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  • 1.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Impaired Toll-like receptor 2 signaling in monocytes from 5-year-old allergic children2009In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 155, no 3, p. 387-394Article in journal (Refereed)
    Abstract [en]

    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)-1β, 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.

  • 2.
    Amoudruz, Petra
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Schollin, Jens
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Montgomery, Scott M
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Maternal country of birth and previous pregnancies are associated with breast milk characteristics2009In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 20, no 1, p. 19-29Article in journal (Refereed)
    Abstract [en]

    Populations in high infectious exposure countries are at low risk of some immune-mediated diseases such as Crohn’s disease and allergy. This low risk is maintained upon immigration to an industrialized country, but the offspring of such immigrants have a higher immune-mediated disease risk than the indigenous population. We hypothesize that early life exposures in a developing country shape the maternal immune system, which could have implications for the offspring born in a developed country with a low infectious load. The aim of this study was to investigate if exposures in childhood (indicated by country of origin) and subsequent exposures influence immunologic characteristics relevant to stimulation of offspring. Breast milk components among 64 mothers resident in Sweden, 32 of whom immigrated from a developing country, were examined using the ELISA and Cytometric Bead Array methods. Immigrants from a developing country had statistically significantly higher levels of breast milk interleukin-6 (IL-6), IL-8 and transforming growth factor-β1. A larger number of previous pregnancies were associated with down-regulation of several substances, statistically significant for soluble CD14 and IL-8. The results suggest that maternal country of birth may influence adult immune characteristics, potentially relevant to disease risk in offspring. Such a mechanism may explain the higher immune-mediated disease risk among children of migrants from a developing to developed country. Older siblings may influence disease risk through the action of previous pregnancies on maternal immune characteristics.

  • 3. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric A.
    Apinjoh, Tobias O.
    Mugri, Regina N.
    Chi, Hanesh Fru
    Tata, Rolland B.
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Troye Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Antenatal care visit attendance, intermittent preventive treatment during pregnancy (IPTp) and malaria parasitaemia at delivery2014In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 162-Article in journal (Refereed)
    Abstract [en]

    Background: The determinants and barriers for delivery and uptake of IPTp vary with different regions in sub-Saharan Africa. This study evaluated the determinants of ANC clinic attendance and IPTp-SP uptake among parturient women from Mount Cameroon Area and hypothesized that time of first ANC clinic attendance could influence uptake of IPTp-SP/dosage and consequently malaria parasite infection status at delivery. Methods: Two cross sectional surveys were carried out at the Government Medical Centre in the Mutengene Health Area, Mt Cameroon Area from March to October 2007 and June 2008 to April 2009. Consented parturient women were consecutively enrolled in both surveys. In 2007, socio-demographic data, ANC clinic attendance, gestational age, fever history and reported use/dosage of IPTp-SP were documented using a structured questionnaire. In the second survey only IPT-SP usage/dosage was recorded. Malaria parasitaemia at delivery was determined by blood smear microscopy and placental histology. Results and discussion: In 2007, among the 287 women interviewed, 2.2%, 59.7%, and 38.1% enrolled in the first, second and third trimester respectively. About 90% of women received at least one dose SP but only 53% received the two doses in 2007 and by 2009 IPTp-two doses coverage increased to 64%. Early clinic attendance was associated (P = 0.016) with fever history while being unmarried (OR = 2.2; 95% CI: 1.3-3.8) was significantly associated with fewer clinic visits (<4visits). Women who received one SP dose (OR = 3.7; 95% CI: 2.0-6.8) were more likely not to have attended >= 4visits. A higher proportion (P < 0.001) of women with first visit during the third trimester received only one dose, meanwhile, those who had an early first ANC attendance were more likely (OR = 0.4; 95% CI = 0.2 - 0.7) to receive two or more doses. Microscopic parasitaemia at delivery was frequent (P = 0.007) among women who enrolled in the third trimester and had received only one SP dose than in those with two doses. Conclusion: In the study area, late first ANC clinic enrolment and fewer clinic visits may prevent the uptake of two SP doses and education on early and regular ANC clinic visits can increase IPTp coverage.

  • 4. Anchang-Kimbi, Judith K
    et al.
    Achidi, Eric A
    Nkegoum, Blaise
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women.2009In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 8, p. 126-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum malaria in pregnancy presents an enormous diagnostic challenge. The epidemiological and clinical relevance of the different types of malaria diagnosis as well as risk factors associated with malaria infection at delivery were investigated. METHOD: In a cross-sectional survey, 306 women reporting for delivery in the Mutenegene maternity clinic, Fako division, South West province, Cameroon were screened for P. falciparum in peripheral blood, placental blood and placental tissue sections by microscopy. Information relating to the use of intermittent preventive treatment in pregnancy with sulphadoxine/pyrimethamine, history of fever attack, infant birth weights and maternal anaemia were recorded. RESULTS: Among these women, P. falciparum infection was detected in 5.6%, 25.5% and 60.5% of the cases in peripheral blood, placental blood and placental histological sections respectively. Placental histology was more sensitive (97.4%) than placental blood film (41.5%) and peripheral blood (8.0%) microscopy. In multivariate analysis, age (< or = 20 years old) (OR = 4.61, 95% CI = 1.47 - 14.70), history of fever attack (OR = 2.98, 95% CI = 1.58 - 5.73) were significant risk factors associated with microscopically detected parasitaemia. The use of > or = 2 SP doses (OR = 0.18, 95% CI = 0.06 - 0.52) was associated with a significant reduction in the prevalence of microscopic parasitaemia at delivery. Age (>20 years) (OR = 0.34, 95% CI = 0.15 - 0.75) was the only significant risk factor associated with parasitaemia diagnosed by histology only in univariate analysis. Microscopic parasitaemia (OR = 2.74, 95% CI = 1.33-5.62) was a significant risk factor for maternal anaemia at delivery, but neither infection detected by histology only, nor past infection were associated with increased risk of anaemia. CONCLUSION: Placenta histological examination was the most sensitive indicator of malaria infection at delivery. Microscopically detected parasitaemia was associated with increased risk of maternal anaemia at delivery, but not low-grade parasitaemia detected by placental histology only.

  • 5. Anchang-Kimbi, Judith K.
    et al.
    Achidi, Eric Akum
    Nkegoum, Blaise
    Mendimi, Joseph-Marie N.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    IgG isotypic antibodies to crude Plasmodium falciparum blood-stage antigen associated with placental malaria infection in parturient Cameroonian women2016In: African Health Sciences, ISSN 1680-6905, E-ISSN 1729-0503, Vol. 16, no 4, p. 1007-1017Article in journal (Refereed)
    Abstract [en]

    Background: Few studies have reported an association between placental malaria (PM) infection and levels of isotypic antibodies against non-pregnancy associated antigens. Objective: To determine and evaluate IgG isotypic antibody levels to crude P. falciparum blood stage in women with and without PM infection. Methods: Levels of IgG (IgG1-IgG4) and IgM to crude P. falciparum blood stage antigen were measured by ELISA in 271 parturient women. Placental malaria infection was determined by placental blood microscopy and placental histology. Age, parity and intermittent preventive treatment during pregnancy with sulphadoxine-pyrimethamine (IPTp-SP) usage were considered during analysis. Results: P. falciparum-specific IgG1 (96.5%) and IgG3 (96.7%) antibodies were predominant compared with IgG2 (64.6%) and IgG4 (49.1%). Active PM infection was associated with significant increased levels of IgG1, IgG4 and IgM while lower levels of these antibodies were associated with uptake of two or more IPTp-SP doses. PM infection was the only independent factor associated with IgG4 levels. Mean IgG1 + IgG3/IgG2 + IgG4 and IgG1 + IgG2 + IgG3/IgG4 ratios were higher among the PM-uninfected group while IgG4/IgG2 ratio prevailed in the infected group. Conclusion: PM infection and IPTp-SP dosage influenced P. falciparum-specific isotypic antibody responses to blood stage antigens. An increase in IgG4 levels in response to PM infection is of particular interest.

