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  • 1. Andersen, G. Neumann
    et al.
    Andersen, M.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J. E. S.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dermal Melanocortin Receptor Rebound in Diffuse Systemic Sclerosis after Anti-TGF ss 1 Antibody Therapy2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 76, no 5, p. 478-482Article in journal (Refereed)
    Abstract [en]

    Disturbed transforming growth factor beta (TGF beta) signalling leads to enhanced synthesis of extracellular matrix (ECM), which is manifested as systemic sclerosis (SSc), but this may be attenuated by the melanocortin system. Here, we report of rebound reaction in the gene expression of melanocortin receptor (MCR) subtypes and of the precursor of these receptors ligands, the pro-opio-melanocortin protein (POMC), in the acute skin lesion of diffuse systemic sclerosis (dSSc) after treatment with a recombinant human anti-TGF beta 1 antibody. Biopsies, taken from the leading edge of the skin lesion, before and after treatment of a patient with recent onset dSSc, were examined. Before treatment, increased levels of TGF beta mRNA and suppressed levels of POMC mRNA and MCR subtypes MC1-3, 5R mRNAs were seen in the lesion, compared with healthy controls. After treatment, there was a rebound expression of POMC, MC2, 3, 5R mRNAs. As the melanocortin system regulates collagen and melanin production, our findings add a new understanding to the pathogenetic mechanisms involved in the acute skin lesion of dSSc, which is characterized by enhanced ECM formation and changes in skin pigmentation.

  • 2.
    Andersen, Grethe
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hägglund, M
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Petrovska, R
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J E S
    Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes2005In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 61, no 3, p. 279-284Article in journal (Refereed)
    Abstract [en]

    Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro-opio-melanocortin (POMC) protein mRNA were measured by the real-time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co-ordinating role for MCR subtypes and their naturally occurring ligands in the co-operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR-mediated tolerance induction in Th cells.

  • 3. Andersen, Grethe N.
    et al.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Wikberg, Jarl E. S.
    The Melanocortin System: A New and Important Actor on the Scene of Systemic Sclerosis2011In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 63, no 10, p. S908-S908Article in journal (Refereed)
  • 4.
    Andersen, Grethe N.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Nilsson, Kenneth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Nagaeva, O
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Cytokine mRNA profile of alveolar T lymphocytes and macrophages in patients with systemic sclerosis suggests a local Tr1 response2011In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 74, no 3, p. 272-81Article in journal (Refereed)
    Abstract [en]

    The development of an autoimmune disease like systemic sclerosis (SSc) is suspected to be driven by an activated T lymphocyte subset, expressing a cytokine profile specific to the disease. To further characterize the type of immune reaction in SSc, we searched for a broad panel of cytokine messenger ribonucleic acids (mRNAs) in T lymphocytes and monocytes/macrophages from paired samples of bronchoalveolar lavage fluid and peripheral blood in 18 patients and 16 age- and sex-matched controls. RNA from CD3(+) T lymphocytes and CD14(+) monocytes/macrophages was examined by means of the reverse transcriptase polymerase chain reaction. SSc alveolar T lymphocytes expressed a cytokine profile suggestive of a mixed Th1/Th2 reaction, showing an increased frequency of mRNA for interleukin (IL)-10, IL-6 and interferon (IFN)γ, while IL-1β, IFNγ and tumour necrosis factor β were expressed in blood T lymphocytes in a higher percentage of patients with SSc than controls. SSc alveolar T cells expressed IL-10 mRNA more often than peripheral T cells, a phenomenon not found in controls and which may point at local IL-10 activation/response in SSc lung. Transforming growth factor β mRNA was present in all alveolar as well as peripheral blood T cell samples in patients and controls. The cytokine mRNA profile in SSc with interstitial lung disease (ILD) was similar to the profile found in SSc without ILD. Our findings point at a mixed Th1/Th2 reaction in SSc and may indicate regulatory T 1 cell activation/response in the lungs of patients with SSc.

  • 5.
    Andersen, Grethe Neumann
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Caidahl, Kenneth
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Kazzam, Elsadig
    Petersson, Ann-Sofi
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular adhesion molecule 12000In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 43, no 5, p. 1085-1093Article in journal (Refereed)
    Abstract [en]

    Objective To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease.

    Methods We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting.

    Results Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate.

    Conclusion NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.

  • 6.
    Andersen, Grethe Neumann
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kazzam, Elsadig
    Mälar Hospital, Eskilstuna, Sweden.
    Nyberg, Gunnar
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Klintland, Natalia
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Petersson, Ann-Sofi
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Caidahl, Kenneth
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Assessment of vascular function in systemic sclerosis: indications of the development of nitrate tolerance as a result of enhanced endothelial nitric oxide production2002In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 46, no 5, p. 1324-1332Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the relationship between endothelium-dependent and endothelium-independent functions and the stiffness of conduit arteries as well as levels of endothelial activation markers in patients with systemic sclerosis (SSc).

    METHODS: Endothelium-dependent (i.e., flow-mediated) and endothelium-independent (i.e., nitroglycerin-induced) dilation of the brachial artery was measured as the percentage of change from baseline (FMD% and NTG%, respectively) in 24 SSc patients and 24 age- and sex-matched healthy controls by high-resolution ultrasound imaging. The maximum increase in systolic pressure per unit of time (dP/dt(max)), as a measure of arterial wall stiffness, was assessed in the radial artery by pulse applanation tonometry. Plasma nitrate, the most important metabolite of nitric oxide, and 24-hour urinary excretion of nitrate were measured by gas chromatography mass spectrometry. Soluble E-selectin and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured by enzyme-linked immunosorbent assay.

    RESULTS: Brachial artery FMD% and NTG% did not differ between SSc patients and controls. Radial artery dP/dt(max) was significantly increased in the patients and correlated significantly with elevated levels of plasma nitrate and sVCAM-1. Twenty-four-hour urinary nitrate excretion tended to be elevated. Brachial artery NTG% was significantly inversely correlated with levels of plasma nitrate and soluble endothelial adhesion molecules.

    CONCLUSION: The ability of the brachial arteries to dilate in response to hyperemia and nitroglycerin challenge is preserved in SSc. Stiffness of the radial artery is increased, however. Endothelial activation seems to determine the extent of the brachial artery NTG% and the radial artery dP/dt(max). The data are compatible with the hypothesis that nitrate tolerance is present in the vascular smooth muscle cells of the brachial artery wall in SSc.

  • 7.
    Andersen, Grethe Neumann
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Nilsson, Kenneth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Hackett, Tillie-Louise
    Kazzam, Elsadig
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Warner, Jane
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Sandström, Thomas
    Bronchoalveolar matrix metalloproteinase 9 relates to restrictive lung function impairment in systemic sclerosis.2007In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 101, no 10, p. 2199-2206Article in journal (Refereed)
    Abstract [en]

    Systemic sclerosis (SSc) is frequently associated with interstitial lung disease (ILD) often leading to lung fibrosis. In this study we investigated whether matrix metalloproteinase 9 (MMP-9) and its natural inhibitor; the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), would be associated with remodelling in ILD in SSc. Levels of total MMP-9, pro-MMP-9 and TIMP-1 were measured in bronchoalveolar lavage (BAL) fluid from nine SSc patients with ILD, seven SSc patients without ILD and 16 age- and sex-matched healthy controls. Total MMP-9 and pro-MMP-9 levels were significantly elevated in SSc patients with ILD, compared to levels in SSc patients without ILD and healthy controls. In SSc patients with ILD calculated active MMP-9 levels were significantly higher than in SSc patients without ILD and tended to be higher than in healthy controls. TIMP-1 levels were elevated in both patient groups compared to healthy controls. Total-, pro- and active MMP-9 levels as well as pro-MMP-TIMP-1 and active MMP-9/TIMP-1 ratios were inversely associated with total lung capacity. The present study suggests that MMP-9 plays a pathophysiological role in the remodelling in ILD and lung fibrosis associated with SSc, and may represent a new therapeutic target in this condition.

