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  • 551.
    Johansson, Henrik J.
    et al.
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, S-17121 Stockholm, Sweden..
    Vallhov, Helen
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, SE-11883 Stockholm, Sweden.;Soder Sjukhuset, Unit Sachs Children & Youth Hosp, SE-11883 Stockholm, Sweden..
    Holm, Tina
    Karolinska Inst, Translat Immunol Unit, Dept Med Solna, S-17176 Stockholm, Sweden.;Univ Hosp, S-17176 Stockholm, Sweden..
    Gehrmann, Ulf
    Karolinska Inst, Translat Immunol Unit, Dept Med Solna, S-17176 Stockholm, Sweden.;Univ Hosp, S-17176 Stockholm, Sweden..
    Andersson, Anna
    Karolinska Inst, Translat Immunol Unit, Dept Med Solna, S-17176 Stockholm, Sweden.;Univ Hosp, S-17176 Stockholm, Sweden..
    Johansson, Catharina
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, SE-11883 Stockholm, Sweden.;Soder Sjukhuset, Unit Sachs Children & Youth Hosp, SE-11883 Stockholm, Sweden..
    Blom, Hans
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Carroni, Marta
    Sci Life Lab, Cryo EM Natl Facil, S-17177 Stockholm, Sweden..
    Lehtio, Janne
    Karolinska Inst, Sci Life Lab, Dept Oncol Pathol, S-17121 Stockholm, Sweden..
    Scheynius, Annika
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, SE-11883 Stockholm, Sweden.;Soder Sjukhuset, Unit Sachs Children & Youth Hosp, SE-11883 Stockholm, Sweden.;Sci Life Lab, Clin Genom, S-17177 Stockholm, Sweden..
    Extracellular nanovesicles released from the commensal yeast Malassezia sympodialis are enriched in allergens and interact with cells in human skin2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9182Article in journal (Refereed)
    Abstract [en]

    Malassezia sympodialis is a dominant commensal fungi in the human skin mycobiome but is also associated with common skin disorders including atopic eczema (AE). M. sympodialis releases extracellular vesicles, designated MalaEx, which are carriers of small RNAs and allergens, and they can induce inflammatory cytokine responses. Here we explored how MalaEx are involved in hostmicrobe interactions by comparing protein content of MalaEx with that of the parental yeast cells, and by investigating interactions of MalaEx with cells in the skin. Cryo-electron tomography revealed a heterogeneous population of MalaEx. iTRAQ based quantitative proteomics identified in total 2439 proteins in all replicates of which 110 were enriched in MalaEx compared to the yeast cells. Among the MalaEx enriched proteins were two of the M. sympodialis allergens, Mala s 1 and s 7. Functional experiments indicated an active binding and internalization of MalaEx into human keratinocytes and monocytes, and MalaEx were found in close proximity of the nuclei using super-resolution fluorescence 3D-SIM imaging. Our results provides new insights into host-microbe interactions, supporting that MalaEx may have a role in the sensitization and maintenance of inflammation in AE by containing enriched amounts of allergens and with their ability to interact with skin cells.

  • 552.
    Johansson, Jeannette
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    Salazar, Janice N
    Aveskogh, Maria
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär Immunologi.
    Munday, Barry
    Miller, Robert D
    Hellman, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Molekylär immunologi.
    High variability in complementarity-determining regions compensates for a low number of V gene families in the lambda light chain locus of the platypus.2005In: Eur J Immunol, ISSN 0014-2980, Vol. 35, no 10, p. 3008-19Article in journal (Other scientific)
  • 553.
    Johansson, Karin
    et al.
    Department of Laboratory Medicine, Molecular Diagnostics, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Hanna
    Department of Laboratory Medicine, Molecular Diagnostics, Örebro University Hospital, Örebro, Sweden.
    Norén, Torbjörn
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Clostridium difficile infection diagnostics: evaluation of the C. DIFF Quik Chek Complete assay, a rapid enzyme immunoassay for detection of toxigenic C. difficile in clinical stool samples2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 11, p. 1016-1020Article in journal (Refereed)
    Abstract [en]

    Diagnostic testing for Clostridium difficile infection (CDI) has, in recent years, seen the introduction of rapid dual-EIA (enzyme immunoassay) tests combining species-specific glutamate dehydrogenase (GDH) with toxin A/B. In a prospective study, we compared the C. DIFF Quik Chek Complete test to a combination of selective culture (SC) and loop-mediated isothermal amplification (LAMP) of the toxin A gene. Of 419 specimens, 68 were positive in SC including 62 positive in LAMP (14.7%). The combined EIA yielded 82 GDH positives of which 47 were confirmed toxin A/B positive (11%) corresponding to a sensitivity and specificity of 94% for GDH EIA compared to SC and for toxin A/B EIA a sensitivity of 71% and a specificity of 99% compared to LAMP. Twenty different PCR ribotypes were evenly distributed except for UK 081 where only 25% were toxin A/B positive compared to LAMP. We propose a primary use of a combined GDH toxin A/B EIA permitting a sensitive 1-h result of 379 of 419 (90%, all negatives plus GDH and toxin EIA positives) referred specimens. The remaining 10% being GDH positive should be tested for toxin A/B gene on the same day and positive results left to a final decision by the physician.

  • 554.
    Johansson, Maria
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Early gut microbiota in relation to cytokine responses and allergic disease2011Licentiate thesis, comprehensive summary (Other academic)
  • 555.
    Johansson, Maria A.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Qazi, Khaleda Rahman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Salvany Celades, Maria
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Bittmann, Julia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Eberl, Matthias
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Probiotic Lactobacilli Modulate Staphylococcus aureus-Induced Activation of Conventional and Unconventional T cells and NK Cells2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 273Article in journal (Refereed)
    Abstract [en]

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

  • 556.
    Johansson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Formation of Composite Islet Grafts: A novel strategy to promote islet survival and revascularization2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The islets of Langerhans are small and delicate spheroid organs scattered in the pancreas responsible for insulin production. Transplantation of isolated islets is a beneficial therapy for patients with a severe form of type 1 diabetes. The islets, which normally are richly vascularized in the pancreas, are completely disconnected from the vascular support by the enzymatic digestion during the isolation procedure. Islet viability is affected throughout all steps in this process, from donor death and isolation of islets to culturing and the transplantation process itself.

    In this thesis a novel strategy to promote islet survival and to re-establish islet vasculature is presented. We show endogenous expression of 51 different genes related to inflammation in cultured islets. Among these genes high expression of MCP-1, MIF, VEGF, thymosin b-10 and IL-8, IL-1β, IL-5R-a, IFN-γ antagonist were found in all donors during the 5- and the 2-day cultures, respectively. Protein expression of these genes can stimulate inflammatory immune responses but also promote tissue repair by attracting curative cells such as endothelial cells (EC) leading to re-establishment of the vasculature.

    We have established a novel technique by formation of composite islets using EC and mesenchymal stem cells (MSC). EC adhered on the surface of the islets and created a potential blood tolerant surface. The EC-islets showed a degree of protection from the detrimental effects of instant blood-mediated inflammatory reaction (IBMIR) with the major components of IBMIR being decreased in in vitro assays. We combined MSC to the EC-islets with success. The MSC were found to have proliferative effect on EC and the combination of these two cell types on the islets further increased the EC covered surface compared to EC-islets. The EC-MSC-islets in co-culture formed vessel-like structures both into the islets and out to the surrounding matrix. The MSC enhanced the exogenous EC to form vessel-like network in the EC-MSC-islets indicating vascular support by the MSC.

    The novel strategy and conditions presented herein could alleviate problems related to survival of the islets by promoting revascularization. This would open up a new era in islet transplantation and allow more patients to benefit from this therapy.