  • 6. Bachmayer, Nora
    et al.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Sundström, Yvonne
    Hamad, Rangeen Rafik
    Berg, Louise
    Bremme, Katarina
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Women with pre-eclampsia have an altered NKG2A and NKG2C receptor expression on peripheral blood natural killer cells.2009In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 62, no 3, p. 147-57Article in journal (Refereed)
    Abstract [en]

    PROBLEM: Preeclampsia, a pregnancy disorder, is associated with exaggerated inflammation and increased serum monokines. Uterine natural killer (NK) cells are implicated in preeclampsia pathology, but little is known regarding peripheral NK cells in the disease. METHOD OF STUDY: We examined blood NK cells at delivery in women with preeclampsia, in healthy pregnant women and in healthy non-pregnant blood donors as a reference. RESULTS: Although the percentages of both NKG2A- and NKG2C-positive NK cells were normal in preeclamptic women, the levels of NKG2A and NKG2C on NK cells were significantly up-regulated in these women. In vitro stimulation of PBMCs from healthy pregnant women and blood donors with monokines resulted in increased percentage of NKG2A(+) NK cells and increased NKG2A levels, while levels of NKG2C were decreased. CONCLUSIONS: Our results suggest that the peripheral NK-cell pool is skewed in preeclampsia and possibly under the influence of monokines like interleukin (IL)-15 and IL-12.

  • 7. Bemark, Mats
    et al.
    Friskopp, Linda
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Koethe, Susanne
    Fasth, Anders
    Abrahamsson, Jonas
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Andersson, Bengt A.
    Mellgren, Karin
    A glycosylation-dependent CD45RB epitope defines previously unacknowledged CD27(-)IgM(high) B cell subpopulations enriched in young children and after hematopoietic stem cell transplantation2013In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 149, no 3, p. 421-431Article in journal (Refereed)
    Abstract [en]

    The immune system is dysfunctional for years after hematopoietic stem cell transplantation (HSCT). A potential cause is an intrinsic B cell deficiency. In a cohort of pediatric HSCT patients few CD27(+) B cells formed after transplantation with the number of CD27(+)IgM(high) cells more affected than class-switched ones. A previously unacknowledged population of CD27(-)IgM(high) cells made up the majority of B cells and this population was also enlarged in healthy children compared to adults. Only a minority of these CD27(-)IgM(high) B cells expressed markers typical for transitional B cells, and the non-transitional CD27(-)IgM(high) cells could be further divided into subpopulations based on their ability to extrude the dye Rhodamine 123 and their expression of CD45RB(MEM55), a glycosylation-dependent epitope. Thus, we define several novel human CD27(-)IgM(high) B cell subpopulations in blood, all of which are present in higher frequencies and numbers in young children and after HSCT than in adults.

  • 8. Beziat, Vivien
    et al.
    Liu, Lisa L.
    Malmberg, Jenny-Ann
    Ivarsson, Martin A.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björklund, Andreas T.
    Retiere, Christelle
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Traherne, James
    Ljungman, Per
    Schaffer, Marie
    Price, David A.
    Trowsdale, John
    Michaelsson, Jakob
    Ljunggren, Hans-Gustaf
    Malmberg, Karl-Johan
    NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 14, p. 2678-2688Article in journal (Refereed)
    Abstract [en]

    Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.

  • 9.
    Björkander, Sofia
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Bremme, K.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    van Vollenhoven, R. F.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Pregnancy-associated inflammatory markers are elevated in pregnant women with systemic lupus erythematosus2012In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 59, no 2, p. 392-399Article in journal (Refereed)
    Abstract [en]

    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)-1 beta, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, TNF, IFN-gamma and IFN-alpha), 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.

  • 10.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lasaviciute, Gintare
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Roos, Stefan
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22083Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus (S. aureus) is a human pathogen as well as a frequent colonizer of skin and mucosa. This bacterium potently activates conventional T-cells through superantigens and it is suggested to induce T-cell cytokine-production as well as to promote a regulatory phenotype in T-cells in order to avoid clearance. This study aimed to investigate how S. aureus impacts the production of regulatory and pro-inflammatory cytokines and the expression of CD161 and HELIOS by peripheral CD4(+)FOXP3(+) T-cells. Stimulation of PBMC with S. aureus 161:2-cell free supernatant (CFS) induced expression of IL-10, IFN-gamma and IL-17A in FOXP3(+) cells. Further, CD161 and HELIOS separated the FOXP3(+) cells into four distinct populations regarding cytokine-expression. Monocyte-depletion decreased S. aureus 161:2-induced activation of FOXP3(+) cells while pre-stimulation of purified monocytes with S. aureus 161:2-CFS and subsequent co-culture with autologous monocyte-depleted PBMC was sufficient to mediate activation of FOXP3(+) cells. Together, these data show that S. aureus potently induces FOXP3(+) cells and promotes a diverse phenotype with expression of regulatory and pro-inflammatory cytokines connected to increased CD161-expression. This could indicate potent regulation or a contribution of FOXP3(+) cells to inflammation and repression of immune-suppression upon encounter with S. aureus.

  • 11.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lasaviciute, Gintare
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Caroline
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    FOXP3+ CD4 T-cell maturity and responses to microbial stimulation alter with age and associate with early-life gut colonization2016In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 138, no 3, p. 905-908Article in journal (Refereed)
  • 12.
    Carvalho-Queiroz, Claudia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Jörtsö, Evelina
    Kjerstadius, Torbjörn
    Nilsson, Caroline
    Saghafian-Hedengren, Shanie
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Associations between EBV and CMV Seropositivity, Early Exposures, and Gut Microbiota in a Prospective Birth Cohort: A 10-Year Follow-up2016In: Frontiers in Pediatrics, ISSN 2296-2360, Vol. 4, article id 93Article in journal (Refereed)
    Abstract [en]

    Early-life infections with persistent Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are delayed in affluent countries, probably due to alterations in early environmental exposures, such as maternal age, siblings, and day-care attendance. We have previously reported that the timing of EBV and CMV contraction is related both to allergic sensitization and changes in functional competence of immune cells, while the presence/absence of lactobacilli [Lactobacillus (L.) casei, L. paracasei, and L. rhamnosus] or Staphylococcus (S.) aureus in feces is related to the risk for allergy. Here, we used the same prospective longitudinal birth cohort of children to investigate early-life environmental exposures and their influence on EBV and CMV contraction over time. Since gut microbes also belong to this category of early exposures, we investigated their association with herpesvirus contraction. Our results show that these two viruses are acquired with different kinetics and that EBV and CMV seroprevalence at 10 years of age was 47 and 57%, respectively. We also observed that a delayed EBV or CMV infection was associated with older maternal age [time ratio (TR) 1.14, 95% confidence interval (CI) 1.07-1.21, P-adj < 0.001 and TR 1.09, CI 1.03-1.16, P-adj = 0.008, respectively]. Further, we present the novel finding that S. aureus colonization reduced the time to CMV acquisition (TR 0.21, CI 0.06-0.78, = 0.02). Together, these findings suggest that there is a relationship between timing of herpesvirus acquisition and early-life immune modulating exposures, which interestingly also includes the early infant gut microbiota.

  • 13.
    Dubicke, Aurelija
    et al.
    Department of Woman and Child Health, Karolinska Institute,Stockholm, Sweden.
    Andersson, Peter
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Fransson, Emma
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    Andersson, Eva
    Department of Woman and Child Health, Karolinska Institute,Stockholm, Sweden.
    Sioutas, Angelos
    Malmström, Anders
    Department of Experimental Medical Science, University of Lund, Sweden.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Ekman-Ordeberg, Gunvor
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    High-mobility group box protein 1 and its signalling receptors in human preterm and term cervix2010In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 84, no 1, p. 86-94Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to identify possible changes in mRNA and protein expression of high-mobility group box protein 1 (HMGB1) and its suggested receptors - receptor for advanced glycation end-products (RAGE) and Toll-like receptor 2 (TLR2) and TLR4 - in human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 58 women: 20 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. Real-time RT-PCR was used to quantify mRNA expression, and immunohistochemistry and ELISA for protein analysis. HMGB1, RAGE, TLR2 and TLR4 proteins were localized and their mRNA expression was detected in the cervix. There was more extranuclear HMGB1 in the cervical epithelium and stroma in preterm and term labor compared to the term not in labor. TLR2 mRNA expression was upregulated 5-fold in term labor and 3-fold in preterm labor compared to term not in labor and non-pregnant controls. There was lower expression of TLR2 and TLR4 mRNAs in preterm labor compared to term. Lower mRNA expression of HMGB1 was found in the subgroup with preterm premature rupture of membranes than in the rest of the preterm group, where levels were significantly higher than in term labor. In conclusion, extranuclear expression of HMGB1 during labor suggests a possible role of HMGB1 during the process of cervical ripening. Changes in expression of mRNAs encoding HMGB1, TLR2 and TLR4 in preterm labor suggest differences in the mechanism of cervical ripening at preterm and term delivery.