  • 8. Andersen, M.
    et al.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Meyer, M. K.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Melanocortin 2, 3 and 4 Receptor Gene Expressions are Downregulated in CD8(+) T Cytotoxic Lymphocytes and CD19(+) B Lymphocytes in Rheumatoid Arthritis Responding to TNF- Inhibition2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 1, p. 31-39Article in journal (Refereed)
    Abstract [en]

    Melanocortin signalling in leucocyte subsets elicits anti-inflammatory and immune tolerance inducing effects in animal experimental inflammation. In man, however, the effects of melanocortin signalling in inflammatory conditions have scarcely been examined. We explored the differential reactions of melanocortin 1-5 receptors (MC1-5R) gene expressions in pathogenetic leucocyte subsets in rheumatoid arthritis (RA) to treatment with TNF- inhibitor adalimumab. Seven patients with active RA donated blood at start and at 3-month treatment. CD4(+) T helper (h) lymphocytes (ly), CD8(+) T cytotoxic (c) ly, CD19(+) B ly and CD14(+) monocytes were isolated, using immunomagnetic beads, total RNA extracted and reverse transcription quantitative polymerase chain reaction (RT-qPCR) performed. Fold changes in MC1-5R, Th1-, inflammatory- and regulatory cytokine gene expressions were assessed for correlation. Six patients responded to adalimumab treatment, while one patient was non-responder. In all lymphocyte subtypes, MC1-5R gene expressions decreased in responders and increased in the non-responder. In responders, decrease in MC2R, MC3R and MC4R gene expressions in CD8(+) Tc and CD19(+) B ly was significant. Fold change in MC1-5R and IFN gene expressions correlated significantly in CD8(+) Tc ly, while fold change in MC1R, MC3R and MC5R and IL-1 gene expressions correlated significantly in CD4(+) Th ly. Our results show regulation of MC2R, MC3R and MC4R gene expressions in CD8(+) Tc ly and CD19(+) B ly. The correlations between fold change in different MCRs and disease driving cytokine gene expressions in CD8(+) Tc ly and CD4(+) Th ly point at a central immune modulating function of the melanocortin system in RA.

  • 9. Andersen, M.
    et al.
    Olesen, M. K.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikberg, J.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Andersen, G. N.
    Vendsyssel Hosp, Clin Res Ctr, Rheumatol Unit, Hjorring, Denmark.
    Adalimumab (Humira (R)) normalizes melanocortin receptor subtype 2, 3, and 4 expression in CD8+, CD14+, and CD19+leucocyte subsets in rheumatoid arthritis2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no Suppl. 127, p. 25-26 Meeting Abstr. PP119Article in journal (Other academic)
  • 10.
    Baranov, Vladimir
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lipids are a constitutive component of cytolytic granules.2000In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 114, no 2, p. 167-71Article in journal (Refereed)
    Abstract [en]

    Cytolytic granules are specific organelles of activated cytotoxic lymphocytes mediating storage and regulated excretion of lytic molecules for killing of target cells. A variety of the other granule components may also participate in granule-mediated cytotoxicity. In this study, the subcellular localization of lipids in the granules of human decidual CD56+ natural killer-like cells was determined by staining with malachite green aldehyde and imidazole-buffered osmium tetroxide. Lipids were shown, for the first time, to be a constitutive component of cytolytic granules. Lipids formed an additional structural microdomain, located between the granule-limiting membrane and the granule core. Images of the granules on serial sections suggested that intragranular lipids wrap the core. We speculate that granule lipids participate in packing of lytic molecules inside the granules, in autocrine signaling ending granule secretion, and in the killing process.

  • 11.
    Daka, Bledar
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Svensson, Maria K
    Lernmark, Åke
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.2009In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 42, no 6, p. 507-514Article in journal (Refereed)
    Abstract [en]

    Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.

  • 12.
    Dimova, Tanya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stenqvist, Ann-Christin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hedlund, Malin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Strand, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples.2011In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 66, no Suppl 1, p. 44-56Article in journal (Refereed)
    Abstract [en]

    PROBLEM: Regulatory T cells (Treg cells), a small subset of CD4(+) T cells maintaining tolerance by immunosuppression, are proposed contributors to the survival of the fetal semiallograft. We investigated Treg cells in paired decidual and peripheral blood (PB) samples from healthy women in early pregnancy and PB samples from non-pregnant women.

    METHOD OF STUDY: Distribution, location, cytokine mRNA, and phenotype were assessed in CD4(+) CD25(+) Treg cells from paired samples using immunohistochemistry, immunofluorescence, flow cytometry, and real-time quantitative RT-PCR.

    RESULTS: The presence and in situ distribution of CD4(+) Foxp3(+) Treg cells in decidua are hereby demonstrated for the first time. Three Foxp3(+) cell populations, CD4(+) CD25(++) Foxp3(+), CD4(+) CD25(+) Foxp3(+), and CD4(+) CD25(-) Foxp3(+), were enriched locally in decidua. In contrast, no statistically significant difference in numbers of circulating Treg cells between pregnant and non-pregnant women was found. The Foxp3(+) cells expressed the surface molecules CD45RO, CTLA-4, CD103, Neuropilin-1, LAG-3, CD62L, and TGFβ1 mRNA consistent with Treg phenotype. The population of CD4(+) CD25(-) Foxp3(+) cells, not described in human decidua before, was enriched 10-fold compared with PB in paired samples. Their cytokine expression was often similar to Th3 profile, and the Foxp3 mRNA expression level in CD4(+) CD25(-) cells was stable and comparable to that of CD4(+) CD25(+) Treg cells implying that the majority of CD4(+) CD25(-) Foxp3(+) cells might be naïve Treg cells.

    CONCLUSION: (i) There is a local enrichment of Treg cells in decidua (ii) The exclusive accumulation of decidual CD4(+) CD25(-) Foxp3(+) cells suggests an additional reservoir of Foxp3(+) naïve Treg cells that can be converted to 'classical' Treg cells in uterus.

  • 13.
    Hedlund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kargl, Dominic
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Thermal- and oxidative stress cause enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia-lymphoma T and B cellsArticle in journal (Other academic)
    Abstract [en]

    Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation to the high incidence of relapse and fatal outcome of many blood malignancies. Using Jurkat and Raji cell lines as a model we show that leukemia/lymphoma T and B cells constitutively secrete exosomes carrying MICA/B, ULBP1 and 2, ligands for the activating NK-cell receptor NKG2D. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate NKG2D receptor-mediated cytotoxicity and impair NK-cell function. Furthermore, we show that thermal and oxidative stress enhances the exosome secretion generating more soluble NKG2D ligands that aggravate the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress enhancing the release of immunosuppressive exosomes should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.

  • 14.
    Hedlund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kargl, Dominic
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16899-Article in journal (Refereed)
    Abstract [en]

    Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.

  • 15.
    Hedlund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stenqvist, Ann-Christin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wulff, Marianne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 1, p. 340-351Article in journal (Refereed)
    Abstract [en]

    During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1-5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1-5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8(+), and gammadelta T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.

  • 16.
    Holm, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lymphocyte profile and cytokine mRNA expression in peripheral blood mononuclear cells of patients with recurrent respiratory papillomatosis suggest dysregulated cytokine mRNA response and impaired cytotoxic capacity2017In: Immunity, Inflammation and Disease, E-ISSN 2050-4527, Vol. 5, no 4, p. 541-550Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a relatively rare, chronic disease caused by Human Papilloma Virus (HPV) 6 and 11, and characterized by wart-like lesions in the airway affecting voice and respiratory function. The majority of HPV infections are asymptomatic and resolve spontaneously, however, some individuals are afflicted with persistent HPV infections. Failure to eliminate HPV 6 and 11 due to a defect immune responsiveness to these specific genotypes is proposed to play a major role in the development of RRP.