  • 557.
    Johar, Dina
    et al.
    Manitoba Institute of Cell Biology, Winnipeg, Canada,Ain Shams University, Heliopolis, Cairo, Egypt.
    Roth, Julie C
    Manitoba Institute of Cell Biology, Winnipeg, Canada.
    Bay, Graham H.
    Manitoba Institute of Cell Biology, Winnipeg, Canada.
    Walker, Jennifer N.
    Manitoba Institute of Cell Biology, Winnipeg, Canada.
    Kroczak, Tadeusz J.
    Park View Clinic, Winnipeg, Canada.
    Los, Marek Jan
    Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
    Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer2004In: Roczniki Akademii Medycznej w Bialymstoku (1995), Vol. 49, p. 31-39Article, review/survey (Refereed)
    Abstract [en]

    In this short review we attempt to establish and/or strengthen connections between clinical, inflammatory manifestation of cancer, inflammatory processes driven by lipoxy-metabolites and their contribution to immortalized phenotype and apoptosis inhibition. Particularly the resemblance between symptoms of inflammation and signs associated with cancer chemotherapy and/or cytokine therapy is illustrated. In this context the role of apoptosis and necrosis in inflammation as well as the role of RedOx processes and lipid-oxidizing enzymes particularly cyclooxygenase-2 (COX-2) and also to lesser extend the 5-lipooxygenase (5-LOX) is highlighted. The multitude of biological effects of reactive oxygen species is shortly summarized and some aspects of it are being discussed in greater detail. Apoptotic cell death is discussed in the context of the "resolve-phase" of an inflammatory response. The disturbance of apoptosis is mainly deliberated in the framework of insufficient removal of immuno-effector cells that may cause autoimmunity. The role of COX-2 in apoptosis resistance is being highlighted mainly in the context of malignant transformation. The mechanism of cell death (apoptotic or necrotic) and its influence on the immune system and potential benefits of necrotic cell death induction during cancer chemotherapy is indicated.

  • 558.
    Johnzon, Carl-Fredrik
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Rönnberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Guss, Bengt
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden..
    Live Staphylococcus aureus Induces Expression and Release of Vascular Endothelial Growth Factor in Terminally Differentiated Mouse Mast Cells2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 247Article in journal (Refereed)
    Abstract [en]

    Mast cells have been shown to express vascular endothelial growth factor (VEGF), thereby implicating mast cells in pro-angiogenic processes. However, the mechanism of VEGF induction in mast cells and the possible expression of VEGF in fully mature mast cells have not been extensively studied. Here, we report that terminally differentiated peritoneal cell-derived mast cells can be induced to express VEGF in response to challenge with Staphylococcus aureus, thus identifying a mast cell-bacteria axis as a novel mechanism leading to VEGF release. Whereas live bacteria produced a robust upregulation of VEGF in mast cells, heat-inactivated bacteria failed to do so, and bacteria-conditioned media did not induce VEGF expression. The induction of VEGF was not critically dependent on direct cell-cell contact between bacteria and mast cells. Hence, these findings suggest that VEGF can be induced by soluble factors released during the co-culture conditions. Neither of a panel of bacterial cell-wall products known to activate toll-like receptor (TLR) signaling promoted VEGF expression in mast cells. In agreement with the latter, VEGF induction occurred independently of Myd88, an adaptor molecule that mediates the downstream events following TLR engagement. The VEGF induction was insensitive to nuclear factor of activated T-cells inhibition but was partly dependent on the nuclear factor kappa light-chain enhancer of activated B cells signaling pathway. Together, these findings identify bacterial challenge as a novel mechanism by which VEGF is induced in mast cells.

  • 559.
    Jonefjäll, Börje
    et al.
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine, Kungälv Hospital, Kungälv, Sweden.
    Öhman, Lena
    University of Skövde, School of Health and Education. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Simrén, Magnus
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Center for Functional GI and Motility Disorders, University of North Carolina, USA.
    Strid, Hans
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
    IBS-like Symptoms in Patients with Ulcerative Colitis in Deep Remission Are Associated with Increased Levels of Serum Cytokines and Poor Psychological Well-being2016In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 22, no 11, p. 2630-2640Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gastrointestinal symptoms (GI) compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in remission. The causes of these symptoms remain to be clarified. Our aim was to investigate prevalence and factors associated with IBS-like symptoms in patients with UC in deep remission.

    METHODS: We included 298 patients with UC and used Mayo score, sigmoidoscopy, and fecal calprotectin to define deep remission versus active disease. Presence of IBS-like symptoms according to the Rome III criteria, severity of GI, extraintestinal and psychological symptoms, stress levels, and quality of life were measured with validated questionnaires. Serum cytokines and high-sensitive C-reactive peptide were determined.

    RESULTS: The criteria for deep remission was fulfilled by 132 patients (44%) and 24 of these fulfilled the Rome III criteria for IBS (18%). Patients with UC in deep remission with IBS-like symptoms had comparable levels of GI symptoms, non-GI somatic symptoms, and quality of life as patients with active UC. The patients with UC in deep remission with IBS-like symptoms had similar levels of fecal calprotectin as patients in deep remission without IBS-like symptoms (18 versus 31 μg/g, P = 0.11), but higher levels of serum cytokines (interleukin [IL]-1β, IL-6, IL-13, IL-10 and IL-8, P < 0.05) and higher levels of anxiety (P < 0.001), depression (P = 0.02) and perceived stress (P = 0.03).

    CONCLUSIONS: IBS-like symptoms in patients with UC in deep remission are common, but not as prevalent as previously reported. Poor psychological well-being and increased serum cytokine levels, but not colonic low-grade inflammation, were associated with IBS-like symptoms.

  • 560.
    Jonsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Microbiology.
    Elmros, Teodor
    Umeå University, Faculty of Medicine, Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Subcutaneous implanted chambers in different mouse strains as an animal model to study genetic stability during infection with Lyme disease Borrelia1995In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 18, no 2, p. 109-14Article in journal (Refereed)
    Abstract [en]

    Tissue metal net cages were implanted subcutaneously in BALB/cJ and C3H/Tif mice as an experimental model of Borrelia burgdorferi infection. B. burgdorferi sensu stricto strain Sh2-82 could be isolated up to 14 weeks after the inoculation. However, a significant difference in infectivity between the two mice strains was observed. C3H/Tif mice were more susceptible to developing chronic B. burgdorferi s.s. infections than BALB/cJ mice. Although a B. burgdorferi infection was established, no rearrangements in the ospA and ospB genes were observed in any of the infected mice.

  • 561. Jonsson, Maria
    et al.
    Noppa, L
    Barbour, A G
    Bergström, S
    Heterogeneity of outer membrane proteins in Borrelia burgdorferi: comparison of osp operons of three isolates of different geographic origins.1992In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 60, no 5, p. 1845-53Article in journal (Refereed)
    Abstract [en]

    Biochemical and immunochemical studies of the outer membrane proteins of Borrelia burgdorferi have shown that the OspA and OspB proteins from strains of different geographic origins may differ considerably in their reactivities with monoclonal antibodies and in their apparent molecular weights. To further characterize this variation in Osp proteins between strains, the osp operons and deduced translation products from two strains, one from Sweden (ACAI) and one from eastern Russia (Ip90), were studied. Polyacrylamide gel electrophoresis and Western blot (immunoblot) analyses confirmed differences between ACAI, Ip90, and the North American strain B31 in their Osp proteins. The sequences of the ospA and ospB genes of ACAI and Ip90 were compared with that of the previously studied osp operon of B31 (S. Bergström, V. G. Bundoc, and A. G. Barbour, Mol. Microbiol. 3:479-486, 1989). The osp genes of ACAI and Ip90, like the corresponding genes of B31, were found on plasmids with apparent sizes of about 50 kb and are cotranscribed as a single unit. Pairwise comparisons of the nucleotide sequences revealed that the ospA genes of ACAI and Ip90 were 85 and 86% identical, respectively, to the ospA gene of strain B31 and 86% identical to each other. The ospB sequences of these two strains were 79% identical to the ospB gene of B31 and 81% identical to each other. There was significantly greater similarity between the ospA genes of the three different strains than there was between the ospA and ospB genes within each strain. These studies suggest that the duplication of osp genes in B. burgdorferi occurred before the geographical dispersion of strains represented by ACAI, Ip90, and B31.

  • 562.
    Jonsson, Yvonne
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology . Linköping University, Faculty of Health Sciences.
    Cytokines and immune balance in preeclampsia: a survey of some immunological variables and methods in the study of preeclampsia2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Preeclampsia is one of the most feared pregnancy complications, with a risk of maternal and fetal death and with no ideal therapy readily available. The cause of this strictly pregnancyrelated disease is still unknown and is therefore a great challenge to all researchers in the field of pregnancy-related pathophysiology.