  • 14.
    Dubicke, Aurelija
    et al.
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Sverremark-Ekström, Eva
    Stockholm University.
    Fransson, Emma
    Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.
    Centini, Gabriela
    Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, 53100 Siena, Ital.
    Andersson, Eva
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Byström, Birgitta
    Department of Woman and Child Health, Karolinska Institute. Stockholm, Sweden.
    Ekman-Ordeberga, Gunvor
    Department of Woman and Child Health, Karolinska Institute, Stockholm, Sweden.
    Malmström, Anders Malmström
    Department of Experimental Medical Science, University of Lund, 221 84 Lund, Sweden.
    Petraglia, Felice
    Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, 53100 Siena, Italy.
    Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening2010In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 84, no 2, p. 176-185Article in journal (Refereed)
    Abstract [en]

    Cervical ripening is necessary for successful delivery. Since cytokines are believed to be involved in this process, the aim of this study was to investigate possible changes in the mRNA and protein expression of pro-inflammatory cytokines (interleukin (IL)-1 alpha, IL-1 beta, IL-12, IL-18) and anti-inflammatory cytokines (IL-4, IL-10, IL-13)in the human cervix during pregnancy, term and preterm labor. Cervical biopsies were taken from 59 women: 21 at preterm labor, 24 at term labor, 10 at term not in labor and 4 from non-pregnant women. mRNA was analyzed with real-time RT-PCR and protein expression and/or secretion with immunohistochemistry and ELISA. There was an upregulation of mRNA for IL-10, IL-13, IL-1 alpha and IL-1 beta in the laboring groups, while mRNA for IL-12 and IL-18 was downregulated. IL-4 mRNA was detected more frequently, while IL-12 mRNA expression was lower, in the preterm labor group than in the term labor group. The protein levels of IL-4 and IL-12 were lower and IL-18 tended to be higher in the labor groups, while IL-10 protein levels were unaffected by labor. IL-4 protein levels were significantly higher in the preterm subgroup with bacterial infection than in the non-infected group. IL-10 had higher expression in squamous epithelium at preterm labor than at term. In conclusion, the major changes in pro-inflammatory and anti-inflammatory cytokine mRNA and protein expression in cervix occur during the labor process irrespective of the length of gestation. Our results indicate that dysregulation of anti-inflammatory cytokines in the human cervix could be involved in the pathogenesis of preterm labor.

  • 15. Ekstrom, Mattias
    et al.
    Liska, Jan
    Eriksson, Per
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Tornvall, Per
    Stimulated in vivo synthesis of plasminogen activator inhibitor 1 in human adipose tissue2012In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 108, no 3, p. 485-492Article in journal (Refereed)
    Abstract [en]

    Plasminogen activator inhibitor type-1 (PAI-1) is one of the most important inhibitors of endogenous fibrinolysis. Adipose tissue is a suggested source of the elevated plasma levels o(-) PAI-1 in obesity. The relation between PAI-1 and inflammation is of particular interest, but current knowledge regarding regulation of PAI-1 in adipose tissue is mainly based on animal studies or ex vivo experiments on human cultured adipocytes. So far, no study has described stimulated gene expression and protein synthesis of PAI-1 in vivo in human adipose tissue. We used open heart surgery as a model of acute systemic inflammation. Twenty-two male patients underwent blood sampling and omental and subcutaneous adipose tissue biopsies for gene expression studies before and after surgery. Expression and localisation of PAI-1 antigen was evaluated by immunohistochemistry. After surgery gene expression of PAI-1 increased 27-fold in omental adipose tissue and three-fold in subcutaneous adipose tissue, but no differences were found in tissue-type plasminogen activator (t-PA) mRNA. PAI-1 antigen was localised within endothelial cells and in the adipose tissue interstitium close to vessels. The upregulated gene expression and protein synthesis in adipose tissue was followed by increased concentrations of PAI-1 antigen in plasma. In conclusion, we present for the first time that an acute systemic inflammation in humans increased gene expression and protein synthesis of PAI-1 in adipose tissue and that this increase was most prominent in omental adipose tissue. PAI-1 synthesis in adipose tissue due to acute systemic inflammation may be a link between inflammation and impaired endogenous fibrinolysis.

  • 16. Fergusson, J. R.
    et al.
    Huehn, M. H.
    Swadling, L.
    Walker, L. J.
    Kurioka, A.
    Llibre, A.
    Bertoletti, A.
    Hollaender, G.
    Newell, E. W.
    Davis, M. M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Powrie, F.
    Capone, S.
    Folgori, A.
    Barnes, E.
    Willberg, C. B.
    Ussher, J. E.
    Klenerman, P.
    CD161(int)CD8+T cells: a novel population of highly functional, memory CD8+T cells enriched within the gut2016In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 9, no 2, p. 401-413Article in journal (Refereed)
    Abstract [en]

    The C-type lectin-like receptor CD161 is expressed by lymphocytes found in human gut and liver, as well as blood, especially natural killer (NK) cells, T helper 17 (Th17) cells, and a population of unconventional Tcells known as mucosalassociated invariant T (MAIT) cells. The association of high CD161 expression with innate T-cell populations including MAITcells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including antiviral populations that display a memory phenotype. These memory CD161(int)CD8+ Tcells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterized by enhanced polyfunctionality, increased levels of cytotoxic mediators, and high expression of the transcription factors T-bet and eomesodermin (EOMES). Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T-cell populations in humans. As induction of such responses represents a major aim of T-cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.

  • 17. Fergusson, Joannah R.
    et al.
    Smith, Kira E.
    Fleming, Vicki M.
    Rajoriya, Neil
    Newell, Evan W.
    Simmons, Ruth
    Marchi, Emanuele
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kang, Yu-Hoi
    Swadling, Leo
    Kurioka, Ayako
    Sahgal, Natasha
    Lockstone, Helen
    Baban, Dilair
    Freeman, Gordon J.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Davis, Mark M.
    Davenport, Miles P.
    Venturi, Vanessa
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, no 3, p. 1075-1088Article in journal (Refereed)
    Abstract [en]

    The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCR gamma delta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.

  • 18.
    Haileselassie, Yeneneh
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Zimmer, Christine L.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petursdottir, Dagbjort H.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Dicksved, Johan
    Petersson, Mikael
    Stockholm University, Faculty of Science, Department of Mathematics.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Fernández, Carmen
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Roos, Stefan
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lactobacilli Regulate Staphylococcus aureus 161:2-Induced Pro-Inflammatory T-Cell Responses In Vitro2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed)
    Abstract [en]

    There seems to be a correlation between early gut microbiota composition and postnatal immune development. Alteration in the microbial composition early in life has been associated with immune mediated diseases, such as autoimmunity and allergy. We have previously observed associations between the presence of lactobacilli and Staphylococcus (S.) aureus in the early-life gut microbiota, cytokine responses and allergy development in children. Consistent with the objective to understand how bacteria modulate the cytokine response of intestinal epithelial cell (IEC) lines and immune cells, we exposed IEC lines (HT29, SW480) to UV-killed bacteria and/or culture supernatants (-sn) from seven Lactobacillus strains and three S. aureus strains, while peripheral blood mononuclear cells (PBMC) and cord blood mononuclear cells (CBMC) from healthy donors were stimulated by bacteria-sn or with bacteria conditioned IEC-sn. Although the overall IEC response to bacterial exposure was characterized by limited sets of cytokine and chemokine production, S. aureus 161: 2-sn induced an inflammatory response in the IEC, characterized by CXCL1/GROa and CXCL8/IL-8 production, partly in a MyD88-dependent manner. UV-killed bacteria did not induce a response in the IEC line, and a combination of both UV-killed bacteria and the bacteria-sn had no additive effect to that of the supernatant alone. In PBMC, most of the Lactobacillus-sn and S. aureus-sn strains were able to induce a wide array of cytokines, but only S. aureus-sn induced the T-cell associated cytokines IL-2, IL-17 and IFN-gamma, independently of IEC-produced factors, and induced up regulation of CTLA-4 expression and IL-10 production by T-regulatory cells. Notably, S. aureus-sn-induced T-cell production of IFN-gamma and IL-17 was down regulated by the simultaneous presence of any of the different Lactobacillus strains, while the IEC CXCL8/IL-8 response was unaltered. Thus these studies present a possible role for lactobacilli in induction of immune cell regulation, although the mechanisms need to be further elucidated.