    METHODS: We performed a phenotypic characterization of peripheral blood mononuclear cells (PBMC) collected from 16 RRP patients and 12 age-matched healthy controls, using immunoflow cytometry, and monoclonal antibodies against differentiation and activation markers. The cytokine mRNA profile of monocytes, T helper-, T cytotoxic-, and NK cells was assessed using RT-qPCR cytokine analysis, differentiating between Th1-, Th2-, Th3/regulatory-, and inflammatory immune responses.

    RESULTS: We found a dominance of cytotoxic T cells, activated NK cells, and high numbers of stressed MIC A/B expressing lymphocytes. There was an overall suppression of cytokine mRNA production and an aberrant cytokine mRNA profile in the activated NK cells.

    CONCLUSION: These findings demonstrate an immune dysregulation with inverted CD4(+) /CD8(+) ratio and aberrant cytokine mRNA production in RRP patients, compared to healthy controls.

  • 17.
    Israelsson, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Labani-Motlagh, Alireza
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Assessment of cytokine mRNA expression profiles in tumor microenvironment and peripheral blood mononuclear cells of patients with high-grade serous carcinoma of the ovary2017In: Journal of Cancer Science & Therapy, ISSN 1948-5956, Vol. 9, no 5, p. 422-429Article in journal (Refereed)
    Abstract [en]

    Objective: Tumor establishment, metastatic spreading and poor survival in ovarian cancer is strongly associated with progressive derangement of the patient’s immune system. Accumulating evidence suggests that immune impairment is influenced by the production and presence of cytokines in the tumor microenvironment. Methods: Cytokine mRNA profiles in tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed in patients with high grade serous carcinoma (HGSC) of the ovary and compared it to patients with benign ovarian conditions and controls with normal ovaries. Cytokine assessment was done by real-time quantitative RT-PCR and specific primers and probes for 12 cytokines-IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, TNF-α, TNF-β/LTA, TGF-β1, and GM-CSF chosen to distinguish between cytotoxic Th1, humoral Th2, regulatory Th3/Tr1 and inflammatory responses. Results: The cytokine mRNA response in the HGSC patients was significantly up regulated compared to patients with benign ovarian conditions and normal ovary controls confirming the immunogenicity of HGSC and implying immune recognition and reaction locally in the tumor microenvironment and systemically in the peripheral blood.There was an up-regulation of inflammatory and inhibitory cytokine mRNA promoting tumor progression, T-regulatory cell priming and T-regulatory cell-mediated immune suppression. In contrast, there was an inability to mount the crucially important IFN gamma response needed for upregulation of the cytotoxic anti-tumor response in the local microenvironment. In addition, systemic IL-4- mediated Th2 response prevailed in the peripheral blood deviating the systemic defense towards humoral immunity. Conclusions: Taken together, these results suggest local and systemic cytokine cooperation promoting tumor survival, progression and immune escape. Our study confirms and extends previous investigations and contributes to the evaluation of potential cytokine candidates for diagnostic cytokine mRNA profiles and for future therapeutic interventions based on cytokine inhibition.

  • 18. Kalra, Hina
    et al.
    Simpson, Richard J
    Ji, Hong
    Aikawa, Elena
    Altevogt, Peter
    Askenase, Philip
    Bond, Vincent C
    Borràs, Francesc E
    Breakefield, Xandra
    Budnik, Vivian
    Buzas, Edit
    Camussi, Giovanni
    Clayton, Aled
    Cocucci, Emanuele
    Falcon-Perez, Juan M
    Gabrielsson, Susanne
    Gho, Yong Song
    Gupta, Dwijendra
    Harsha, HC
    Hendrix, An
    Hill, Andrew F
    Inal, Jameel M
    Jenster, Guido
    Krämer-Albers, Eva-Maria
    Lim, Sai Kiang
    Llorente, Alicia
    Lötvall, Jan
    Marcilla, Antonio
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nazarenko, Irina
    Nieuwland, Rienk
    Nolte-'t Hoen, Esther NM
    Pandey, Akhilesh
    Patel, Tushar
    Piper, Melissa G
    Pluchino, Stefano
    Prasad, TS Keshava
    Rajendran, Lawrence
    Raposo, Graca
    Record, Michel
    Reid, Gavin E
    Sánchez-Madrid, Francisco
    Schiffelers, Raymond M
    Siljander, Pia
    Stensballe, Allan
    Stoorvogel, Willem
    Taylor, Douglas
    Thery, Clotilde
    Valadi, Hadi
    van Balkom, Bas WM
    Vázquez, Jesús
    Vidal, Michel
    Wauben, Marca HM
    Yáñez-Mó, María
    Zoeller, Margot
    Mathivanan, Suresh
    Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation2012In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 10, no 12, p. e1001450-Article in journal (Refereed)
    Abstract [en]

    Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.

  • 19.
    Labani-Motlagh, Alireza
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Israelsson, Pernilla
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dehlin, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Differential expression of ligands for NKG2D and DNAM-1 receptors by epithelial ovarian cancer-derived exosomes and its influence on NK cell cytotoxicity2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 4, p. 5455-5466Article in journal (Refereed)
    Abstract [en]

    Cancers constitutively produce and secrete into the blood and other biofluids 30-150 nm-sized endosomal vehicles called exosomes. Cancer-derived exosomes exhibit powerful influence on a variety of biological mechanisms to the benefit of the tumors that produce them. We studied the immunosuppressive ability of epithelial ovarian cancer (EOC) exosomes on two cytotoxic pathways of importance for anticancer immunity-the NKG2D receptor-ligand pathway and the DNAM-1-PVR/nectin-2 pathway. Using exosomes, isolated from EOC tumor explant and EOC cell-line culture supernatants, and ascitic fluid from EOC patients, we studied the expression of NKG2D and DNAM-1 ligands on EOC exosomes and their ability to downregulate the cognate receptors. Our results show that EOC exosomes differentially and constitutively express NKG2D ligands from both MICA/B and ULBP families on their surface, while DNAM-1 ligands are more seldom expressed and not associated with the exosomal membrane surface. Consequently, the NKG2D ligand-bearing EOC exosomes significantly downregulated the NKG2D receptor expression on peripheral blood mononuclear cells (PBMC) while the DNAM-1 receptor was unaffected. The downregulation of NKG2D receptor expression was coupled to inhibition of NKG2D receptor-ligand-mediated degranulation and cytotoxicity measured in vitro with OVCAR-3 and K562 cells as targets. The EOC exosomes acted as a decoy impairing the NKG2D mediated cytotoxicity while the DNAM-1 receptor-ligand system remained unchanged. Taken together, our results support and explain the mechanism behind the recently reported finding that in EOC, NK-cell recognition and killing of tumor cells was mainly dependent on DNAM-1 signaling while the contribution of the NKG2D receptor-ligand pathway was complementary and uncertain.

  • 20.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schröder, Mona
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8(+) T Cells: Mechanism of Immune Evasion2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108925-Article in journal (Refereed)
    Abstract [en]

    Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8(+) T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8(+) T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8(+) T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  • 21. Maguire, Casey A.
    et al.
    Balaj, Leonora
    Sivaraman, Sarada
    Crommentuijn, Matheus H. W.
    Ericsson, Maria
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Gianni, Davide
    Tannous, Bakhos A.
    Sena-Esteves, Miguel
    Breakefield, Xandra O.
    Skog, Johan
    Microvesicle-associated AAV Vector as a Novel Gene Delivery System2012In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 20, no 5, p. 960-971Article in journal (Refereed)
    Abstract [en]

    Adeno-associated virus (AAV) vectors have shown remarkable efficiency for gene delivery to cultured cells and in animal models of human disease. However, limitations to AAV vectored gene transfer exist after intravenous transfer, including off-target gene delivery (e.g., liver) and low transduction of target tissue. Here, we show that during production, a fraction of AAV vectors are associated with microvesicles/exosomes, termed vexosomes (vector-exosomes). AAV capsids associated with the surface and in the interior of microvesicles were visualized using electron microscopy. In cultured cells, vexosomes outperformed conventionally purified AAV vectors in transduction efficiency. We found that purified vexosomes were more resistant to a neutralizing anti-AAV antibody compared to conventionally purified AAV. Finally, we show that vexosomes bound to magnetic beads can be attracted to a magnetized area in cultured cells. Vexosomes represent a unique entity which offers a promising strategy to improve gene delivery.