    Today, the dominating theory of the origin of preeclampsia is defective initial placentation with insufficient penetration of the trophoblasts, leading to impaired maternal blood flow through narrow spiral arteries. However, the cause of this defective trophoblast behavior is not known. The maternal immune system has been proposed to have an influence on both the placentation and the subsequent systemic reactions. Therefore, it is very interesting to study the maternal immune system during preeclampsia, in hope of achieving a better understanding of this puzzling disease.

    Earlier studies have suggested that normal pregnancy requires a shift to a Th2/antiinflammatory type of immunity, at least directed towards the fetus and placenta, while some pregnancy complications, such as preeclampsia, could be due to a skewed Th1/proinflammatory type of immunity. However, the results from earlier studies designed to test the Th1/Th2 hypothesis in preeclampsia have not been consistent. Therefore, the aim of this thesis was to examine if established preeclampsia is associated with increased innate inflammatory responses and a deviation of adaptive responses towards Th1 when compared with normal pregnancy.

    Enumerations of cytokine-producing cells from peripheral blood did not show any difference in the production of IFN-γ, IL-4, IL-10 and IL-12 between women with preeclampsia and normal pregnancies. However, a decrease in the spontaneously produced levels of IL-5 was detected in cell cultures on peripheral blood mononuclear cells in women with preeclampsia. Furthermore, a decreased production of IL-10 in response to paternal antigens, believed to represent the fetus, was also detected for the preeclamptic women.

    Serum analysis showed increased levels of the pro-inflammatory mediators IL-6 and IL-8 during preeclampsia. Also, preeclamptic women displayed increased serum levels of the soluble IL-4 receptor, but no difference in the levels of IL-4 compared to normal pregnant women. This was an elusive finding, since the receptor was originally thought to reflect the levels of IL-4, but has recently been shown to have both agonistic and antagonistic properties on the IL-4 levels. Further studies of the local immune responses in the placenta showed no difference in the immunohistochemical staining of IL-4 and TNF-α between women with preeclampsia and women with normal pregnancies. In general, there were no hallmarks of abnormal morphology in the placental sections examined, regardless of diagnosis.

    In conclusion, the decreased levels of IL-10 in response to paternal antigens and the systemically increased levels of IL-6 and IL-8 suggest a specific decrease in antiinflammatory responses towards fetal antigens, together with a systemic activation of proinflammatory mediators during preeclampsia. Furthermore, the decreased production of IL-5 also indicates, at least partly, decreased Th2 responses in the established preeclampsia.

  • 563. Jordan, Stanley C
    et al.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Choi, Jua
    IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 17, p. 1693-4Article in journal (Refereed)
  • 564. Junevik, K.
    et al.
    Werlenius, O.
    Fogelstrand, L.
    Karlsson-Parra, Alex
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Andersson, P-O
    High Functional CD70 Expression on alpha-Type 1-Polarized Dendritic Cells from Patients with Chronic Lymphocytic Leukaemia2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 415-422Article in journal (Refereed)
    Abstract [en]

    Antigen-loaded dendritic cells (DCs) used as anticancer vaccine holds promise for therapy, but needs to be optimized. The most frequently described DC vaccine is being matured with a cocktail containing prostaglandin E2 (PGE2DC). However, even though PGE2DCs express both costimulatory and migratory receptors, their IL-12p70-prodcution is low, leading to an insufficient Th1 immune response. As an alternative, -type-1 polarized DCs (DC1s) have shown a superior production of IL-12p70 and subsequent activation of effector cells. From chronic lymphocytic leukaemia (CLL) patients, DC1s can be generated to induce a functional Th1-immune response. Yet, another costimulatory receptor, CD70, appears to be essential for optimal DC function by promotion of T cell survival and function. So far, PGE2 is suggested as one of the most important factors for the induction of CD70 expression on DCs. Therefore, we wanted to investigate whether DC1s have the ability to express functional CD70. We found that CD70 expression on DC1s could be upregulated in the same manner as PGE2DCs. In an allogeneic mixed leucocyte reaction, we found that antibody-blocking of CD70 on DC1s from controls reduced effector cell proliferation although this could not be found when using CLL DC1s. Nevertheless, CD70-blocking of DC1s from both controls and patients with CLL had a negative influence on the production of both IL-12p70 and the Th1 cytokine IFN-, while the production of the Th2 cytokine IL-5 was enhanced. Together, this study further suggests that DC1s should be considered as a suitable candidate for clinical antitumour vaccine strategies in patients with CLL.

  • 565.
    Jönsson, Agnez
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Foerster, Sunniva
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden; Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hamasuna, Ryoichi
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Dermatovenerology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Jensen, Jörgen Skov
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991-2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC50 and MIC90 was ≤0.001-1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC50 and MIC90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial.

  • 566.
    Jönsson, Gun
    Stockholm University, Faculty of Science, The Wenner-Gren Institute.
    Apoptosis regulation in bladder cancer and multiple sclerosis2003Doctoral thesis, comprehensive summary (Other academic)
  • 567.
    Jönsson, Simon
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Inflammation is closely associated with development of atherosclerosis. The proteolytic enzyme matrix metalloproteinase (MMP)-9 is considered to play a prominent role in this process. MMP-9 has also been introduced as a marker for plaque vulnerability. Still, the possible mechanisms behind altered levels of MMP-9 and its tissue inhibitors (TIMPs) in patients with atherosclerotic disease remain unclear. The general aim of this thesis was to compare leukocyte-derived MMP-9 and TIMPs in patients with coronary artery disease (CAD) and healthy controls and to further relate the findings to psychological stress and glucocorticoid sensitivity.

    Levels of leukocyte-derived MMP-9 and TIMP-1 showed a significant difference between CAD patients and controls. Neutrophils in CAD patients were more prone to release MMP-9 and furthermore, PBMCs in patients expressed higher levels of MMP-9 and TIMP-1 and -2 mRNA than PBMCs in controls while there were no differences in plasma or serum levels. The increase in leukocyte-derived levels of MMP-9 and TIMPs indicate the presence of preactivated leukocytes in CAD.

    Inflammation has been proposed as a mechanistic link between cardiovascular risk and depressive symptoms. We investigated whether the overexpression of leukocyte-derived MMP-9 and TIMPs in CAD patients was associated with psychological factors. Patients exhibited sustained elevations in depressive symptoms, however, these symptoms were not related to any MMP-9 or TIMP variables. The findings suggest that overexpression of leukocyte-derived MMP-9 and TIMPs and elevated depressive scores represent two parallel phenomena in CAD.

    Chronic inflammation may be associated with reduced glucocorticoid sensitivity. We found that PBMCs in CAD patient expressed significantly increased levels of glucocorticoid receptor (GR)-α mRNA, whereas GR-β mRNA levels did not differ between patients and controls. Moreover, in ex vivo assays, dexamethasone efficiently suppressed MMP-9 and TIMPs equally or even more in patients compared to controls. The findings provide evidence for enhanced glucocorticoid sensitivity in CAD patients and also suggest that a state of relative hypocortisolism may contribute to the overexpression of leukocyte-derived MMP-9 and TIMPs.

    Lastly, we explored the release of MMP-9, TIMPs and cortisol in response to acute mental stress in CAD patients. Patients who exhibited a significant stress-induced increase in serum MMP-9 also exhibited an altered cortisol response. Moreover, the susceptibility to stressinduced increase in serum MMP-9 was associated with shorter leukocyte telomere length and atherosclerotic plaque burden. The findings highlight the existence of a high-risk group which may be in need of improved diagnostic and therapeutic strategies.

  • 568. Kadri, Nadir
    et al.
    Korpos, Eva
    Gupta, Shashank
    Briet, Claire
    Löfbom, Linda
    Yagita, Hideo
    Lehuen, Agnes
    Boitard, Christian
    Holmberg, Dan
    Department of Disease Biology, Faculty of Life Science, University of Copenhagen.
    Sorokin, Lydia
    Cardell, Susanna L
    CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes2012In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 188, no 7, p. 3138-3149Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.