  • 19.
    Haileselassie, Yeneneh
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Navis, Marit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vu, Nam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rethi, Bence
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lactobacillus reuteri and Staphylococcus aureus differentially influence the generation of monocyte-derived dendritic cells and subsequent autologous T cell responses2016In: Immunity, Inflammation and Disease, ISSN 2050-4527, Vol. 4, no 3, p. 315-326Article in journal (Refereed)
    Abstract [en]

    Introduction: In early-life, the immature mucosal barrier allows contact between the gut microbiota and the developing immune system. Due to their strategic location and their ability to sample luminal antigen, dendritic cells (DC) play a central role in the interaction of microbes and immune cells in the gut. Here, we investigated how two bacteria associated with opposite immune profiles in children, that is, Lactobacillus (L.) reuteri and Staphylococcus (S.) aureus, influenced the differentiation of monocytes in vitro as well how the generated DC impacted T cell responses.

    Methods: We exposed monocyte cultures to cell-free supernatants (CFS) from these bacteria during their differentiation to DC.

    Results: The presence of L. reuteri-CFS during DC differentiation resulted in DC with a more mature phenotype, in terms of up-regulated surface markers (HLA-DR, CD86, CD83, CCR7) and enhanced cytokine production (IL6, IL10, and IL23), but had a reduced phagocytic capacity compared with non-treated monocyte-derived DC (Mo-DC). However, upon LPS activation, L. reuteri-CFS-generated DC displayed a more regulated phenotype than control Mo-DC with notable reduction of cytokine responses both at mRNA and protein levels. In contrast, S. aureus-CFS-generated DC were more similar to control Mo-DC both without and after LPS stimulation, but they were still able to induce responses in autologous T cells, in the absence of further T cell stimulation.

    Conclusions: We show that bacterial signals during DC differentiation have a profound impact on DC function and possibly also for shaping the T cell pool.

  • 20.
    Haileselassie, Yeneneh
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Navis, Marit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vu, Nam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rethi, Bence
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Postbiotic Modulation of retinoic acid imprinted Mucosal-like Dendritic cells by Probiotic Lactobacillus reuteri 17938 In Vitro2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, p. 1-11, article id 96Article in journal (Refereed)
    Abstract [en]

    Lactobacilli are widely used as probiotics with beneficial effects on infection-associated diarrhea, but also used in clinical trials of e.g., necrotizing enterocolitis and inflammatory bowel diseases. The possibility of using probiotic metabolic products, so-called postbiotics, is desirable as it could prevent possible side effects of live bacteria in individuals with a disturbed gut epithelial barrier. Here, we studied how Lactobacillus reuteri DSM 17938 cell-free supernatant (L. reuteri-CFS) influenced retinoic acid (RA)-driven mucosal-like dendritic cells (DC) and their subsequent effect on T regulatory cells (Treg) in vitro. RA clearly imprinted a mucosal-like DC phenotype with higher IL10 production, increased CD103 and CD1d expression, and a downregulated mRNA expression of several inflammatory-associated genes (NFκB1, RELB, and TNF). Treatment with L. reuteri-CFS further influenced the tolerogenic phenotype of RA-DC by downregulating most genes involved in antigen uptake, antigen presentation, and signal transduction as well as several chemokine receptors, while upregulating IL10 production. L. reuteri-CFS also augmented CCR7 expression on RA-DC. In cocultures, RA-DC increased IL10 and FOXP3 expression in Treg, but pre-treatment with L. reuteri-CFS did not further influence the Treg phenotype. In conclusion, L. reuteri-CFS modulates the phenotype and function of mucosal-like DC, implicating its potential application as postbiotic.

  • 21. Hales, B. J.
    et al.
    Hizawa, N.
    Jenmalm, M.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wardlaw, A. J.
    Developments in the field of allergy in 2014 through the eyes of Clinical and Experimental Allergy2015In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 45, no 12, p. 1723-1745Article, review/survey (Refereed)
    Abstract [en]

    The pathogenesis of asthma continues to be a major topic of interest to our authors with reviews and original papers on the role of viruses, mechanisms of inflammation, biomarkers, and phenotypes of asthma being major topics. A number of papers described new treatments for asthma focusing on blocking the Th2 response reflecting the fact that two decades of work in this area is finally bearing fruit. The pathogenesis of chronic rhinosinusitis is a growing area of interest, but there has been less on the genetics of airways disease than in previous years possibly reflecting the degree of rigour (and therefore a smaller body of work), with which these sorts of studies are now being undertaken. There continues to be a wide range of papers dealing with mechanisms of allergic disease ranging from clinical-based studies to basic research and the use of in vivo animal models especially mice. As before, mechanisms and new approaches to immunotherapy are common themes. Several were published in the allergens section investigating modification of allergens to increase their effectiveness and reduce the risk of adverse events. Risk factors for allergic disease was a common theme in the epidemiology section and food allergy a common theme in clinical allergy with papers on the development of protocols to induce tolerance and attempts to find biomarkers to distinguish sensitization from allergic disease. This was another exciting year for the editors, and we hope the readers of the journal.

  • 22.
    Holmlund, U.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Amoudruz, P.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Johansson, M. A.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Haileselassie, Y.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Ongoiba, A.
    Kayentao, K.
    Traoré, B.
    Doumbo, S.
    Schollin, J.
    Doumbo, O.
    Montgomery, S. M.
    Sverremark-Ekström, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Maternal country of origin, breast milk characteristics and potential influences on immunity in offspring2010In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 162, no 3, p. 500-509Article in journal (Refereed)
    Abstract [en]

    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-β1 and soluble CD14, compared to the other two groups of women. This may have implications for maturation of their children's immune responses.

  • 23.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Salvany Celades, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bittmann, Julia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eberl, Matthias
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 273Article in journal (Refereed)
    Abstract [en]

    Lactobacilli are probiotic commensal bacteria and potent modulators of immunity. When present in the gut or supplemented as probiotics, they beneficially modulate ex vivo immune responsiveness. Further, factors derived from several lactobacilli strains act immune regulatory in vitro. In contrast, Staphylococcus aureus (S. aureus) is known to induce excessive T cell activation. In this study, we aimed to investigate S. aureus-induced activation of human mucosal-associated invariant T cells (MAIT cells), gamma delta T cells, NK cells, as well as of conventional CD4(+) and CD8(+) T cells in vitro. Further, we investigated if lactobacilli-derived factors could modulate their activation. PBMC were cultured with S. aureus 161: 2 cell-free supernatants (CFS), staphylococcal enterotoxin A or CD3/CD28-beads alone, or in combination with Lactobacillus rhamnosus GG-CFS or Lactobacillus reuteri DSM 17938-CFS and activation of T and NK cells was evaluated. S. aureus-CFS induced IFN-gamma and CD107a expression as well as proliferation. Costimulation with lactobacilli-CFS dampened lymphocyte-activation in all cell types analyzed. Preincubation with lactobacilli-CFS was enough to reduce subsequent activation, and the absence of APC or APC-derived IL-10 did not prevent lactobacilli-mediated dampening. Finally, lactate selectively dampened activation of unconventional T cells and NK cells. In summary, we show that molecules present in the lactobacilli-CFS are able to directly dampen in vitro activation of conventional and unconventional T cells and of NK cells. This study provides novel insights on the immune-modulatory nature of probiotic lactobacilli and suggests a role for lactobacilli in the modulation of induced T and NK cell activation.