  • 22.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Immune cells and molecules in pregnancy: friends or foes to the fetus?2006In: Expert Reviews in Clinical Immunology, ISSN 1744-666X, Vol. 2, no 3, p. 457-470Article, review/survey (Refereed)
    Abstract [en]

    Considering the allograft rejection as a basic feature of the immune system, the mammalian pregnancy is an immunologic paradox where the semiallogeneic fetus is not rejected. How are the demands of pregnancy solved in the context of the maternal immunity? Medawar`s original proposal of maternal immune inertness during pregnancy should be revised to active materno-placental tolerance. Multiple mechanisms are involved in the peripheral and local tolerance induction that prevents fetal rejection while maintaining competent immune surveillance and protection. The goal of this review is to discuss the major cellular and molecular components of the immune system during pregnancy that control and promote fetal survival.

  • 23.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Immune cells in pregnant uterine mucosa: functional properties, cellular composition and tissue organization1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The pregnant uterus mucosa - decidua - is an "immunologically privileged" site. A semiallogeneic embryo is allowed to survive, develop, and grow while the same tissue implanted outside the uterus will be rejected. The decidua basalis, which participates in the placenta formation, is a tissue rich in lymphoid cells. We have studied decidua associated mononuclear cells (DMC) from normal early pregnancies in humans. The cells were investigated with respect to surface marker profiles, ultrastructure, organization in the tissue, and functional properties. In addition, we have studied the expression of receptors for the iron-binding protein lactoferrin on these cells, and characterized the receptor (Lf-R).

    Ten to fiftee percent of all cells in decidua belong to the lymphoid cell lineage. They are present in aggregates [lymphoid cell clusters (LCC) mainly located in the vicinity of decidual/endometrial glands] and as individual cells, intra- or subepithelially along the glands (IEL) , and in the stroma. The LCC appear to be centres of immune reactivity. They occur at a frequency of 0.40.2/mm2 tissue and are composed of different population of activated T cells and NK cells in close contact with each other. Interestingly, B cells are not present in the LCC. DMC consist of four major lymphocyte subpopulation of similar sizes: TCRγδ+/CD56+cells, TCRγδ+/CD56-cells, TCRγδ-/CD56+cells and TCRαβ+/CD8+cells. TCRαβ+/CD4+ cells and monocytes are also present. Most DMC have long, thick processes, microvilli, and cytoplasmic granules. They are in intimate contact with surrounding lymphoid, epithelial and stromal cells. Signs of cellular movement and excretion of granules are also seen.

    About half of the T cells are TCRαβ cells. These cells lack CD4 and CD8. A large fraction of them are CD56+, a rare phenotype at other sites. Most of the TCRγδ+ cells express activation/memory markers (CD45RO, the Kp43 antigen, transferrin receptor, and MHC class II antigens), and many cells express the mucosa homing receptor HML-1. Morphologically these cells either display features characteristic for cytotoxic cells or contain unique nuclear inclusions.

    More than half of TCRαβ cells are CD8+, but CD4+ cells are also found. These cells also display activation markers.

    DMC use both transferrin and lactoferrin for their iron supply. The Lf-R on activated lymphocytes appears to be made of two peptides of 47 and 65 kD MW.

    Freshly isolated DMC respond poorly or not at all to activation through the TCR/CD3 complex, probably due to the low surface density of the complex. However, the TCR/CD3 complex can be up-regulated by stimulation with PMA/Ionomycin in vitro, suggesting that the lymphocytes are suppressed in vivo. Glandular epithelial cells produce immunosuppressive factor(s) that act on CD8+, TCRγδ+, and CD56+ cells. The proximity between the LCC and the glands indicates that this factor(s) may play a role in local immunosuppression. The identity of the factor(s) is presently unknown. The cytokine mRNA profile of DMC, as determined by RT-PCR, reveals IFN-γ, IL-8 and TGF-β1 mRNA in all samples, and IL-1β, IL-2, IL-10, TNF-α and GM-CSF mRNA in some samples. The cytokine profile is compatible with down-regulation of CTL activity.

    The demands on the immune system in pregnant uterus mucosa are unique. On one hand, a genetically incompatible fetus must be accepted, the development of the placenta must be allowed, and the uteral mucosal tissue must be remodelled. On the other hand, the invasiveness of the trophoblast must be controlled, and the fetomaternal unit must be protected against infections. Our studies indicate that this is achieved through a highly regulated process involving different types of activated lymphoid cells interacting with each other and with glandular epithelial cells.

  • 24.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Placental exosome-mediated immune protection of the fetus: feeling groovy in a cloud of exosomes2010In: Expert Review of Obstetrics & Gynecology, ISSN 1747-4108, E-ISSN 1747-4116, Vol. 5, no 5, p. 619-634Article, review/survey (Refereed)
    Abstract [en]

    Exosomes are nanosized membrane-bound microvesicles that originate from the endosomal compartment and convey cell-cell contact “by proxy” transporting signals/packages of information between donor and recipient cells locally or/and at a distance. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram the recipient cells. Recently, it was discovered that the syncytiotrophoblast of human placenta continuously and constitutively secretes exosomes throughout pregnancy. These exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, are immunosuppressive and pluripotent carrying proteins, mRNA and microRNA that can influence a number of biologic mechanisms and promote the fetal allograft survival. The current knowledge about placental exosomes and their role in pregnancy is summarized and discussed in this article.

  • 25.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Cancer exosomes and NKG2D receptor-ligand interactions: impairing NKG2D-mediated cytotoxicity and anti-tumour immune surveillance2014In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 28, p. 24-30Article, review/survey (Refereed)
    Abstract [en]

    Human cancers constitutively produce and release endosome-derived nanometer-sized vesicles called exosomes that carry biologically active proteins, messenger and micro RNAs and serve as vehicles of intercellular communication. The tumour exosomes are present in the blood, urine and various malignant effusions such as peritoneal and pleural fluid of cancer patients and can modulate immune cells and responses thus deranging the immune system of cancer patients and giving advantage to the cancer to establish and spread itself. Here, the role of exosomes in the NKG2D receptor ligand system's interactions is discussed. The activating NK cell receptor NKG2D and its multiple ligands, the MHC class I-related chain (MIC) A/B and the retinoic acid transcript-1/UL-16 binding proteins (RAET1/ULBP) 1-6 comprise a powerful stress-inducible danger detector system that targets infected, inflamed and malignantly transformed cells and plays a decisive role in anti-tumour immune surveillance. Mounting evidence reveals that the MIC- and RAET1/ULBP ligand family members are enriched in the endosomal compartment of various tumour cells and expressed and released into the intercellular space and bodily fluids on exosomes thus preserving their entire molecule, three-dimensional protein structure and biologic activity. The NKG2D ligand-expressing exosomes serve as decoys with a powerful ability to down regulate the cognate receptor and impair the cytotoxic function of NK-, NKT-, gamma/delta- and cytotoxic T cells. This review summarizes recent findings concerning the role of NKG2D receptor ligand system in cancer with emphasis on regulation of NKG2D ligand expression and the immunosuppressive role of exosomally expressed NKG2D ligands.