  • 569.
    Kalbina, Irina
    et al.
    Örebro University, School of Science and Technology. Orebro Life Science Center.
    Lagerqvist, Nina
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Moiane, Bélisario
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Eduardo Mondlane University, Maputo, Mozambique.
    Ahlm, Clas
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Örebro Life Science Center, Department of Science and Technology, Örebro University, Örebro, Sweden; Department of Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Strid, Åke
    Örebro University, School of Science and Technology.
    Falk, Kerstin I.
    Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Arabidopsis thaliana plants expressing Rift Valley fever virus antigens: Mice exhibit systemic immune responses as the result of oraladministration of the transgenic plants2016In: Protein Expression and Purification, ISSN 1046-5928, E-ISSN 1096-0279, Vol. 127, p. 61-67Article in journal (Refereed)
    Abstract [en]

    The zoonotic Rift Valley fever virus affects livestock and humans in Africa and on the Arabian Peninsula.The economic impact of this pathogen due to livestock losses, as well as its relevance to public health,underscores the importance of developing effective and easily distributed vaccines. Vaccines that can bedelivered orally are of particular interest.

    Here, we report the expression in transformed plants (Arabidopsis thaliana) of Rift Valley fever virusantigens. The antigens used in this study were the N protein and a deletion mutant of the Gn glycoprotein.Transformed lines were analysed for specific mRNA and protein content by RT-PCR and Westernblotting, respectively. Furthermore, the plant-expressed antigens were evaluated for their immunogenicityin mice fed the transgenic plants. After oral intake of fresh transgenic plant material, a proportionof the mice elicited specific IgG antibody responses, as compared to the control animals that were fedwild-type plants and of which none sero-converted.

    Thus, we show that transgenic plants can be readily used to express and produce Rift Valley Fever virusproteins, and that the plants are immunogenic when given orally to mice. These are promising findingsand provide a basis for further studies on edible plant vaccines against the Rift Valley fever virus.

  • 570. Kalderén, Christina
    et al.
    Stadler, Charlotte
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsgren, Margareta
    Kvastad, Linda
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Johansson, Elin
    KTH, School of Biotechnology (BIO), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Sydow-Bäckman, Mona
    Gelius, Stefan Svensson
    CCL2 mediates anti-fibrotic effects in human fibroblasts independently of CCR22014In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 20, no 1, p. 66-73Article in journal (Refereed)
    Abstract [en]

    CCL2 is known for its major role as a chemoattractant of monocytes for immunological surveillance and to site of inflammation. CCL2 acts mainly through the G-protein-coupled receptor CCR2 but has also been described to mediate its effects independently of this receptor in vitro and in vivo. Emerging pieces of evidence indicate that the CCL2/CCR2 axis is involved in fibrotic diseases, such as increased plasma levels of CCL2 and the presence of CCL2-hyperresponsive fibroblasts explanted from patients with systemic sclerosis and idiopathic pulmonary fibrosis. One of the profibrotic key mediators is the myofibroblast characterized by overexpression of alpha-smooth muscle actin and collagen I. However, the correlation between the CCL2/CCR2 axis and the activation of fibroblasts is not yet fully understood. We have screened human fibroblasts of various origins, human pulmonary fibroblasts (HPF), human fetal lung fibroblasts (HFL-1) and primary preadipocytes (SPF-1) in regard to CCL2 stimulated fibrotic responses. Surprisingly we found that CCL2 mediates anti-fibrotic effects independently of CCR2 in human fibroblasts of different origins.

  • 571.
    Kaleviste, Epp
    et al.
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Saare, Mario
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Leahy, Timothy Ronan
    Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland.
    Bondet, Vincent
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Duffy, Darragh
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Mogensen, Trine H.
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Jörgensen, Sofie E.
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.
    Nurm, Helke
    Tallinn Childrens Hosp, Dept Emergency Care & Acute Infect, Tallinn, Estonia.
    Ip, Winnie
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Davies, E. Graham
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Sauer, Sascha
    Max Planck Inst Mol Genet, Otto Warburg Lab, Berlin, Germany;Max Delbruck Ctr Mol Med, BIMSB, BIH, Lab Funct Genom Nutrigen & Syst Biol, Berlin, Germany.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Kisand, Kai
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined2019In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 49, no 5, p. 790-800Article in journal (Refereed)
    Abstract [en]

    STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-alpha were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-alpha levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

  • 572. Kanatsuna, Norio
    et al.
    Taneera, Jalal
    Vaziri-Sani, Fariba
    Lund University.
    Wierup, Nils
    Larsson, Helena Elding
    Delli, Ahmed
    Skarstrand, Hanna
    Balhuizen, Alexander
    Bennet, Hedvig
    Steiner, Donald F.
    Torn, Carina
    Fex, Malin
    Lernmark, Ake
    Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 40, p. 29013-29023Article in journal (Refereed)
    Abstract [en]

    Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.

  • 573.
    Kang Lim, Che
    et al.
    Karolinska University, Sweden; Singapore Gen Hospital, Singapore.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Elvin, Kerstin
    Karolinska Institute, Sweden.
    Andersson, Bengt A.
    Sahlgrens University Hospital, Sweden.
    Ronnelid, Johan
    Uppsala University, Sweden.
    Melen, Erik
    Karolinska Institute, Sweden; Stockholm South Gen Hospital, Sweden.
    Bergstrom, Anna
    Karolinska Institute, Sweden.
    Truedsson, Lennart
    Lund University, Sweden.
    Hammarstrom, Lennart
    Karolinska University, Sweden.
    Reversal of Immunoglobulin A Deficiency in Children2015In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 35, no 1, p. 87-91Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in the general population. It is defined as a serum IgA level below or equal to 0.07 g/l with normal IgM and IgG levels in children over the age of 4. However, a few cases of reversal of IgAD at later ages have been observed previously, especially in pediatric patients. This study aimed at investigating the frequency of reversal in a large cohort of children and young adults in order to evaluate the present definition of IgAD. Clinical laboratory records from 654 pediatric IgA deficient patients, 4-13 years of age, were retrieved from five university hospitals in Sweden. Follow up in the children where IgA serum levels had been routinely measured was subsequently performed. In addition, follow up of the IgA-levels was also performed at 4, 8 and 16 years of age in children who were IgA deficient at the age of 4 years in a Swedish population-based birth cohort study in Stockholm (BAMSE). Nine out of 39 (23.1 %) children who were identified as IgAD at 4 years of age subsequently increased their serum IgA level above 0.07 g/L. The average age of reversal was 9.53 +/- 2.91 years. In addition, 30 out of the 131 (22.9 %) children with serum IgAD when sampled between 5 and 9.99 years of age reversed their serum IgA level with time. The BAMSE follow up study showed a reversal of IgAD noted at 4 years of age in 8 out of 14 IgAD children at 16 years of age (5 at 8 years of age) where 4 were normalized their serum IgA levels while 4 still showed low serum levels of IgA, yet above the level defining IgAD. The results indicate that using 4 years of age, as a cut off for a diagnosis of IgAD may not be appropriate. Our findings suggest that a diagnosis of IgAD should not be made before the early teens using 0.07 g/L of IgA in serum as a cut off.

  • 574.
    Karasu, Ebru
    et al.
    Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Köhl, Jörg
    Univ Lubeck, Inst Syst Inflammat Res ISEF, Lubeck, Germany;Cincinnati Childrens Hosp, Div Immunobiol, Cincinnati, OH USA.
    Lambris, John D.
    Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA.
    Huber-Lang, Markus
    Univ Hosp Ulm, Inst Clin & Expt Trauma Immunol, Ulm, Germany.
    Targeting Complement Pathways in Polytrauma- and Sepsis-Induced Multiple-Organ Dysfunction2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 543Article, review/survey (Refereed)
    Abstract [en]

    Exposure to traumatic or infectious insults results in a rapid activation of the complement cascade as major fluid defense system of innate immunity. The complement system acts as a master alarm system during the molecular danger response after trauma and significantly contributes to the clearance of DAMPs and PAMPs. However, depending on the origin and extent of the damaged macro- and micro-milieu, the complement system can also be either excessively activated or inhibited. In both cases, this can lead to a maladaptive immune response and subsequent multiple cellular and organ dysfunction. The arsenal of complement-specific drugs offers promising strategies for various critical conditions after trauma, hemorrhagic shock, sepsis, and multiple organ failure. The imbalanced immune response needs to be detected in a rational and real-time manner before the translational therapeutic potential of these drugs can be fully utilized. Overall, the temporal-spatial complement response after tissue trauma and during sepsis remains somewhat enigmatic and demands a clinical triad: reliable tissue damage assessment, complement activation monitoring, and potent complement targeting to highly specific rebalance the fluid phase innate immune response.