  • 24.
    Johansson, Maria A
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Roos, Stefan
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early-Life Gut Bacteria Associate with IL-4-, IL-10- and IFN-γ Production at Two Years of Age2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, p. e49315-(9 pp)Article in journal (Refereed)
    Abstract [en]

    Microbial exposure early in life influences immune maturation and potentially also the development of immune-mediated disease. Here we studied early-life gut colonization in relation to cytokine responses at two years of age. Fecal samples were collected from infants during the first two months of life. DNA was extracted from the fecal samples and Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, a group of lactobacilli (L. casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus were detected with real time PCR. Peripheral mononuclear cells were stimulated with phytohaemagglutinin (PHA) and numbers of IL-4-, IL-10- and IFN-γ secreting cells were evaluated using ELISpot. We further stimulated peripheral blood mononuclear cells with bacterial supernatants in vitro and assessed the IL-4-, IL-10- and IFN-γ inducing capacity by flow cytometry and ELISA. Early S. aureus colonization associated with higher numbers of IL-4- (p = 0.022) and IL-10 (p = 0.016) producing cells at two years of age. In contrast to colonization with S. aureus alone, co-colonization with lactobacilli associated with suppression of IL-4- (p = 0.004), IL-10- (p = 0.004) and IFN-γ (p = 0.034) secreting cells. In vitro stimulations of mononuclear cells with bacterial supernatants supported a suppressive role of L. rhamnosus GG on S. aureus-induced cytokine responses. We demonstrate that the early gut colonization pattern associates with the PHA-induced cytokine profile at two years of age and our in vitro findings support that specific bacterial species influence the T helper cell subsets. This suggests that dysbiosis in the early microbiota may modulate the risk of developing inflammatory conditions like allergy.

  • 25.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sjögren, Ylva M.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Nilsson, Caroline
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Early colonization with a group of Lactobacilli decreases the risk for allergy at five years of age despite allergic heredity.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23031-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microbial deprivation early in life can potentially influence immune mediated disease development such as allergy. The aims of this study were to investigate the influence of parental allergy on the infant gut colonization and associations between infant gut microbiota and allergic disease at five years of age.

    METHODS AND FINDINGS: Fecal samples were collected from 58 infants, with allergic or non-allergic parents respectively, at one and two weeks as well as at one, two and twelve months of life. DNA was extracted from the fecal samples and Real time PCR, using species-specific primers, was used for detection of Bifidobacterium (B.) adolescentis, B. breve, B. bifidum, Clostridium (C.) difficile, a group of Lactobacilli (Lactobacillus (L.) casei, L. paracasei and L. rhamnosus) as well as Staphylococcus (S.) aureus. Infants with non-allergic parents were more frequently colonized by Lactobacilli compared to infants with allergic parents (p = 0.014). However, non-allergic five-year olds acquired Lactobacilli more frequently during their first weeks of life, than their allergic counterparts, irrespectively of parental allergy (p = 0.009, p = 0.028). Further the non-allergic children were colonized with Lactobacilli on more occasions during the first two months of life (p = 0.038). Also, significantly more non-allergic children were colonized with B. bifidum at one week of age than the children allergic at five years (p = 0.048).

    CONCLUSION: In this study we show that heredity for allergy has an impact on the gut microbiota in infants but also that early Lactobacilli (L. casei, L. paracasei, L. rhamnosus) colonization seems to decrease the risk for allergy at five years of age despite allergic heredity.

  • 26.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Navis, Marit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cooper, Callum
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Anders S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Immunogenic profiling of structurally distinct bacteriophages and their interaction with human cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Due to a global increase in the range and number of infections caused by multi-resistant bacteria, 11 phage therapy is currently experiencing a resurgence of interest. However, there are a number of 12 well-known concerns over the use of phages to treat bacterial infections. In order to address concerns 13 over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, 14 immunological characterization is required. In the current investigation, the immunogenicity of four 15 distinct phages and their interaction with donor derived peripheral blood mononuclear cells and 16 immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using 17 standard immunological techniques. When exposed to high phage concentrations (109 PFU/well), 18 cytokine driven inflammatory responses were induced from all cell types. Although phages appeared 19 to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite 20 co-incubation with different cell types, phages maintained a high killing efficiency, reducing 21 extended-spectrum beta-lactamase-producing Escherichia coli numbers by 1-4 log10 compared to 22 untreated controls. Phages were also able to actively reproduce in the presence of human cells 23 resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. 24 Through an increased understanding of the complex pharmacokinetics of phages, it may be possible 25 to address some of the safety concerns surrounding phage preparations prior to creating new 26 therapeutic strategies.

  • 27.
    Khan Mirzaei, Mohammadali
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Navis, Marit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cooper, Callum
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Anders S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Morphologically Distinct Escherichia coli Bacteriophages Differ in Their Efficacy and Ability to Stimulate Cytokine Release In Vitro2016In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 7, article id 437Article in journal (Refereed)
    Abstract [en]

    Due to a global increase in the range and number of infections caused by multi resistant bacteria, phage therapy is currently experiencing a resurgence of interest. However, there are a number of well-known concerns over the use of phages to treat bacterial infections. In order to address concerns over safety and the poorly understood pharmacokinetics of phages and their associated cocktails, immunological characterization is required. In the current investigation, the immunogenicity of four distinct phages (taken from the main families that comprise the Caudovirales order) and their interaction with donor derived peripheral blood mononuclear cells and immortalized cell lines (HT-29 and Caco-2 intestinal epithelial cells) were investigated using standard immunological techniques. When exposed to high phage concentrations (10(9) PFU/well), cytokine driven inflammatory responses were induced from all cell types. Although phages appeared to inhibit the growth of intestinal epithelial cell lines, they also appear to be non-cytotoxic. Despite co-incubation with different cell types, phages maintained a high killing efficiency, reducing extended-spectrum betalactamase-producing Escherichia colinumbers by 1-4 log(10) compared to untreated controls. When provided with a suitable bacterial host, phages were also able to actively reproduce in the presence of human cells resulting in an approximately 2 log10 increase in phage titer compared to the initial inoculum. Through an increased understanding of the complex pharmacokinetics of phages, it may be possible to address some of the safety concerns surrounding phage preparations prior to creating new therapeutic strategies.

  • 28. Kurioka, Ayako
    et al.
    Jahun, Aminu S.
    Hannaway, Rachel F.
    Walker, Lucy J.
    Fergusson, Joannah R.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Corbett, Alexandra J.
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    Shared and Distinct Phenotypes and Functions of Human CD161++ V alpha 7.2+T Cell Subsets2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1031Article in journal (Refereed)
    Abstract [en]

    Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of V alpha 7.2-J alpha 33/J alpha 20/J alpha 12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ V alpha 7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ V alpha 7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ V alpha 7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ V alpha 7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ V alpha 7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ V alpha 7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ V alpha 7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo.