  • 26.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success2014In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 72, no 5, p. 440-457Article, review/survey (Refereed)
    Abstract [en]

    The syncytiotrophoblast (STB) of human placenta constitutively produces and secretes extracellular vesicles of different size, morphology and function that enter the maternal circulation, and participate in the maternal-fetal cross-talk during pregnancy. Syncytiotrophoblast-derived microvesicles/microparticles (STBM) are larger microvesicles (0.2-2m) shed by the apical plasma membrane of the STB as a result of cell activation and turnover. Simultaneously with the STBM shedding, the STB produces and secretes exosomes - nanosized (30-100/150nm) membrane-bound microvesicles that originate from the endosomal compartment. They convey cell-cell contact by proxy' transporting signals/packages of information between donor and recipient cells locally or/and at a distance. STBM and exosomes, delivered directly in the maternal blood surrounding the chorionic villi of the placenta, have contrasting biological functions. While the exosomes are immunosuppressive down regulating maternal immunity in pluripotent ways, the main effects of STBM on the maternal immune system are pro-inflammatory, immune activating, and pro-coagulant. Since both STBM and exosomes are present in the maternal circulation throughout normal pregnancy logical questions are what is the net effect of these vesicles on the maternal immune system and is this effect beneficial or detrimental to pregnancy. In this review, the current knowledge about placenta-derived extracellular vesicles with a main focus on exosomes is summarized and discussed. In a concluding remark, a hypothetical proposal on how STBM and exosomes might interact in pregnancy is discussed and a way to evaluate this interaction is suggested.

  • 27.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    The role of placental exosomes in reproduction2010In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 63, no 6, p. 520-533Article in journal (Refereed)
    Abstract [en]

    Cell communication comprises cell-cell contact, soluble mediators and intercellular nanotubes. There is, however, another cell-cell communication by released membrane-bound microvesicles that convey cell-cell contact 'by proxy' transporting signals/packages of information from donor to recipient cells locally and/or at a distance. The nanosized exosomes comprise a specialized type of microvesicles generated within multivesicular bodies (MVB) and released upon MVB fusion with the plasma membrane. Exosomes are produced by a variety of immune, epithelial and tumor cells. Upon contact, exosomes transfer molecules that can render new properties and/or reprogram their recipient cells. Recently, it was discovered that the syncytiotrophoblast constitutively and throughout the pregnancy secretes exosomes. The placenta-derived exosomes are immunosuppressive and carry proteins and RNA molecules that in a redundant way influence a number of mechanisms and promote the fetal allograft survival. In this review, we summarize the current knowledge on the nature of placenta-derived exosomes and discuss their role in pregnancy.

  • 28.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Yeung, M M
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Immunomorphologic studies of human decidua-associated lymphoid cells in normal early pregnancy.1994In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 152, no 4, p. 2020-32Article in journal (Refereed)
    Abstract [en]

    Human decidual lymphocytes from early, normal pregnancy were characterized in situ with respect to ultrastructure and distribution of subsets. The ultrastructure of isolated decidual gamma delta T cells was also studied. CD45+ cells comprised 11 +/- 2% of all decidual cells. The majority were localized in large lymphoid cell clusters (LCC), near endometrial glands, or as intraepithelial lymphocytes (IEL) in glandular epithelium. The major cell populations in LCC were CD56+TCR-gamma delta+ cells, CD56+ cells, TCR-alpha beta+CD4+ cells, and TCR-alpha beta+CD8+ cells. All expressed activation markers (CD45RO, Kp43, and/or HML-1) and MHC class II Ag (HLA-DR, HLA-DP, and/or HLA-DQ). No B cells were found. Almost all IEL were activated TCR-gamma delta+ cells (CD56+ and CD56-). The glandular epithelial cells expressed heat shock protein 60 at the basolateral side facing the TCR-gamma delta+ IEL. Decidual lymphocytes displayed cytoplasmic processes, microvilli, characteristic cytoplasmic granules, and had intimate contact with neighboring cells. Lymphocytes in the outer rim of LCC and the stroma showed signs of cellular movement. Two main morphotypes of gamma delta T cells could be distinguished. One had single microvilli, membrane-bound granules, and nuclear inclusions. The other had many microvilli, nonmembrane-bound granules and cytoplasmic multivesicular bodies. Our data suggest that LCC are centers of immune reactivity where T and NK cells become activated. The activated cells may guard against infections and undue trophoblast invasion and/or be involved in modulating the local maternal immune system toward unresponsiveness against the semiallogeneic fetus.

  • 29.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Juto, Per
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Human milk contains proteins that stimulate and suppress T lymphocyte proliferation.1990In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 79, no 3, p. 463-9Article in journal (Refereed)
    Abstract [en]

    The modulatory effect of human milk proteins from colostrum and late milk on the proliferative response of human T lymphocytes activated by mitogens (OKT3 and leucoagglutinin from Phaseolus vulgaris) and alloantigens was studied. High concentrations (10-100 micrograms/ml) of crude colostral milk proteins had an inhibitory effect on T cell growth while low concentrations (0.1-1 microgram/ml) enhanced T cells growth. In contrast, proteins from late milk did not inhibit T lymphocyte proliferation while the enhancing effect was retained. Colostrum was fractionated by ammonium sulphate precipitation and gel filtration on sepharose 6B. The inhibitory activity was recovered in a protein fraction containing lactoferrin as its major component. Lactoferrin was, however, not responsible for the observed inhibition. On the contrary, lactoferrin in most cases augmented the proliferative response induced by polyclonal activators. The inhibitory activity was found to bind concanavalin A-sepharose suggesting an association with glycoprotein. Inhibitory fractions contained glycoproteins of the following molecular sizes 26, 74/76 (doublet), 84, 145 and 160 kD under reducing conditions. The inhibitory effect appeared to be lymphocyte specific since the active fraction did not inhibit the growth of tissue culture cells (HeLa cells and human fibroblasts) or bacteria. Furthermore, the fraction was not toxic for lymphocytes. The inhibitory colostrum factor may prevent the newborn from overreacting immunologically against the environmental antigens encountered at birth.

  • 30.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Activated human gamma delta T lymphocytes express functional lactoferrin receptors.1997In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 46, no 6, p. 609-18Article in journal (Refereed)
    Abstract [en]

    Lactoferrin (Lf), an iron-binding protein in milk, mucosal secretions and neutrophil granules has bactericidal properties and is a source of iron for breast-fed infants. In this paper the authors show that most in vivo activated lymphocytes, i.e. freshly isolated lymphocytes from first trimester human decidua, and most in vitro activated human blood lymphocytes, express lactoferrin receptors (Lf-R), while unstimulated blood lymphocytes do not. All major lymphocyte subsets, i.e. alpha beta T cells, gamma delta T cells, CD8+ T cells, CD4+ T cells, B cells and NK cells, express Lf-R after activation. The proportion of Lf-R expressing activated gamma delta T cells is significantly larger than that of activated alpha beta T cells. Lf-R and transferrin receptors (Tr-R/CD71) show the same kinetics of appearance on activated blood lymphocytes and are, to a large extent, expressed on the same cells. However, 35% of decidual lymphocytes and 15% of activated blood lymphocytes express Lf-R only. Addition of Lf to cultures containing an optimal concentration of Tr augments the proliferative response to polyclonal T cell activators and alloantigens, suggesting that presently used standard culture conditions for in vitro activation are suboptimal in particular for gamma delta T cells. Lf-R on decidual lymphocytes contain bound Lf, which probably is produced locally. The results suggest that Lf is a growth-supporting factor, especially important in local immune responses in the mucosa.