  • 575.
    Karefylaki, Styliani
    et al.
    Department of Pediatrics, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Gustafsson, Dan
    Örebro University, School of Health Sciences. Department of Pediatrics, Örebro University Hospital, Örebro, Sweden.
    Recovery from food protein-induced enterocolitis syndrome caused by fish2016In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 27, no 1, p. 105-106Article in journal (Refereed)
  • 576.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gigg, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Antigen Signaling Enhances Proliferation and Cytotoxic Capacity of CD19-Targeting CD28/4-1BB CAR T Cells During Expansion Without Inducing Exhaustion2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 577.
    Karlsson, Hannah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafsson, Wictor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Savoldo, Barbara
    Dotti, Gianpietro
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    CAR T Cells Express CD40L and Activates Human Dendritic Cells2014In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 22, p. S61-S61Article in journal (Other academic)
  • 578.
    Karlsson-Parra, Alex
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Immunicum AB, Gothenburg, Sweden.
    Kovacka, Juliana
    Immunicum AB, Gothenburg, Sweden.
    Heimann, Emilia
    Immunicum AB, Gothenburg, Sweden.
    Jorvid, Margareth
    Immunicum AB, Gothenburg, Sweden.
    Zeilemaker, Sijme
    Immunicum AB, Gothenburg, Sweden.
    Longhurst, Sharon
    Immunicum AB, Gothenburg, Sweden.
    Suenaert, Peter
    Immunicum AB, Gothenburg, Sweden.
    Ilixadencel - an Allogeneic Cell-Based Anticancer Immune Primer for Intratumoral Administration2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 8, article id UNSP 156Article, review/survey (Refereed)
    Abstract [en]

    Intratumoral administration of an immune primer is a therapeutic vaccine strategy aimed to trigger dendritic cell (DC)-mediated cross-presentation of cell-associated tumor antigens to cytotoxic CD8(+) T cells without the need for tumor antigen characterization. The prevailing view is that these cross-presenting DCs have to be directly activated by pathogen-associated molecular patterns (PAMPS), including Toll-like receptor ligands or live microbial agents like oncolytic viruses. Emerging data are however challenging this view, indicating that the cross-presenting machinery in DCs is suboptimally activated by direct PAMP recognition, and that endogenous inflammatory factors are the main drivers of DC-mediated cross-presentation within the tumor. Here we present preclinical mode of action data, CMC and regulatory data, as well as initial clinical data on ilixadencel. This cell-based drug product is an off-the-shelf immune primer, consisting of pro-inflammatory allogeneic DCs secreting high amounts of pro-inflammatory chemokines and cytokines at the time of intratumoral administration. The mechanism of action of ilixadencel is to induce recruitment and activation of endogenous immune cells, including NK cells that subsequently promotes cross-presentation of cell-associated tumor antigens by co-recruited DCs.

  • 579.
    Karpman, D
    et al.
    Lunds universitet.
    Manea, M
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Stahl, A L
    Lunds universitet.
    Kristoffersson, A C
    Lunds universitet.
    Platelet activation in hemolytic uremic syndrome2006In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 32, no 2, p. 128-145Article in journal (Refereed)
    Abstract [en]

    Platelet consumption in platelet-fibrin aggregates leading to thrombocytopenia and small vessel obstruction are major features of the hemolytic uremic syndrome (HUS). Although thrombocytopenia has been correlated to poor prognosis, the mechanisms by which thrombocytopenia develops in HUS have not been completely elucidated. However, plausible explanations have been platelet contact with thrombogenic surfaces and/or direct contact with an aggregating agent. This article summarizes several mechanisms of platelet activation, interactions with leukocytes, chemokine release, complement activation, and antimicrobial defense. Specific mechanisms are outlined by which platelets may be activated, leading to thrombocytopenia during HUS. In diarrhea-associated HUS Shiga toxin has been shown to injure the endothelium, thus exposing the subendothelium, releasing tissue factor, and rendering the vessel wall prothrombotic. Shiga toxin also binds to and activates platelets. The toxin may activate endothelial cells and platelets simultaneously. In atypical HUS the alternative complement pathway is activated because of mutations in complement regulatory proteins. Mutated factor H does not bind to endothelium and platelets efficiently, enabling complement activation on these cells. In thrombotic thrombocytopenic purpura, intravascular platelet clotting Occurs due to dysfunction of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Thrombi are formed by binding of platelets to ultralarge VWF multimers.

  • 580. Karshikoff, B.
    et al.
    Jensen, K. B.
    Ingvar, M.
    Kosek, E.
    Kalpouzos, G.
    Soop, A.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Axelsson, J.
    LPS increases pain sensitivity by decreased pain inhibition and increased insular activation2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, p. e1-e1Article in journal (Refereed)
    Abstract [en]

    We have shown that women are more prone to developing LPS-induced pain sensitivity than men, and that the descending endogenous pain inhibition is disrupted in women during experimental systemic inflammation. The aim of the present study was to investigate some of the central neural mechanisms underlying our previous findings. 51 participants (29 women) were injected with 0.6 ng/kg LPS or saline and went through a thumb-pressure pain fMRI paradigm 2 h after injection. As hypothesized, the subjects injected with LPS had decreased activity in the ventromedial prefrontal cortex and rostral anterior cingulate cortex (rACC), areas involved in descending pain inhibition. In addition, the LPS group had higher activity in the anterior insula, an area involved in medial/affective pain processing and interoception. These effects were not sex dependent. However, the male participants had overall stronger descending pain inhibition, reflected as a stronger rACC activity compared to women. It is possible that the more robust activation of descending pain inhibition rendered the men more resistant to the immune provocation, which may explain previously seen sex differences in LPS-induced pain sensitivity. Our findings give an indication to how the pain matrix is affected during a sickness response. The results strengthen the proposed link between systemic inflammation and weakened pain regulation in chronic pain disorders, and offers a possible mechanism underlying the female predominance in chronic pain disorders.

  • 581. Karshikoff, B.
    et al.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Olgart Höglund, C.
    Axelsson, J.
    Pain sensitivity during experimentally induced systemic inflammation in humans2013In: Brain, Behavior, and Immunity, 2013, Vol. 32, p. e32-Conference paper (Refereed)
  • 582.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Jensen, K. B.
    Kosek, E.
    Kalpouzos, Grégoria
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Soop, A.
    Ingvar, M.
    Olgart Höglund, C.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska University Hospital, Sweden; Karolinska Institutet, Sweden.
    Why sickness hurts: A central mechanism for pain induced by peripheral inflammation2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 57, p. 38-46Article in journal (Refereed)
    Abstract [en]

    Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders.

  • 583.
    Karshikoff, Bianka
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Biological psychology. Karolinska Institutet, Sweden.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University Hospital Essen, Germany.
    Role of inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 21Article, review/survey (Refereed)
    Abstract [en]

    Fatigue is a highly disabling symptom in various medical conditions. While inflammation has been suggested as a potential contributor to the development of fatigue, underlying mechanisms remain poorly understood. In this review, we propose that a better assessment of central fatigue, taking into account its multidimensional features, could help elucidate the role and mechanisms of inflammation in fatigue development. A description of the features of central fatigue is provided, and the current evidence describing the association between inflammation and fatigue in various medical conditions is reviewed. Additionally, the effect of inflammation on specific neuronal processes that may be involved in distinct fatigue dimensions is described. We suggest that the multidimensional aspects of fatigue should be assessed in future studies of inflammation-induced fatigue and that this would benefit the development of effective therapeutic interventions.