  • 29.
    Lasaviciute, Gintare
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carvalho-Queiroz, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hed Myrberg, Ida
    Nussbaum, Bianca
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nilsson, Caroline
    Bemark, Mats
    Nilsson, Anna
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Saghafian-Hedengren, Shanie
    Epstein-Barr Virus, but Not Cytomegalovirus, Latency Accelerates the Decay of Childhood Measles and Rubella Vaccine Responses-A 10-Year Follow-up of a Swedish Birth Cohort2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1865Article in journal (Refereed)
    Abstract [en]

    Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are ubiquitous and persistent herpesviruses commonly acquired during childhood. Both viruses have a significant impact on the immune system, especially through mediating the establishment of cellular immunity, which keeps these viruses under control for life. Far less is known about how these viruses influence B-cell responses. Objectives: To evaluate the impact of latent EBV and CMV infection on rubella- and measles-specific antibody responses as well as on the B-cell compartment in a prospective birth cohort followed during the first 10 years of life. Methods: IgG titers against rubella and measles vaccines were measured in plasma obtained from the same donors at 2, 5, and 10 years of age. Peripheral B-cell subsets were evaluated ex vivo at 2 and 5 years of age. Factors related to optimal B-cell responses including IL-21 and CXCL13 levels in plasma were measured at all-time points. Results: EBV carriage in the absence of CMV associated with an accelerated decline of rubella and measles-specific IgG levels (p = 0.003 and p = 0.019, respectively, linear mixed model analysis), while CMV carriage in the absence of EBV associated with delayed IgG decay over time for rubella (p = 0.034). At 5 years of age, EBV but not CMV latency associated with a lower percentage of plasmablasts, but higher IL-21 levels in the circulation. Conclusion: Our findings suggest that EBV carriage in the absence of CMV influences the B-cell compartment and the dynamics of antibody responses over time during steady state in the otherwise healthy host.

  • 30. Nilsson, C.
    et al.
    Larsson Sigfrinius, A-K
    Montgomery, S M
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Linde, A
    Lilja, G
    Blomberg, Marita Troye
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Epstein-Barr virus and cytomegalovirus are differentially associated with numbers of cytokine-producing cells and early atopy2009In: Clinical and experimental allergy, ISSN 1365-2222, Vol. 39, no 4, p. 509-17Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We have previously shown that Epstein-Barr virus (EBV) seropositivity, at 2 years of age, was inversely related to IgE-sensitization and that this effect was enhanced when EBV is combined with cytomegalovirus (CMV) seropositivity. We hypothesize that early exposure to EBV or CMV will affect the cytokine balance in the individual. OBJECTIVE: The aim of this study was to relate the cytokine profile in peripheral blood mononuclear cells (PBMC) to the EBV and CMV serostatus and IgE-sensitization in children at 2 years of age. METHODS: Seventy-five children were followed prospectively from birth until 2 years of age. Their EBV and CMV serostatus was correlated to the numbers of IFN-gamma, IL-4, IL-10 and IL-12-producing PBMC following PHA stimulation in vitro. Skin prick tests and allergen-specific IgE antibodies were used to assess IgE-sensitization. RESULTS: In the study cohort, there was an inverse association between EBV seropositivity and IgE-sensitization but not with CMV seropositivity. Following linear regression analysis, we did not detect any statistically significant associations between children with IgG antibodies against EBV at 2 years of age and the investigated cytokines. However, there was a non-significant tendency to a positive association between high numbers of all individual cytokine-producing cells and EBV seropositivity. Children who were CMV seropositive had significantly higher numbers of IFN-gamma and lower numbers of IL-4-producing cells compared with CMV negative children. There was a significant, positive association between the number of IL-4-producing cells and IgE-sensitization. CONCLUSION: Taken together our results indicate that infections with EBV and CMV in different ways will interact with the immune system and may protect children from developing early atopy.

  • 31.
    Petursdottir, Dagbjort H.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nordlander, Sofia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carvalho-Queiroz, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Osman, Omneya Ahmed
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Haileselassie, Yeneneh
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Navis, Marit
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kokkinou, Efthymia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lio, Ivan Zong Long
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hennemann, Julia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brodin, Björn
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Huseby, Douglas L.
    Nilsson, Caroline
    Hughes, Diarmaid
    Udekwu, Klas I.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Early-Life Human Microbiota Associated With Childhood Allergy Promotes the T Helper 17 Axis in Mice2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1699Article in journal (Refereed)
    Abstract [en]

    The intestinal microbiota influences immune maturation during childhood, and is implicated in early-life allergy development. However, to directly study intestinal microbes and gut immune responses in infants is difficult. To investigate how different types of early-life gut microbiota affect immune development, we collected fecal samples from children with different allergic heredity (AH) and inoculated germ-free mice. Immune responses and microbiota composition were evaluated in the offspring of these mice. Microbial composition in the small intestine, the cecum and the colon were determined by 16S rRNA sequencing. The intestinal microbiota differed markedly between the groups of mice, but only exposure to microbiota associated with AH and known future allergy in children resulted in a T helper 17 (Th17)-signature, both systemically and in the gut mucosa in the mouse offspring. These Th17 responses could be signs of a particular microbiota and a shift in immune development, ultimately resulting in an increased risk of allergy.

  • 32. Rizzo, Roberta
    et al.
    Stignani, Marina
    Amoudruz, Petra
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Nilsson, Caroline
    Melchiorri, Loredana
    Baricordi, Olavio
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Allergic women have reduced sHLA-G plasma levels at delivery.2009In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 61, no 5, p. 368-76Article in journal (Refereed)
    Abstract [en]

    PROBLEM: HLA-G antigen maintains a tolerogenic condition at the foeto-maternal interface, counteracts inflammation in autoimmune diseases and soluble HLA-G (sHLA-G) levels decrease in allergic-asthmatics. Taking into consideration these findings, we analyzed if sHLA-G and interleukin-10 (IL-10) could be influenced by pregnancy and labour in allergic and non-allergic women. METHOD OF STUDY: sHLA-G isoforms and IL-10 levels were determined in the plasma samples of 43 women (15 non-allergic, 28 allergic) during third trimester, at delivery and 2 years after pregnancy by immunoenzymatic assays. RESULTS: A significant increase in sHLA-G and IL-10 levels was documented at delivery in both allergic and non-allergic women. Allergic women showed lower sHLA-G concentrations. sHLA-G1 was evidenced as the predominant plasma isoform. CONCLUSION: The data showed increased sHLA-G and IL-10 concentrations at delivery, regardless of the allergic status. The sHLA-G1 isoform is mainly responsible for the increased sHLA-G levels at delivery.

  • 33.
    Saghafian-Hedengren, S.
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Holmlund, U.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Amoudruz, P.
    Nilsson, C.
    Sverremark-Ekström, E.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Maternal allergy influences p38-mitogen-activated protein kinase activity upon microbial challenge in CD14+ monocytes from 2-year-old children2008In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, ISSN 1365-2222, Vol. 38, no 3, p. 449-57Article in journal (Refereed)
  • 34.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theorell, Jakob
    Carvalho-Queiroz, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nagy, Noemi
    Persson, Jan-Olov
    Stockholm University, Faculty of Science, Department of Mathematics.
    Nilsson, Caroline
    Bryceson, Yenan T.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Epstein-Barr Virus Coinfection in Children Boosts Cytomegalovirus-Induced Differentiation of Natural Killer Cells2013In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 87, no 24, p. 13446-13455Article in journal (Refereed)
    Abstract [en]

    During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active, as well as latent, CMV infection is associated with enlarged subsets of differentiated natural killer (NK) and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. We found that EBV coinfection selectively influenced the NK cell compartment of CMV-seropositive (CMV+) children. Coinfected children had significantly higher proportions of peripheral-blood NKG2C(+) NK cells than CMV+ EBV- children. Ex vivo NK cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV+ children. EBV coinfection was related to the highest levels of plasma interleukin-15 (IL-15) and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBV- CMV+ children increased NKG2C(+) NK cell proportions. A similar tendency was seen in cocultures of PBMC with EBV+ lymphoblastoid B-cell lines (LCL) and IL-15. After K562 challenge, NKG2C(+) NK cells excelled in regard to degranulation and production of gamma interferon, regardless of whether there was previous coculture with LCL. Taken together, our data suggest that dual latency with these herpesviruses during childhood could contribute to an in vivo environment supporting differentiation and maintenance of distinct NK cell populations. This viral imprint may affect subsequent immune responses through altered distributions of effector cells.