  • 31.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Human decidual leukocytes from early pregnancy contain high numbers of gamma delta+ cells and show selective down-regulation of alloreactivity.1992In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 149, no 6, p. 2203-11Article in journal (Refereed)
    Abstract [en]

    The mononuclear lymphoid cell population in human pregnant uterus mucosa, decidua, from early normal pregnancies was studied phenotypically and functionally. The phenotype was determined in situ by immunohistochemistry, and in isolated decidual mononuclear cell preparations by immunofluorescence and flow cytometry. A mild isolation procedure of gentle mechanical disruption followed by density gradient centrifugation was used. Leukocytes comprised a large part of the decidual tissue. They were present in aggregates mainly situated adjacent to the glandular epithelium. In addition, individual leukocytes were present intraepithelially, as well as scattered between the stromal cells and around vessels and lacunes. Four lymphocyte populations of approximately the same size were identified: TCR gamma delta+/CD56+ cells, TCR gamma delta+/CD56- cells, TCR gamma delta-/CD56+ cells, and TCR alpha beta+/CD8+ cells. TCR gamma delta- expressing cells comprised about 60% of the T cells. They were CD4-/CD8-, and about half of the TCR gamma delta+ cells expressed the memory/activation marker CD45RO. The Kp 43 Ag, earlier described on activated CD56+ and TCR gamma delta+ cells in peripheral blood, was essentially only expressed on the TCR gamma delta-/CD56+ cell population in decidua. At least 50% of the TCR alpha beta+ cells were CD8+. The function(s) of either one of these populations might be to prevent immunologic reactions against the fetus, to protect the uterus from unwanted extensive invasion of trophoblasts, or to protect the uteroplacental unit from infection. Decidual T cells did not respond to stimulation by alloantigens or mitogenic anti-CD3 mAb but responded to the same extent as PBMC to mitogenic lectins. The surface density of the TCR/CD3 complex was low on freshly isolated decidual lymphocytes, but could be up-regulated upon stimulation with PMA/Ionomycin. Local selective down-regulation of surface expression of the TCR/CD3 complex and of activation involving this complex might be one of the mechanisms by which a maternal immunologic reaction against the semiallogeneic fetus is prevented.

  • 32.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Immunomodulatory role of decidual epithelial cells in early human pregnancyManuscript (preprint) (Other academic)
  • 33.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kling, M
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Nagaeva, O
    Sundqvist, K G
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Gamma delta T cells of human early pregnancy decidua: evidence for local proliferation, phenotypic heterogeneity, and extrathymic differentiation.1997In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 159, no 7, p. 3266-77Article in journal (Refereed)
    Abstract [en]

    The uterine mucosa in pregnancy, the decidua, allows placenta formation and survival of the fetus despite the fact that it is semiallogeneic. Decidua contains large numbers of lymphocytes, of which CD56+ cells dominate, followed by T cells expressing either alpha beta or gamma delta TCR. We have investigated the developmental relationship between the CD56- and TCR gamma delta-expressing cells in early pregnancy decidua using dual labeling immunoelectron microscopy, immunoflow cytometry, and cell fractionation. Lymphocyte subpopulations were, in addition, analyzed for expression of the cytokine receptor for IL-7 and c-kit and for mRNA expression of recombinase-activating genes 1 and 2. Four different cell populations could be distinguished: CD56+bright, CD56+dim/TCR gamma delta+low, CD56+dim/TCR gamma delta+high, and TCR gamma delta+low. Recombinase-activating genes 1 and 2 were expressed in the CD56+bright cells and to a limited degree in CD56+dim/TCR gamma delta+low cells. c-kit was preferentially expressed on the CD56+bright cells, while IL-7R was preferentially expressed on CD56+dim/TCR gamma delta+low and CD56+dim/TCR gamma delta+high cells. The CD56+dim TCR gamma delta+low and CD56+dim/TCR gamma delta+high cells displayed the characteristic morphology of large granular lymphocytes, while single positive TCR gamma delta+low cells were usually smaller and did not contain cytoplasmic granules. The gamma delta 1 gene segment was almost exclusively used in the TCR. Gamma delta T cells in mitosis were seen. We suggest that human early pregnancy decidua is a transient site for extrathymic maturation and that the progenitors of TCR gamma delta+ cells are bone marrow-derived immature cells expressing the CD56 (neural cell adhesion molecule) homing receptor.

  • 34.
    Mincheva-Nilsson, Lucia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Chen, Ting
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Stendahl, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Antsiferova, Julia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mogren, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hernestål, Jenny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 6, p. 3585-3592Article in journal (Refereed)
  • 35.
    Muthukrishnan, Uma
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Natarajan, Balasubramanian
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Mäger, Imre
    Levén May, Hanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Jones, Iwan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Corso, Giulia
    Nordin, Joel Z.
    Wiklander, Oscar
    Johansson, Henrik J.
    Lehtiö, Janne
    Hällbrink, Mattias
    Wood, Matthew J.
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rome, Sophie
    Pini, Adrian
    Andaloussi, Samir EL
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    The exosome membrane localization of histones is independent of DNA and upregulated in response to stressManuscript (preprint) (Other academic)
    Abstract [en]

    Extracellular histones contribute to many acute and chronic diseases but also populate the secretomes of healthy cells and biofluids. However, a secretory pathway for histones has not been described. Here we report that core and linker histones localize to multivesicular bodies and are secreted via exosomes. Histones are tightly associated with the exosome membrane, with N-terminal domains exposed, in a DNA-independent manner. Furthermore, rapid upregulation of exosomal histones occurs following heat stress, accompanied by enhanced vesicle secretion and a shift towards a population of smaller vesicles. Proteomic analyses identified the downregulation of endosomal sorting complex required for transport (ESCRT) complex as a possible mechanism underlying increased histone secretion.We show for the first time that membrane-associated histones are actively secreted from intact cells via the multivesicular body/exosomal pathway. We demonstrate a novel pathway for extracellular histone release that may have a role in both health and disease.

  • 36.
    Nilsson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Skog, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Breakefield, X O
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer.2009In: British journal of cancer, ISSN 1532-1827, Vol. 100, no 10, p. 1603-1607Article in journal (Refereed)
    Abstract [en]

    Herein, we describe a novel approach in the search for prostate cancer biomarkers, which relies on the transcriptome within tumour exosomes. As a proof-of-concept, we show the presence of two known prostate cancer biomarkers, PCA-3 and TMPRSS2:ERG the in exosomes isolated from urine of patients, showing the potential for diagnosis and monitoring cancer patients status.

  • 37.
    Olofsson, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Studie av larynxpapillom i norra Sverige: två fall av onkogena HPV bland 26 patienter2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 21, p. 1187-1189Article in journal (Refereed)
    Abstract [en]

    Laryngeal papilloma is associated with human papillomavirus (HPV) 6, 11, 16, 18 and 31. The variation in the frequency of surgical treatment between patients for the same subtypes of HPV is inconsistent and poorly understood. Comparisons of the female laryngeal papilloma group (n?=?8, median age 46 yrs) with the male (n= 18, median age 32 yrs) with respect to gender, age, time of disease, period of life for diagnosis, disease progression profile, frequency of surgery (CO2 laser) during time of disease, localisation of papilloma in the upper airway and HPV subtype did not reach significance. In contrast the comparison between the high frequency (Ž 1 treatment/yr, n?=?11, median age 31 yrs) and low frequency (<1 treatment/yr, n?=?15 median age 45 yrs) treatment groups with regard to the same parameters as the female-male comparison, showed a clear-cut higher median age in the low frequency group (P?=?0,01).

  • 38. Ronquist, Gunnar
    et al.
    Lötvall, Jan
    Gabrielsson, Susanne
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Svanvik, Joar
    Telemo, Esbjörn
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Exosomen: intercellulär signalbärare med framtidspotential. Kan ge nya diagnostiska och terapeutiska möjligheter.2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 46, p. 2050-2052Article in journal (Refereed)
  • 39.
    Sehlstedt, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Andersen, Grethe Neumann
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Nilsson, Kenneth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Suppressed signal transduction in the bronchial epithelium of patients with systemic sclerosis2009In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 103, no 2, p. 301-308Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disorder, which frequently affects the lungs, with manifestations of interstitial lung disease (ILD) with lung fibrosis and of pulmonary hypertension. The pathogenesis remains largely unrecognised.

    OBJECTIVE: The aim of this study was to elucidate the inflammation in the bronchial mucosa in patients with SSc.