  • 584. Kasparek, Petr
    et al.
    Ileninova, Zuzana
    Zbodakova, Olga
    Kanchev, Ivan
    Benada, Oldrich
    Chalupsky, Karel
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Beck, Inken M.
    Sedlacek, Radislav
    KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 1, article id e1006566Article in journal (Refereed)
    Abstract [en]

    Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.

  • 585.
    Katargina, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Geller, Julia
    Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Ivanova, Anna
    Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Vaerv, Kairi
    Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Tefanova, Valentina
    Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Vene, Sirkka
    Publ Hlth Agcy Sweden, SE-17182 Solna, Sweden..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Publ Hlth Agcy Sweden, SE-17182 Solna, Sweden..
    Golovljova, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol, EE-11619 Tallinn, Estonia..
    Detection and identification of Rickettsia species in Ixodes tick populations from Estonia2015In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 6, no 6, p. 689-694Article in journal (Refereed)
    Abstract [en]

    A total of 1640 ticks collected in different geographical parts of Estonia were screened for the presence of Rickettsia species DNA by real-time PCR. DNA of Rickettsia was detected in 83 out of 1640 questing ticks with an overall prevalence of 5.1%. The majority of the ticks infected by rickettsiae were Ixodes ricinus (74 of 83), while 9 of the 83 positive ticks were Ixodes persulcatus. For rickettsial species identification, a part of the citrate synthasegltA gene was sequenced. The majority of the positive samples were identified as Rickettsia helvetica (81 out of 83) and two of the samples were identified as Rickettsia monacensis and Candidatus R. tarasevichiae, respectively. Genetic characterization based on the partial gltA gene showed that the Estonian sequences within the R. helvetica, R. monacensis and Candidatus R. tarasevichiae species demonstrated 100% similarity with sequences deposited in GenBank, originating from Rickettsia species distributed over large territories from Europe to Asia.

  • 586. Keib, Anna
    et al.
    Mei, Ya-Fang
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Cicin-Sain, Luka
    Busch, Dirk H.
    Dennehy, Kevin M.
    Measuring Antiviral Capacity of T Cell Responses to Adenovirus2019In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 202, no 2, p. 618-624Article in journal (Refereed)
    Abstract [en]

    Adenoviruses are a major cause of infectious mortality in children following allogeneic hematopoietic stem cell transplantation, with adoptive transfer of adenovirus-specific T cells being an effective therapeutic approach. We have previously shown that T cells specific for the peptide epitope LTDLGQNLLY were protective. In this study, we aimed to establish a viral dissemination assay to measure the antiviral capacity of T cells specific for this and other peptide epitopes in an infectious setting. We used replication-competent adenovirus 11 (Ad11pGFP) and adenovirus 5 containing adenovirus 35 fiber (Ad5F35GFP) viruses and T cells specific for HLA-A*01-restricted LTDLGQNLLY, HLA-B*07-restricted KPYSGTAYNAL, and HLA-A*02-restricted LLDQLIEEV peptide epitopes. T cells in PBMC from healthy donors were expanded with peptide and IL-2 or treated with IL-2 alone to serve as nonstimulated control cells, and then these expanded or nonstimulated CD8(+) cells were purified and cocultured with autologous monocytes infected with adenovirus at low multiplicity of infection. After 3 d, the number of infected GFP(+) monocytes and, hence, viral dissemination was quantified by flow cytometry. T cells expanded with LTDLGQNLLY peptide from multiple HLA-A*01(+) donors prevented adenovirus dissemination, and nonstimulated T cells did not prevent dissemination, thus, indicating that LTDLGQNLLY-specific T cells have high antiviral capacity. Similarly, expanded KPYSGTAYNAL- and LLDQLIEEV-specific T cells could prevent viral dissemination. However, the frequency of expanded T cells specific for these last two epitopes was variable between donors with consequent variable prevention of adenoviral dissemination. Taken together, we demonstrate that T cells specific for three peptide epitopes, from both structural and nonstructural proteins, can prevent adenoviral dissemination and provide a novel method to measure the antiviral capacity of adenovirus-specific T cell responses.

  • 587.
    Kelly, Anne
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Hussain, Shahida
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olcen, Per
    Mölling, Paula
    Örebro University Hospital.
    Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 1, p. 56-63Article in journal (Refereed)
    Abstract [en]

    The factor H binding protein (fHbp) is currently being evaluated in clinical trials as a vaccine candidate for a meningococcal group B vaccine. We have previously described the prevalence and sequence variation of fHbp (Jacobsson et al., 2009) and here we investigate the expression of the antigen. The present study includes isolates from carriers (n = 62) and patients with invasive Neisseria meningitidis infections (n = 146), of which 62 had a fatal outcome. Among the invasive isolates from patients with fatal and non-fatal infections fHbp allele 1 was most common (42% and 29% respectively), but it was only identified in 3% of the carrier isolates, where allele 16 was most frequent (13%). The Fluorescence-activated cell sorting analysis identified fHbp expression in all except seven isolates and further analysis by Western blot showed that five of these seven samples were indeed negative using a polyclonal anti-fHbp serum. The negative isolates belonged to serogroup B fHbp allele 24, Y allele 104, and W-135 allele 16 (all invasive). Two were non-serogroupable carrier isolates (allele 21 and 101). An interesting finding is that isolates from invasive infections with fatal outcome had lower expression of fHbp or lower affinity for the fHbp antibody compared to isolates from non-fatal invasive infections and carriers.

  • 588.
    Kempe, Per
    et al.
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Obstetrics & Gynaecology, County Hospital Sundsvall, Sundsvall, Sweden.
    Eklund, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hallin, Agnes
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hammar, Mats
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Brynhildsen, Jan
    Obstetrics and Gynaecology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Ernerudh, Jan
    Clinical Immunology and Transfusion Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Immune profile in relation to sex steroid cyclicity in healthy women and women with multiple sclerosis2018In: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 1, no 26, p. 53-59Article in journal (Refereed)
    Abstract [en]

    To prospectively study systemic in vivo immunological effects of sex hormones, using different phases of oral combined hormonal contraceptives (CHC), and the natural menstrual cycles in both healthy women and in women with multiple sclerosis (MS), blood samples from sixty female MS patients and healthy controls with and without CHC were drawn in high and low estrogenic/progestogenic phases. Expression of Th-associated genes in blood cells was determined by qPCR and a panel of cytokines and chemokines was measured in plasma. High hormone level phases were associated with increases in Th1 (TBX21) and Th2 (GATA3) associated markers, as well as the B cell-associated chemokine CXCL13, while the inhibitory regulator CTLA-4 was decreased. These changes were not observed in MS patients, of whom most were treated with immunomodulatory drugs. Our data indicate immune activating properties in vivo of high steroid sex hormone levels during both CHC and normal menstrual cyclicity.

  • 589.
    Khairullin, Rafil
    et al.
    Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russia; The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Vorobyev, Denis
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Obukhov, Andrey
    Tuvan Republican Skin and Venereal Diseases Dispensary, Tuva, Russia.
    Kuular, Ural-Herel
    Tuvan Republican Skin and Venereal Diseases Dispensary, Tuva, Russia.
    Kubanova, Anna
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Kubanov, Alexey
    The State Research Center of Dermatology, Venereology and Cosmetology of The Russian Ministry of Health (SRCDVC), Moscow, Russia.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Syphilis epidemiology in 1994-2013, molecular epidemiological strain typing and determination of macrolide resistance in Treponema pallidum in 2013-2014 in Tuva Republic, Russia2016In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 7, p. 595-602Article in journal (Refereed)
    Abstract [en]

    The incidence of syphilis in the Tuva Republic (geographical centre of Asia), Russia has been exceedingly high historically. No detailed examinations and no molecular investigations of Treponema pallidum strains transmitted in the Tuva Republic, or in general, in Russia, were published internationally. We examined the syphilis epidemiology in 1994-2013, and the molecular epidemiology and macrolide resistance in T. pallidum strains in 2013-2014 in the Tuva Republic. Among 95 mainly primary or secondary syphilis patients, the arp, tpr, tp0548 and 23S rRNA genes in 85 polA gene-positive genital ulcer specimens were characterized. The syphilis incidence in Tuva Republic peaked in 1998 (1562), however declined to 177 in 2013. Among the 70 (82%) completely genotyped specimens, six molecular strain types were found. Strain type 14d/f accounted for 91%, but also 14c/f, 14d/g, 14b/f, 14i/f, 9d/f, and 4d/f were identified. Two (2.4%) specimens contained the 23S rRNA A2058G macrolide resistance mutation. This is the first internationally published typing study regarding T. pallidum in Russia, performed in the Tuva Republic with the highest syphilis incidence in Russia. The two molecular strain types 4d/f and 9d/f have previously been described only in Eastern and Northern China and for the first time, macrolide-resistant syphilis was described in Russia.