  • 35.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Theorell, Jakob
    Carvalho-Queiroz, Claudia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nagy, Noémi
    Persson, Jan-Olov
    Nilsson, Caroline
    Bryceson, Yenan T.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Epstein-Barr Virus Co-infection in Children Boosts Cytomegalovirus-induced Differentiation of Natural Killer CellsManuscript (preprint) (Other academic)
    Abstract [en]

    During childhood, infections with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can occur in close temporal proximity. Active as well as latent CMV infection is associated with enlarged subsets of differentiated NK- and cytotoxic T cells. How EBV infection may influence CMV-driven immune differentiation is not known. Here we found that EBV co-infection selectively influenced the NK-cell compartment of CMV-seropositive (CMV+) children. Co-infected children had significantly higher proportions of peripheral-blood NKG2C+ NK cells than CMV+EBV children. Ex vivo NK-cell degranulation after target cell stimulation and plasma IL-15 levels were significantly higher in CMV+ children. EBV co-infection related with the highest levels of plasma IL-15 and IL-12p70. Remarkably, in vitro EBV infection of peripheral blood mononuclear cells (PBMC) from EBVCMV+ children increased NKG2C+ NK-cell proportions. A similar tendency was seen in co-cultures of PBMC with EBV+ lymphoblastoid B-cell lines (LCL) and IL-15. Following K562 challenge, NKG2C+ NK cells excelled in regards to degranulation and production of IFN-g, regardless of previous co-culture with LCL. Taken together, our data suggest that herpesvirus interplay during childhood could contribute to an in vivo environment supporting differentiation and maintenance of distinct NK-cell populations. This viral imprint may affect subsequent immune responses through altered distributions of effector cells.

  • 36.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sundström, Yvonne
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, Caroline
    Linde, Annika
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Berg, Louise
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Herpesvirus seropositivity in childhood associates with decreased monocyte-induced NK-cell IFN-γ production2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 4, p. 2511-2517Article in journal (Refereed)
    Abstract [en]

    EBV infection is inversely associated with IgE sensitization in children, and this association is further enhanced by CMV coinfection. In mice, herpesvirus latency causes systemic innate activation and protection from bacterial coinfection, implying the importance of herpesviruses in skewing immune responses during latent infection. Early control of viral infections depends on IFN- release by NK cells, which generally requires the presence of accessory cells. We investigated IFN- production by NK cells in PBMCs from children seropositive (SP) for EBV alone, for both EBV and CMV, or seronegative for both viruses. The ability of classical (CD14++CD16–) and proinflammatory (CD14+CD16+) monocytes to induce autologous NK cell IFN- was studied by coculture experiments with enriched CD3–CD56+ cells. Transwell experiments were used to evaluate how monocytes interact with NK cells to induce IFN- synthesis. SP children had a significantly reduced proportion of IFN-+ NK cells and cognate intracellular IFN- levels, which was more pronounced in CMV-coinfected subjects. Also, resting PBMCs of SP children displayed lower proportions of proinflammatory monocytes. IFN- production by NK cells was dependent on interactions with monocytes, with the proinflammatory subset inducing the highest IFN-. Finally, SP children had markedly lower levels of plasma IFN-, concurrent with in vitro findings. Herpesvirus infections could be one contributing factor for maturation toward balanced Th1-Th2 responses. Our data indicate that early infection by herpesviruses may affect NK cell and monocyte interactions and thereby also influence the development of allergies.

  • 37.
    Saghafian-Hedengren, Shanie
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Linde, Annika
    Department of Epidemiology, Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Lilja, Gunnar
    Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.
    Nilsson, Caroline
    Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institutet and Sachs' Children's Hospital, Stockholm, Sweden.
    Early-life EBV infection protects against persistent IgE sensitization.2010In: The Journal of allergy and clinical immunology, ISSN 1097-6825, Vol. 125, no 2, p. 433-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies. OBJECTIVE: This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization. METHODS: A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV. RESULTS: After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized-that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01). CONCLUSION: Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.

  • 38. Simon, KC
    et al.
    Saghafian Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Nilsson, C
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Aschero, A
    Age at Epstein-Barr virus infection and Epstein-Barr virus nuclear antigen-1 antibodies in Swedish children2012In: Elsevier, ISSN 2211-0348, Vol. 1, no 3, p. 136-138Article in journal (Refereed)
    Abstract [en]

    There is strong evidence supporting a role for Epstein-Barr virus (EBV) in the etiopathogenesis of multiple sclerosis (MS). Because of the strong association between antibody (Ab) titer against EBV nuclear antigen 1 (EBNA1) and late age at EBV infection, manifested as infectious mononucleosis (IM), and MS risk, we sought to determine whether age at primary EBV infection was associated with subsequent anti-EBNA1 Ab titer in a longitudinal study of Swedish children with EBV seropositivity and anti-EBNA1 Ab titers measured at ages 2, 5, and 10.

  • 39.
    Sjögren, Y M
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Jenmalm, M C
    Böttcher, M F
    Björkstén, B
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Altered early infant gut microbiota in children developing allergy up to 5 years of age.2009In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, ISSN 1365-2222, Vol. 39, no 4, p. 518-526Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium (C.) difficile colonization might be associated with allergic disease. Previous studies of infant gut microbiota in relation to subsequent allergy development have mostly employed culture-dependent techniques, studied genera of bacteria and the follow-up period was limited to 2 years. OBJECTIVE: To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first 5 years of life and study if environmental factors influence the early infant gut microbiota. METHODS: Fecal samples were collected at 1 week, 1 month and 2 months after birth from 47 Swedish infants, followed prospectively to 5 years of age. Bacterial DNA was analysed with real-time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to C. difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first 5 years while non-allergic children were neither. RESULTS: Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and C. difficile during their first 2 months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species. CONCLUSION: A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.

  • 40.
    Sjögren, Ylva Margareta
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Duchén, Karel
    Lindh, Frank
    Björkstén, Bengt
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Neutral oligosaccharides in colostrum in relation to maternal allergy and allergy development in children up to 18 months of age2007In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 18, no 1, p. 20-26Article in journal (Refereed)
  • 41.
    Sjögren, Ylva Margareta
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Jenmalm, Maria C.
    Linköpings universitet.
    Böttcher, Malin F.
    Linköpings universitet.
    Björkstén , Bengt
    Karolinska institutet.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Altered early infant gut microbiota in children developing allergy up to 5 years of age2009In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 39, p. 518-526Article in journal (Refereed)
    Abstract [en]

    Background: Early colonization with bifidobacteria and lactobacilli is postulated to protect children from allergy, while Clostridium difficile colonization might be associated with allergic disease. Previous studies of the infant gut microbiota in relation to subsequent allergy development have mostly employed culture dependent techniques, studied genera of bacteria and the follow up period was limited to two years.

    Objective: To relate gut microbiota in early infancy, notably bifidobacteria and lactobacilli at species level, to allergy development during the first five years of life and study if environmental factors influence the early infant gut microbiota.

    Methods: Faecal samples were collected at one week, one month and two months after birth from 47 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analysed with Real-time PCR and related to allergy development, family size as well as endotoxin and Fel d 1 levels in house dust samples. Primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis were used. Children regarded as allergic manifested allergic symptoms and were skin prick test positive during their first five years while non-allergic children were neither.

    Results: Children who developed allergy were significantly less often colonized with lactobacilli group I (Lactobacillus (L.) rhamnosus, L. casei, L. paracasei), Bifidobacterium adolescentis and Clostridium difficile during their first two months. Infants colonized with several Bifidobacterium species had been exposed to higher amounts of endotoxin and grew up in larger families than infants harbouring few species.

    Conclusion: A more diverse gut microbiota early in life might prevent allergy development and may be related to the previously suggested inverse relationship between allergy, family size and endotoxin exposure.

  • 42.
    Sjögren, Ylva Margareta
    et al.
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Tomicic, Sara
    Linköpings universitet.
    Lundberg, Anna
    Linköpings universitet.
    Böttcher, Malin F
    Linköpings universitet.
    Björkstén, Bengt
    Karolinska institutet.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Wenner-Gren Institute for Experimental Biology.
    Jenmalm, Maria C.
    Linköpings universitet.
    Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responsesManuscript (Other academic)
    Abstract [en]

    Introduction: Among sensitized infants those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear.

    Objective: To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous toll like receptor (TLR) 2 and TLR4 mRNA expression and LPS-induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMC).