    SUBJECTS AND METHODS: Twenty-three subjects diagnosed with SSc participated. Twelve of the SSc patients showed signs of ILD, four were smokers and seven were treated with oral corticosteroids. Seventeen non-smoking, age- and sex-matched healthy subjects served as controls. Bronchoscopy was performed to sample endobronchial mucosal biopsies, which were immunohistochemically stained using a panel of antibodies against inflammatory markers.

    RESULTS: The number of neutrophils was significantly elevated in the submucosa of SSc patients, regardless of ILD, or whether the subject was smoking or using oral corticosteroids. No up-regulation of neutrophil chemoattractants or cytokines was seen in the bronchial epithelium. The signal transduction pathways and adhesion molecule expression tended to be suppressed or unchanged in SSc patients compared with controls.

    CONCLUSION: It is concluded that SSc is associated with a chronic neutrophilic inflammation in the bronchial mucosal, with signs of suppressed signal transduction, regardless of the presence of interstitial lung disease.

  • 40. Skogberg, Gabriel
    et al.
    Gudmundsdottir, Judith
    van der Post, Sjoerd
    Sandström, Kerstin
    Bruhn, Sören
    Benson, Mikael
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Telemo, Esbjörn
    Ekwall, Olov
    Characterization of human thymic exosomes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e67554-Article in journal (Refereed)
    Abstract [en]

    Exosomes are nanosized membrane-bound vesicles that are released by various cell types and are capable of carrying proteins, lipids and RNAs which can be delivered to recipient cells. Exosomes play a role in intercellular communication and have been described to mediate immunologic information. In this article we report the first isolation and characterization of exosomes from human thymic tissue. Using electron microscopy, particle size determination, density gradient measurement, flow cytometry, proteomic analysis and microRNA profiling we describe the morphology, size, density, protein composition and microRNA content of human thymic exosomes. The thymic exosomes share characteristics with previously described exosomes such as antigen presentation molecules, but they also exhibit thymus specific features regarding surface markers, protein content and microRNA profile. Interestingly, thymic exosomes carry proteins that have a tissue restricted expression in the periphery which may suggest a role in T cell selection and the induction of central tolerance. We speculate that thymic exosomes may provide the means for intercellular information exchange necessary for negative selection and regulatory T cell formation of the developing thymocytes within the human thymic medulla.

  • 41.
    Stenqvist, Ann-Christin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Chen, Ting
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Hedlund, Malin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Dimova, Tanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Innala, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    An efficient optimized method for isolation of villous trophoblast cells from human early pregnancy placenta suitable for functional and molecular studies2008In: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 60, no 1, p. 33-42Article in journal (Refereed)
    Abstract [en]

    PROBLEM: The uniqueness of the human placenta cannot be replaced by animal models. In vitro studies are compulsory to elucidate the biology of human placenta and require isolation and purification of villous trophoblasts, which can be used in molecular and functional studies. Constant improvement in the isolation technique is required to obtain a high yield of pure trophoblast cells with high viability and well preserved morphology.

    METHOD OF STUDY: Optimized isolation procedure for human villous trophoblasts based on mild enzymatic treatment, Percoll gradient centrifugation and additional purification step involving positive or negative immunoselection on magnetic beads is described.

    RESULTS: A simple and effective isolation protocol gave a reasonably high yield of villous trophoblast cells with high purity and viability, and excellent morphology as assessed by flow cytometry and electron microscopy.

    CONCLUSION: This protocol provides an efficient, optimized method for isolation and enrichment of villous trophoblast cells, suitable for phenotypic, ultrastructural, molecular and functional analyses and for establishment of primary cultures.

  • 42.
    Stenqvist, Ann-Christin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, no 11, p. 5515-5523Article in journal (Refereed)
    Abstract [en]

    Apoptosis is crucially important in mediating immune privilege of the fetus during pregnancy. We investigated the expression and in vitro apoptotic activity of two physiologically relevant death messengers, the TNF family members Fas ligand (FasL) and TRAIL in human early and term placentas. Both molecules were intracellularly expressed, confined to the late endosomal compartment of the syncytiotrophoblast, and tightly associated to the generation and secretion of placental exosomes. Using immunoelectron microscopy, we show that FasL and TRAIL are expressed on the limiting membrane of multivesicular bodies where, by membrane invagination, intraluminal microvesicles carrying membranal bioactive FasL and TRAIL are formed and released in the extracellular space as exosomes. Analyzing exosomes secreted from placental explant cultures, to our knowledge, we demonstrate for the first time that FasL and TRAIL are clustered on the exosomal membrane as oligomerized aggregates ready to form death-inducing signaling complex. Consistently, placental FasL-and TRAIL-carrying exosomes triggered apoptosis in Jurkat T cells and activated PBMC in a dose-dependent manner. Limiting the expression of functional FasL and TRAIL to exosomes comprise a dual benefit: 1) storage of exosomal FasL and TRAIL in multivesicular bodies is protected from proteolytic cleavage and 2) upon secretion, delivery of preformed membranal death molecules by exosomes rapidly triggers apoptosis. Our results suggest that bioactive FasL-and TRAIL-carrying exosomes, able to convey apoptosis, are secreted by the placenta and tie up the immunomodulatory and protective role of human placenta to its exosome-secreting ability.

  • 43. Tirado-Gonzalez, Irene
    et al.
    Freitag, Nancy
    Barrientos, Gabriela
    Shaikly, Valerie
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Strand, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Kjellberg, Lennart
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Klapp, Burghard F.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Cohen, Marie
    Blois, Sandra M.
    Galectin-1 influences trophoblast immune evasion and emerges as a predictive factor for the outcome of pregnancy2013In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 19, no 1, p. 43-53Article in journal (Refereed)
    Abstract [en]

    Galectin-1 (gal-1) is expressed at the feto-maternal interface and plays a role in regulating the maternal immune response against placental alloantigens, contributing to pregnancy maintenance. Both decidua and placenta contribute to gal-1 expression and may be important for the maternal immune regulation. The expression of gal-1 within the placenta is considered relevant to cell-adhesion and invasion of trophoblasts, but the role of gal-1 in the immune evasion machinery exhibited by trophoblast cells remains to be elucidated. In this study, we analyzed gal-1 expression in preimplantation human embryos and first-trimester decidua-placenta specimens and serum gal-1 levels to investigate the physiological role played by this lectin during pregnancy. The effect on human leukocyte antigen G (HLA-G) expression in response to stimulation or silencing of gal-1 was also determined in the human invasive, proliferative extravillous cytotrophoblast 65 (HIPEC65) cell line. Compared with normal pregnant women, circulating gal-1 levels were significantly decreased in patients who subsequently suffered a miscarriage. Human embryos undergoing preimplantation development expressed gal-1 on the trophectoderm and inner cell mass. Furthermore, our in vitro experiments showed that exogenous gal-1 positively regulated the membrane-bound HLA-G isoforms (HLA-G1 and G2) in HIPEC65 cells, whereas endogenous gal-1 also induced expression of the soluble isoforms (HLA-G5 and -G6). Our results suggest that gal-1 plays a key role in pregnancy maternal immune regulation by modulating HLA-G expression on trophoblast cells. Circulating gal-1 levels could serve as a predictive factor for pregnancy success in early human gestation.

  • 44.
    Vinnars, Marie-Therese
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Björk, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Bremme, Katarina
    Holmlund, Ulrika
    Sverremark-Ekström, Eva
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Enhanced Th1 and inflammatory mRNA responses upregulate NK cell cytotoxicity and NKG2D ligand expression in human pre-eclamptic placenta and target it for NK cell attack2018In: American Journal of Reproductive Immunology, ISSN 1046-7408, E-ISSN 1600-0897, Vol. 80, no 1, article id e12969Article in journal (Refereed)
    Abstract [en]

    Problem: Pre-eclampsia (PE), a severe human pregnancy disorder, is associated with exaggerated systemic inflammation, enhanced cytokine production, and increased shedding of microvesicles leading to endothelial dysfunction, coagulopathy, and extensive placenta destruction. The cause of PE is still unclear. Evidence suggests that its origin lies in the placenta and that the maternal immune system is involved. A shift in cytokine production in PE pregnancy promotes NK cell activation, suggested to be important in PE pathogenesis. In line with this suggestion, we studied NK cell cytotoxicity in peripheral blood of PE patients and controls and the mRNA expression of cytokines and of the NKG2D receptor and its ligands MICA/B and ULBP1-3 in PE- and normal placenta.