  • 590. King, Ben
    et al.
    Kulak, Klaudia
    Papac-Milicevic, Nikolina
    Westermark, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Binder, Christoph
    Renstrom, Erik
    Blom, Anna
    C4BP inhibits IAPP-mediated inflammasome activation in type 2 diabetes2015In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 152-152Article in journal (Other academic)
  • 591.
    Kjellerås, Jennifer
    et al.
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Agardh, Daniel
    Lunds universitet.
    Improved efficacy by using the pTnT-rhtTG plasmid for the detection of celiac disease specific tissue transglutaminase autoantibodies in radioligand binding assays2011In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 71, no 8, p. 701-704Article in journal (Refereed)
    Abstract [en]

    Background: Tissue transglutaminase (tTG) autoantibodies are serological markers for celiac disease. The aim was to study the efficacy of the pTnT-rhtTG plasmid and subsequent diagnostic accuracy of tTG autoantibodies for childhood celiac disease using radioligand binding assays.

    Methods: Coupled in vitro transcription and translation of tTG were performed by pTnT-rhtTG as well as by the pGEMt Easy-rhtTG vectors using the TNT SP6 Coupled Reticulocyte Lysate System in the presence of [(35)S] methionine. Sera from 190 celiac disease children and 74 controls were measured for tTG autoantibodies in two separate radioligand binding assays using anti-human IgA agarose and protein A sepharose beads for the detection of IgA-tTG and IgG-tTG, respectively.

    Results: Median incorporation of [(35)S] methionine into the pTnT-rhtTG was 26% compared to 16% for the pGEMt Easy-rhtTG plasmid (p = 0.0016). Using pTnT-rhtTG (as compared to pGEMt Easy-rhtTG), sensitivities were IgA-tTG = 96.3% (95.7%) and IgG-tTG = 95.8% (97.3%) and specificities were IgA-tTG = 91.9% (90.5%) and IgG-tTG = 94.6% (98.4%). According to receiver operator characteristics for the pTnT (pGEMt Easy) assays, area under the curves were IgA-tTG = 98.4% (98.4%) and IgG-tTG = 97.7% (97.2%), respectively.

    Conclusion: The pTnT-rhtTG plasmid increased the efficacy of tTG antigen usage without reducing the diagnostic accuracy of IgA-tTG and IgG-tTG for childhood celiac disease. The pTnT-rhtTG plasmid is therefore recommended over the pGEMt Easy-rhtTG for the assessment of IgA-tTG and IgG-tTG using radioligand binding assays.

  • 592. Klapper, Yvonne
    et al.
    Maffre, Pauline
    Shang, Li
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hettler, Simon
    Dries, Manuel
    Gerthsen, Dagmar
    Nienhaus, G. Ulrich
    Low affinity binding of plasma proteins to lipid-coated quantum dots as observed by in situ fluorescence correlation spectroscopy2015In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 7, no 22, p. 9980-9984Article in journal (Refereed)
    Abstract [en]

    Protein binding to lipid-coated nanoparticles has been pursued quantitatively by using fluorescence correlation spectroscopy. The binding of three important plasma proteins to lipid-enwrapped quantum dots (QDs) shows very low affinity, with an apparent dissociation coefficient in the range of several hundred micromolar. Thus, the tendency to adsorb is orders of magnitude weaker than for QDs coated with dihydrolipoic acid.

  • 593.
    Klawonn, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Molecular Mechanisms of Reward and Aversion2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us.

    In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion.

    In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.

    In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.

    The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning.  Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality.

  • 594.
    Klein, O.
    et al.
    Tel Aviv Univ, Sackler Fac Med, Dept Cell & Dev Biol, Tel Aviv, Israel..
    Ngo-Nyekel, F.
    INSERM, UMRS 1149, Paris, France.;CNRS, ERL 8252, Paris, France.;Univ Paris Diderot, INFLAMEX, Lab Excellence, Sorbonne Paris Cite, Paris, France..
    Stefanache, T.
    Univ Med & Pharm Gr T Popa, Dept Periodontol, Iasi, Romania..
    Torres, R.
    Leitat Technol Ctr, Safety & Sustainabil Div, Barcelona, Spain..
    Salomonsson, Maya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hallgren, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Radinger, M.
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, Krefting Res Ctr, Gothenburg, Sweden..
    Bambouskova, M.
    Acad Sci Czech Republic, Inst Mol Genet, Dept Signal Transduct, Prague, Czech Republic..
    Campbell, M.
    Univ Manchester, Inst Inflammat & Repair, Manchester, Lancs, England.;Univ Manchester, MCCIR, Manchester, Lancs, England..
    Cohen-Mor, S.
    Hebrew Univ Jerusalem, Sch Pharm, Fac Med, Inst Drug Res, Jerusalem, Israel..
    Dema, B.
    INSERM, UMRS 1149, Paris, France.;CNRS, ERL 8252, Paris, France.;Univ Paris Diderot, INFLAMEX, Lab Excellence, Sorbonne Paris Cite, Paris, France..
    Rose, C. G.
    Univ Southampton, Fac Engn & Environm, Bioengn, Southampton, Hants, England.;Univ Southampton, Southampton Gen Hosp, Fac Med, Immunopharmacol Grp,Clin Expt Sci, Southampton, Hants, England..
    Abrink, M.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Immunol Sect, VHC, Uppsala, Sweden..
    Charles, N.
    INSERM, UMRS 1149, Paris, France.;CNRS, ERL 8252, Paris, France.;Univ Paris Diderot, INFLAMEX, Lab Excellence, Sorbonne Paris Cite, Paris, France..
    Ainooson, G.
    Karlsruhe Inst Technol, Inst Toxicol & Genet, Karlsruhe, Germany..
    Paivandy, Aida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pavlova, V. G.
    Bulgarian Acad Sci, Inst Expt Morphol Pathol & Anthropol Museum, Dept Expt Morphol, Sofia, Bulgaria..
    Serrano-Candelas, E.
    Univ Barcelona, Fac Med, Biochem Unit, Barcelona, Spain..
    Yu, Y.
    Univ Utrecht, Fac Sci, Inst Pharmaceut Sci, Div Pharmacol, Utrecht, Netherlands..
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Jensen, B. M.
    Gentofte Univ Hosp, Copenhagen Univ Hosp, Allergy Clin, Hellerup, Denmark..
    Van Anrooij, B.
    Univ Groningen, Univ Med Ctr Groningen, Dept Allergol, Groningen Res Inst Asthma, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, COPD, Groningen, Netherlands..
    Grootens, J.
    Karolinska Inst, Dept Med Solna, Clin Immunol & Allergy Unit, Stockholm, Sweden..
    Gura, H. K.
    Aarhus Univ Hosp, Dept Resp Dis & Allergy, Aarhus, Denmark.;Aarhus Univ Hosp, Dept Clin Med, Aarhus, Denmark..
    Stylianou, M.
    Umea Univ, Dept Clin Microbiol, Antifungal Immun Grp, Umea, Sweden..
    Tobio, A.
    INSERM, UMRS 1149, Paris, France.;CNRS, ERL 8252, Paris, France.;Univ Paris Diderot, INFLAMEX, Lab Excellence, Sorbonne Paris Cite, Paris, France..
    Blank, U.
    INSERM, UMRS 1149, Paris, France.;CNRS, ERL 8252, Paris, France.;Univ Paris Diderot, INFLAMEX, Lab Excellence, Sorbonne Paris Cite, Paris, France..
    Öhrvik, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Maurer, M.
    Charite, Dept Dermatol & Allergy, Allergie Ctr Charite, Berlin, Germany..
    Identification of Biological and Pharmaceutical Mast Cell- and Basophil-Related Targets2016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 83, no 6, p. 465-472Article in journal (Refereed)
  • 595.
    Kloster-Jensen, Kristine
    et al.
    Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway..
    Vethe, Nils Tore
    Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway..
    Bremer, Sara
    Oslo Univ Hosp, Dept Med Biochem, Oslo, Norway..
    Abadpour, Shadab
    Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Foss, Aksel
    Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway.;Univ Oslo, Fac Med, N-0316 Oslo, Norway..
    Bergan, Stein
    Oslo Univ Hosp, Dept Pharmacol, Oslo, Norway.;Univ Oslo, Sch Pharm, N-0316 Oslo, Norway..
    Scholz, Hanne
    Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway.;Univ Oslo, Inst Surg Res, N-0316 Oslo, Norway..
    Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets invitro2015In: Transplant International, ISSN 0934-0874, E-ISSN 1432-2277, Vol. 28, no 10, p. 1152-1161Article in journal (Refereed)
    Abstract [en]

