siblings and peers, and a longer education. It may be hypothesized that high scores on Defence of Status and Guilt Feelings in combination with less favourable background variables may constitute a vulnerability factor for depression and anxiety.

CD14 and development of atopic disease at 2 years of age in children with atopic or non-atopic mothers.

BACKGROUND: CD14, a myeloid cell marker and LPS receptor has been acclaimed to play a role in development and manifestation of atopic allergy, as the gene encoding CD14 is located in a chromosomal region linked to total IgE levels and atopic disease. OBJECTIVE: To investigate the levels of soluble (s) and membrane bound (m) CD14 in cord blood and at 2 years of age from children with atopic or non-atopic mothers and relate these parameters to atopy development at 2 years of age. METHODS: Blood samples were collected at delivery (cord blood) and at 2 years of age among infants with atopic (n = 41) and non-atopic (n = 32) mothers. Blood samples were also obtained from mothers at the same occasions. Levels of sCD14 and total IgE were measured in plasma, and percentages of CD14+ cells were measured in cord and peripheral blood mononuclear cells. RESULTS: We observed significant differences in sCD14 levels in cord blood, where children with atopic mothers had the highest levels. The same pattern could be observed in the mothers at delivery. At 2 years of age no significant differences in sCD14 levels were observed between children with atopic mothers and children with non-atopic mothers and no association between sCD14 and atopic disease was found. Further, we observed large differences in sCD14 and mCD14 with respect to age, where newborns displayed a higher frequency of CD14+ cells compared with the 2-year-olds and the mothers. The reverse was observed for sCD14, with significantly lower values in cord blood than those seen in the 2-year-olds and mothers. CONCLUSION: Based on our findings, we suggest that CD14 could be involved in the regulation of IgE production, but that it might also be important for the maturation and development of the neonatal immune system.

IgE is expressed on, but not produced by, fetal cells in the human placenta irrespective of maternal atopy.

The prevalence of atopic diseases in children has increased during the last decades. Atopic symptoms usually appear early in life. This implies an early priming for atopic disease, possibly even at the fetal level. We therefore compared the presence and production of IgE in the local in utero environment during pregnancy in atopic and non-atopic women. Eighty-six women were included in the study. Fifty women were demonstrated to be atopics, based on clinical symptoms of atopic disease together with a positive Phadiatop and/or skin prick test. Placentas from these term pregnancies were obtained. Slices covering the full thickness of the placenta were cut clockwise around the umbilical cord and were analysed with immunohistochemistry. Surprisingly, numerous IgE+ cells, located primarily in the fetal villous stroma, were detected in a majority of the investigated placentas irrespective of the atopy of the mother or maternal or fetal total serum IgE levels. The placental IgE could not be demonstrated to be bound to IgE receptors, but was shown to be bound to fetal macrophages, possibly via FcgammaRI. No evidence was found for local fetal IgE production, although cells producing epsilon transcripts were occasionally detected in the decidua. We describe here the novel finding of numerous IgE+ cells in the human placenta, suggesting an hitherto unknown role for IgE in a successful pregnancy outcome, irrespective of whether or not the mother is atopic.

Levels of soluble CD30 in cord blood and peripheral blood during childhood are not correlated with the development of atopic disease or a family history of atopy.

BACKGROUND: The CD30 molecule has been linked to Th2 responses. Furthermore, elevated levels of the soluble form of CD30 (sCD30) in blood as well as of the expression of CD30 on the plasma membrane of T cells are associated with atopic disease. OBJECTIVE: To assess the potential usefulness of sCD30 levels as a prognostic indicator of and/or diagnostic marker for the development of atopic disease in children. METHODS: sCD30 levels in cord blood and peripheral blood from 36 2-year-old (10 atopic and 26 non-atopic) and 74 7-year-old (35 atopic and 39 non-atopic) children were determined employing an ELISA procedure. Atopy was diagnosed on the basis of clinical evaluation in combination with a positive skin prick test. RESULTS: No significant correlation between sCD30 levels in cord blood and the development of atopic disease at 2 or 7 years of age was observed. At 7 years of age, the circulating sCD30 levels in children with atopic disease (median 41 U/mL, range 6-503 U/mL) did not differ from the corresponding values for non-atopic subjects (median 41 U/mL, range 8-402 U/mL). The same was true for children at 2 years of age. Furthermore, the sCD30 levels of children who had developed atopic eczema/dermatitis syndrome by the age of 7 years (median 49 U/mL, range 14-503 U/mL) were not significantly elevated in comparison with those of the non-atopic children. Finally, neither sCD30 levels in cord blood nor peripheral blood at 2 or 7 years of age could be linked to a family history of atopy. CONCLUSION: These findings indicate that the sCD30 concentration in cord blood is not a reliable prognostic indicator of, nor a useful diagnostic marker for, atopic disease in children up to 7 years of age. If such correlations do exist, they might be masked by age-dependent variations in the circulating levels of sCD30, which may reflect individual differences in the maturation of children's immunological responses.