    Method of study: The cytotoxic capacity of peripheral blood NK cells was analyzed using K562 target cells. The cytokine mRNA profiles and the mRNA expression of the NKG2D receptor and its ligands MICA/B and ULBP 1-3 in PE placenta were assessed and compared to those in normal placenta using real-time quantitative RT-PCR.

    Results: The cytotoxicity of peripheral blood NK cells was upregulated in PE cases. Further, we found an enhanced inflammatory cytokine mRNA response combined with a dysregulated regulatory response and a significant mRNA overexpression of NKG2D receptor and its ligands MICA/B and ULBP in PE placenta.

    Conclusion: The destruction of chorionic villi observed in PE placenta might be conveyed by an enhanced local cytotoxic response through the NKG2D receptor-ligand pathway, which in turn might be promoted by an intense inflammatory response not counteracted by regulatory cytokine responses.

  • 45. Wang, Ning
    et al.
    Truedsson, Lennart
    Elvin, Kerstin
    Andersson, Bengt A
    Rönnelid, Johan
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindkvist, Annica
    Ludvigsson, Jonas F
    Hammarström, Lennart
    Dahle, Charlotte
    Serological assessment for celiac disease in IgA deficient adults2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93180-Article in journal (Refereed)
    Abstract [en]

    Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet.

    Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-even IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected.

    Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti- DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not.

    Conclusions: IgG anti- tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.

  • 46.
    Wikström-Frisén, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Larsson, Peter
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Mincheva Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. The Swedish School of Sport and Health Sciences, Sweden.
    Mood and oxytocin blood levels in physically active women with and without oral contraceptive use in relation to seasonal daylight variation2017In: International Journal of Sports and Exercise Medicine, ISSN 2469-5718, Vol. 3, no 3, article id 058Article in journal (Refereed)
    Abstract [en]

    Background

    The aim is to provide normative data on oxytocin, and its seasonality in users and non-users of Oral Contraceptives (OC) in physically active women. Further, to elucidate the relationship between Oxytocin and Profile of Mood States (POMS) for further research to see if Oxytocin can be used as an additional diagnostic marker to detect overreaching/overtraining syndrome or other stress disorders.

    Methods

    Forty-eight women (18-35 years old), 19 with and 29 without OC use, physically active at least 3 times a week at > 13 on the Borg RPE scale. Thirty-three subjects completed the study, 15 with and 18 without OC use. The number of hours from sunrise to sunset averaged 10 h during the autumn, 6 h during the winter, and 15 h during the spring. Once a month, blood samples were taken, weight and the day of menstrual cycle was documented, the POMS questionnaire was filled out as well as a personal daily logbook recording exercise type, duration, and intensity. To evaluate seasonal variations in Oxytocin and Global POMS, repeated measures analysis of variance was used.

    Results

    A significant seasonal variation in Oxytocin levels within the groups with and without OC respectively and significant differences in Oxytocin levels between the groups at diverse seasons were found. No significant difference in seasonal variation of Global POMS within the groups and no significant differences in levels of Global POMS between the groups with and without OC were seen. Furthermore, no clear relationship between Oxytocin, Global POMS scores, and hours of daylight respectively were detected.

    Conclusions

    Due to seasonality, impact of OC use on oxytocin levels, methodological considerations, and no convincing relationship to Global POMS, oxytocin is not suggested to be an optimal, diagnostic marker alone or in combination with others to detect overreaching and overtraining syndrome in physically active women.

  • 47.
    Wikström-Frisén, Lisbeth
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Nordström, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine. The Swedish School of Sport and Health Sciences, Stockholm, Sweden.
    Impact of Season and Oral Contraceptive use on Cortisol Levelsin Physically Active Women2016In: Journal of Exercise, Sports & Orthopedics, ISSN 2374-6904, Vol. 3, no 2Article in journal (Refereed)
    Abstract [en]

    When athletes optimize their physical performance, an imbalance could occur between the strain of training, time for recovery and the athlete’s individual tolerance of stress that could lead to overreaching and overtraining syndrome. Cortisol has been suggested to be a biological, diagnostic marker to detect overreaching and overtraining syndrome, since it is thought to indicate stress. This study aimed to provide normative data on cortisol levels, hence investigate seasonality and impact of oral contraceptive use to elucidate if cortisol could be used as a diagnostic marker to detect overreaching and overtraining syndrome in female athletes. The women, divided in two groups, oral contraceptive users (n = 15) and non-users (n = 18), were followed over a nine-month period with monthly blood sampling for cortisol testing and a Profile of Mood State questionnaire (POMS) as a subjective measure of overreaching and overtraining syndrome.Findings indicated seasonal variations in cortisol levels, with different pattern in oral contraceptive users to non-users and moreover, higher cortisol levels in users to nonusers irrespective of season. No differences in seasonal variation in Global POMS score within the groups and no differences in Global POMS score between the groups were detected. Due to seasonality, impact of oral contraceptive use on cortisol levels, methodological considerations and standardization, as well as due to no convincing relationship to Global POMS score, cortisol is not suggested to be an optimal biological, diagnostic marker to detect overreaching and overtraining syndrome in physically active women.

  • 48.
    Winberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaev, Ivan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lundell, Catarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Arencibia, Ignacio
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    West, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Dynamics of cytokine mRNA expression and fecal biomarkers in school-children undergoing a double-blind placebo-controlled food challenge series2016In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 88, p. 259-266Article in journal (Refereed)
    Abstract [en]

    Background: There is need for prognostic markers for symptomatic food allergy since current diagnostic methods are insufficient and/or time and labor consuming. Objective: To estimate the cytokine mRNA profiles in peripheral blood mononuclear cells (PBMC) before and after a double-blind placebo-controlled food challenge series in schoolchildren with suspected allergy to milk, egg or cod and in healthy controls. Analyses of fecal inflammatory biomarkers before and after the challenge were included. Methods: Twelve-year-old children from a population-based cohort reporting complete avoidance of milk, egg, cod or wheat due to perceived hypersensitivity were clinically examined and those with suspected food allergy were evaluated with a 3-session double-blind placebo-controlled food challenge (n = 18). Seven healthy controls participated in a double-blind challenge with egg. Before and after the challenge series, the cytokine mRNA expression was quantified for 13 cytokines discriminating between humoral Th2-, cytotoxic Thl-, regulatory Th3/Tr1- and inflammatory responses. Fecal calprotectin and eosinophil-derived neurotoxin (EDN) were also analyzed in children with suspected food allergy before and after the challenge series. Results: Pre challenge, children with suspected food allergy had higher IL-13 and TNF-alpha expression and lower IFN-gamma and IL-15 expression compared to healthy controls (all p < 0.05). Children with challenge proven food allergy had increased IL13 and IL-10 expression compared to the levels seen in negative challenges (p < 0.05). Post challenge, IL-1 beta and IL-6 mRNA levels were elevated in the food allergic children compared to controls (p < 0.05). Fecal calprotectin and EDN levels were higher in challenge-proven food allergy compared to a negative challenge although not statistically significantly. Conclusion & clinical relevance: Increased baseline mRNA levels of the Th2-related cytokine IL-13 and the regulatory cytokine IL-10 predicted a positive food challenge outcome. These cytokines in combination with fecal calprotectin and EDN might serve as future prognostic markers for symptomatic, IgEmediated food allergy but need further validation in a larger patient cohort.

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