    Main problemIslet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets. MethodsWe determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR. ResultsIslets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR-signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus. ConclusionThese findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets.

  • 596.
    Knight, Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hjorton, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Smedby, Karin E
    Askling, Johan
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 4, p. 690-694Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

    METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

    RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

    CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

  • 597.
    Koefoed-Nielsen, P.
    et al.
    Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark..
    Weinreich, I.
    Scandiatransplant Off, Aarhus, Denmark..
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lauronen, J.
    Finnish Red Cross Blood Serv, Helsinki, Finland..
    Naper, C.
    Oslo Univ Hosp, Dept Immunol & Transfus Med, Oslo, Norway..
    Gabel, M.
    Sahlgrens Univ Hosp, Inst Transplantat, Gothenburg, Sweden..
    Sorensen, S. S.
    Rigshosp, Univ Hosp Copenhagen, Dept Nephrol, Copenhagen, Denmark..
    Wennberg, L.
    Karolinska Univ Hosp, Dept Transplantat Surg, Stockholm, Sweden..
    Reisaeter, A. V.
    Natl Hosp Norway, Oslo Univ Hosp, Dept Transplantat Med, Oslo, Norway..
    Moller, B. K.
    Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark..
    Scandiatransplant acceptable mismatch program (STAMP) a bridge to transplanting highly immunized patients2017In: HLA, ISSN 2059-2302, Vol. 90, no 1, p. 17-24Article in journal (Refereed)
    Abstract [en]

    Background: Highly immunized patients are a challenge for organ transplantation programs. One way of increasing the likelihood of transplantation in this group of patients is to expand the possible donations by defining acceptable HLA mismatches. In the Scandiatransplant Acceptable Mismatch Program (STAMP), a decentralized approach has been implemented in 2009. Aims: The program has been improved during the years from utilizing HLA-A, -B, -DR matching only to include typing of all deceased donors for HLA-A, -B, -C, -DRB1 and -DQB1. The calculation of a transplantability score (TS) has been introduced in order to take both HLA and AB0 into consideration resulting in a more realistic picture of the transplantability chance. Materials and Methods: Patients were selected for eligibility and results of immunisation status were prepared in each of the 9 tissue typing laboratories, while access to the program is finally governed by a common steering group of immunologists and clinicians. Results: In the period from March 2009 until February 2015, 96 patients were transplanted within this program. The mean recipient age was 49 years and 57% were females, 30% of the patients were first transplants and of these 93% were females. The majority of the patients had 2-5 HLA-A, -B. -DR mismatches. The allograft survival at 60 months was 79.1%. Applying the TS to the cohort confirmed that patients with a low TS score had longer waiting times. Conclusion: The program has matured during the years and now proves to be a valid approach for transplanting highly immunized patients.

  • 598.
    Kofteridis, Diamantis P.
    et al.
    Univ Hosp Heraklion, Dept Internal Med, Infect Dis Unit, Iraklion 71110, Greece..
    Valachis, Antonis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Malarsjukhuset, Dept Oncol, Eskilstuna, Sweden..
    Dimopoulou, Dimitra
    Univ Hosp Heraklion, Dept Internal Med, Infect Dis Unit, Iraklion 71110, Greece..
    Andrianaki, Angeliki M.
    Univ Hosp Heraklion, Dept Internal Med, Infect Dis Unit, Iraklion 71110, Greece..
    Christidou, Athanasia
    Univ Hosp Heraklion, Clin Microbiol, Iraklion 71110, Crete, Greece..
    Maraki, Sofia
    Univ Hosp Heraklion, Clin Microbiol, Iraklion 71110, Crete, Greece..
    Spernovasilis, Nikolaos A.
    Univ Hosp Heraklion, Dept Internal Med, Infect Dis Unit, Iraklion 71110, Greece..
    Samonis, George
    Univ Hosp Heraklion, Dept Internal Med, Infect Dis Unit, Iraklion 71110, Greece..
    Factors Influencing Non-albicans Candidemia: A Case-Case-Control Study2017In: Mycopathologia, ISSN 0301-486X, E-ISSN 1573-0832, Vol. 182, no 7-8, p. 665-672Article in journal (Refereed)
    Abstract [en]

    The study identified factors predisposing to non-albicans candidemia with special interest to prior antimicrobial treatment. A retrospective, case-case-control study was performed at the University Hospital of Heraklion, Greece, from November 2007 through September 2011 including adult patients. The study had three groups. The first included 58 patients with non-albicans candidemia, the second 48 with C. albicans candidemia, while the third (control) 104 without candidemia. Each of the two candidemia groups was compared with the control using multivariate logistic regression model. The mean (SD) age of the non-albicans, the albicans and the control patients was 67 (12), 67 (18) and 59 (19) years, respectively. The most common non-albicans Candida spp. isolated were C. parapsilosis in 19 patients (33%), C. glabrata in 17 (29%) and C. tropicalis in 15 (26%). Independent risk factors for non-albicans candidemia were prior treatment with quinolones (p < 0.001), b-lactam-b-lactamase inhibitors (p = 0.011) and presence of central venous catheter (p = 0.05), while for C. albicans candidemia were prior treatment with quinolones (p < 0.001), carbapenems (p = 0.003) along with cardiac disease (p < 0.001). Neither duration of hospitalization nor in-hospital mortality [41% for the non-albicans vs 29% for C. albicans group (p = 0.192)] was significantly different between the two candidemia groups. The study reveals the role of antimicrobial exposure as a risk factor for candidemia caused by different species. Prior treatment with b-lactam-b-lactamase inhibitors was associated with non-albicans, while with carbapenems with C. albicans candidemia. Prior use of quinolones was associated with candidemia in general.

  • 599.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boman, Andreas
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan..
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells2015In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 460, no 3, p. 645-650Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein α (SIRPα) is an immunoglobulin super family protein predominantly expressed by myeloid but not lymphoid cells, and its role in lymphocyte homeostasis and function is still to be revealed. We demonstrate that mice bearing a mutant SIRPα lacking the cytoplasmic signaling domain (SIRPα MT) had an increased amount of splenic marginal zone (MZ) B cells compared to wild-type controls. Immunohistochemical analysis revealed an increased localization of MZB cells into B cell follicular areas of the white pulp in SIRPα MT spleens. However, we found no signs of an increased MZB cell activation level in MT mice. The immune response to T-independent antigens in vivo was slightly increased in SIRPα MT mice while sorted MZB from these mice responded normally to LPS in vitro. Bone marrow reconstitution experiments demonstrated that the MZB cell phenotype of SIRPα MT mice was due to lack of SIRPα signaling in non-hematopoietic cells. In contrast, MZ retention of MZ macrophages required hematopoietic SIRPα, while normal distribution of metallophilic macrophages required non-hematopoietic SIRPα signaling. In summary, these data identified SIRPα signaling in non-hematopoietic cells to play an important role in regulating the numbers and positioning MZB cell in the spleen.

  • 600.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe, Japan.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen2015In: PLoS One, Vol. 10, no 7, article id e0134113Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.

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