    Methods: Faecal samples were collected at one week, one month and two months after birth from 64 Swedish infants, followed prospectively to five years of age. Bacterial DNA was analyzed with real-time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age six and twelve months and at two and five years and SIgA was measured with ELISA. The PBMC, collected twelve months after birth, were analyzed for TLR2 and TLR4 mRNA expression with real-time PCR. Further, the PBMC were stimulated with LPS and cytokine/chemokine responses were measured with Luminex.

    Results: The number of Bifidobacterium species in the early faecal samples correlated significantly with the total salivary SIgA levels at six months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMC. However, PBMC from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS-induced production of inflammatory cytokines and chemokines, e.g. IL-6 and CCL4 (MIP-1β), were inversely correlated to the relative amounts of Bacteroides fragilis in the early faecal samples.

    Conclusion: Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early high colonization with Bacteroides fragilis might down-regulate LPS responsiveness in infancy.

  • 43.
    Sohlberg, Ebba
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Bremme, Katarina
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute, Immunology.
    Cord blood monocyte subsets are similar to adult and show potent peptidoglycan-stimulated cytokine responses2011In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 133, no 1, p. 41-50Article in journal (Refereed)
    Abstract [en]

    P>Human monocytes can be divided into two major subpopulations, CD14++ CD16- and CD14+ CD16+ cells, which are suggested to play different roles in antimicrobial responses. In neonates, characteristics and functional responses of monocyte subsets have not previously been explored, and might contribute to the qualitative difference between neonatal and adult cytokine profiles. We report that at baseline, monocyte subsets in cord blood and adult peripheral blood are present in similar frequencies, and show similar expression of CD11c, CD80/CD86, CD163 and HLA-DR. In response to the bacterial ligand peptidoglycan, cord blood monocytes had high inherent capacity for production of the early-response cytokines with levels of tumour necrosis factor and interleukin-12p70 exceeding adult levels, and also a higher phosphorylation of p38-mitogen-activated protein kinase. The CD14+ CD16+ cells expressed more interleukin-12p70 than CD14++ CD16- cells and were present in a higher frequency in peptidoglycan-stimulated cord blood mononuclear cell cultures. Together, the behaviour of cord blood CD14+ CD16+ cells following peptidoglycan stimulation might indicate a qualitative difference between the neonatal antimicrobial response and that of the adult. In addition we found that serum factors in cord blood and adult sera affected cytokine production similarly, with the exception of tumour necrosis factor, regardless of the source of serum or cells. Overall, our data provide new insights into monocyte heterogeneity in cord blood and monocyte subset responses to a bacterial ligand at birth.

  • 44.
    Sohlberg, Ebba
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rasul, Eahsan
    Marchini, Giovanna
    Nilsson, Caroline
    Klein, Eva
    Nagy, Noemi
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cytomegalovirus-Seropositive Children Show Inhibition of In Vitro EBV Infection That Is Associated with CD8(+)CD57(+) T Cell Enrichment and IFN-gamma2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 11, p. 5669-5676Article in journal (Refereed)
    Abstract [en]

    EBV, a human herpesvirus, is commonly acquired during childhood and persists latently in B cells. EBV seropositivity has been connected to immunomodulatory effects such as altered T and NK cell functional responses as well as protection against early IgE sensitization; however, owing to the asymptomatic presentation during childhood little is known regarding the infection process in children of different ages. In this study, we used mononuclear cells from cord blood and from 2- and 5-y-old EBV-naive children for in vitro EBV infection. We show that the degree of EBV-induced B cell activation and expansion differs between age groups and in particular in relationship to IFN-gamma production capacity. EBV infection induced redistribution between B cell subsets with enrichment of IgD(+)CD27(+) cells (commonly referred to as non-switched memory) in infected cord blood cell cultures, and of IgD(-)CD27(+) cells (switched memory) in cell cultures from older children. We also related results to serostatus to CMV, a persistent herpesvirus that can affect differentiation status of T and NK cells. As compared with CMV- children, the EBV-induced enrichment of IgD(-)CD27(+) B cells was significantly reduced in infected cell cultures from CMV+ children. This effect was associated with high levels of IFN-gamma and frequencies of highly mature CD8(+)CD57(+) T cells in CMV+ children. Our results demonstrate that both a child's age and serostatus to CMV will have an impact on EBV-induced B cell activation and expansion, and they point to the ability of viruses with immunomodulatory functions, such as CMV, to affect immune responses within the host system.

  • 45.
    Sohlberg, Ebba
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Saghafian-Hedengren, Shanie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rasul, Eashan
    Marchini, Giovanna
    Nilsson, Caroline
    Klein, Eva
    Nagy, Noémi
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    CMV Seropositive Children Show Inhibition of In Vitro EBV Infection that is Associated with CD8+CD57+ T-cell Enrichment and IFN-gManuscript (preprint) (Other academic)
    Abstract [en]

    Epstein-Barr virus (EBV), a human herpesvirus, is commonly acquired during childhood and persists latently in B cells. EBV seropositivity has been connected to immune modulatory effects such as altered T- and NK-cell functional responses as well as protection against early IgE-sensitization, but due to the asymptomatic presentation during childhood little is known regarding the infection process in children of different ages. Here, we used mononuclear cells from cord blood, 2-year and 5-year old EBV-naïve children for in vitro EBV infection. We show that the degree of EBV-induced B-cell activation and expansion differs between age groups and in particular in relation to IFN-g production capacity. EBV infection induced redistribution between B-cell subsets with enrichment of IgD+CD27+ cells (commonly referred to as non-switched memory) in infected cord blood cell cultures, and of IgD-CD27+ cells (switched memory) in cell cultures of older children. We also related results to serostatus to cytomegalovirus (CMV), a persistent herpesvirus that can affect differentiation status of T- and NK cells. As compared to CMV- children, the EBV-induced enrichment of IgD-CD27+ B cells was significantly reduced in infected cell cultures from CMV+ children. This effect was associated with high levels of IFN-g  and frequencies of highly mature CD8+CD57+ T cells in CMV+ children. Our results demonstrate that both a child’s age and serostatus to CMV will have an impact on EBV-induced B-cell activation and expansion, and points to the ability of viruses with immune-modulatory functions, like CMV, to impact on immune responses within the host system.

  • 46.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    CD30 expression in relation to atopic heredity and allergic disease during childhood.2009In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, ISSN 1399-3038, Vol. 20, no 2, p. 204-5Article in journal (Refereed)
  • 47.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Division of cytokines into TH1/TH2: a word of caution.2010In: Reproductive sciences (Thousand Oaks, Calif.), ISSN 1933-7205, Vol. 17, no 4, p. 318-9Article in journal (Refereed)
  • 48.
    Sverremark-Ekström, Eva
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Hultgren, E. H.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Borres, M. P.
    Nilsson, C.
    Peanut sensitization during the first five years of life is associated with elevated levels of peanut-specific IgG2012In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 23, no 3, p. 224-229Article in journal (Refereed)
    Abstract [en]

    Background: Allergen-specific IgE antibodies are implicated in allergic diseases while allergen-specific IgG antibodies have been proposed to prevent allergic reactions. The objective for this study was to study if the immune response (IgG and IgG4) to peanut differs in IgE sensitized and non-sensitized young children.

    Methods: A total of 239 children have been followed prospectively from birth to 5 years of age. Levels of IgG and IgG4 to peanut, Ara h 2 and Ara h 8 were analyzed at 2 and 5 years of age and related to IgE-sensitization and peanut consumption.

    Results:  Levels of peanut-specific IgG and IgG4 were significantly higher in peanut-sensitized children at 2 and 5 years of age when compared to non-sensitized children and children sensitized to other food/inhalant allergens. A strong correlation was seen between levels of peanut-specific IgG/IgG4-ratios and peanut-specific IgE at 5 years of age. Children avoiding peanuts, a subgroup of the peanut sensitized, had statistically significant higher levels of IgE to peanut and a tendency of higher IgG and IgG4 levels to peanut. In the avoidance-group significant correlations between IgE and IgG/IgG4 to peanut was found compared to children eating peanuts. 

    Conclusion: Peanut-specific IgG or IgG4 levels were elevated in peanut-sensitized children especially those avoiding peanuts. In our study, IgG and IgG4 do not seem to indicate tolerance or protection from sensitization.

1 - 48 of 48
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