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  • 1. Bagawath-Singh, Sunitha
    et al.
    Staaf, Elina
    Stoppelenburg, Arie Jan
    Spielmann, Thiemo
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Kambayashi, Taku
    Widengren, Jerker
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Johansson, Sofia
    Cytokines Induce Faster Membrane Diffusion of MHC Class I and the Ly49A Receptor in a Subpopulation of Natural Killer Cells2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7Article in journal (Refereed)
    Abstract [en]

    Cytokines have the potential to drastically augment immune cell activity. Apart from altering the expression of a multitude of proteins, cytokines also affect immune cell dynamics. However, how cytokines affect the molecular dynamics within the cell membrane of immune cells has not been addressed previously. Molecular movement is a vital component of all biological processes, and the rate of motion is, thus, an inherent determining factor for the pace of such processes. Natural killer (NK) cells are cytotoxic lymphocytes, which belong to the innate immune system. By fluorescence correlation spectroscopy, we investigated the influence of cytokine stimulation on the membrane density and molecular dynamics of the inhibitory receptor Ly49A and its ligand, the major histocompatibility complex class I allele H-2D(d), in freshly isolated murine NK cells. H-2D(d) was densely expressed and diffused slowly in resting NK cells. Ly49A was expressed at a lower density and diffused faster. The diffusion rate in resting cells was not altered by disrupting the actin cytoskeleton. A short-term stimulation with interleukin-2 or interferon- alpha + beta did not change the surface density of moving H-2D(d) or Ly49A, despite a slight upregulation at the cellular level of H-2D(d) by interferon-alpha + beta, and of Ly49A by IL-2. However, the molecular diffusion rates of both H-2D(d) and Ly49A increased significantly. A multivariate analysis revealed that the increased diffusion was especially marked in a subpopulation of NK cells, where the diffusion rate was increased around fourfold compared to resting NK cells. After IL-2 stimulation, this subpopulation of NK cells also displayed lower density of Ly49A and higher brightness per entity, indicating that Ly49A may homo-cluster to a larger extent in these cells. A faster diffusion of inhibitory receptors could enable a faster accumulation of these molecules at the immune synapse with a target cell, eventually leading to a more efficient NK cell response. It has previously been assumed that cytokines regulate immune cells primarily via alterations of protein expression levels or posttranslational modifications. These findings suggest that cytokines may also modulate immune cell efficiency by increasing the molecular dynamics early on in the response.

  • 2.
    Dezfouli, Mahya
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol & Transfus Med, Stockholm, Sweden..
    Bergström, Sofia
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Skattum, Lillemor
    Lund Univ, Sect Microbiol Immunol & Glycobiol, Dept Lab Med, Lund, Sweden.;Reg Skane, Clin Immunol & Transfus Med, Lund, Sweden..
    Abolhassani, Hassan
    Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol & Transfus Med, Stockholm, Sweden.;Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Neiman, Maja
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Torabi-Rahvar, Monireh
    Univ Tehran Med Sci, Sch Med, Dept Immunol, Tehran, Iran..
    Franco Jarava, Clara
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Immunol Dept, Barcelona, Spain..
    Martin-Nalda, Andrea
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Pediat Infect Dis & Immunodeficiencies Unit, Barcelona, Spain..
    Ferrer Balaguer, Juana M.
    Hosp Univ Son Espases, Immunol, Inst Invest Sanitaria Illes Balears, Palma De Mallorca, Spain..
    Slade, Charlotte A.
    Royal Melbourne Hosp, Melbourne, Vic, Australia.;Walter & Eliza Hall Inst Med Res, Melbourne, Vic, Australia..
    Roos, Anja
    St Antonius Hosp, Dept Microbiol & Immunol, Nieuwegein, Netherlands..
    Fernandez Pereira, Luis M.
    Hosp San Pedro Alcantara, Dept Immunol, Caceres, Spain..
    Lopez-Trascasa, Margarita
    Univ Autonoma Madrid, Hosp La Paz Inst Hlth Res IdiPAZ, Dept Med, Madrid, Spain.;Complement Res Grp, Madrid, Spain..
    Gonzalez-Granado, Luis, I
    Univ Hosp 12 Octubre, Res Inst Hosp 12 Octubre 1 12, Dept Pediat, Primary Immunodeficiencies Unit, Madrid, Spain..
    Allende-Martinez, Luis M.
    Univ Hosp 12 Octubre, Res Inst Hosp 12 Octubre 1 12, Immunol Dept, Madrid, Spain..
    Mizuno, Yumi
    Kyushu Univ, Fukuoka Childrens Hosp, Fukuoka, Japan..
    Yoshida, Yusuke
    Natl Def Med Coll, Dept Pediat, Saitama, Japan..
    Friman, Vanda
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden..
    Lundgren, Asa
    Cent Hosp Kristianstad, Dept Infect Dis, Kristianstad, Sweden..
    Aghamohammadi, Asghar
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Rezaei, Nima
    Univ Tehran Med Sci, Res Ctr Immunodeficiencies, Pediat Ctr Excellence, Childrens Med Ctr, Tehran, Iran..
    Hernandez-Gonzalez, Manuel
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Vall dHebron Res Inst, Immunol Dept, Barcelona, Spain..
    von Dobeln, Ulrika
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Lab Med, Div Metab Dis, Stockholm, Sweden..
    Truedsson, Lennart
    Lund Univ, Sect Microbiol Immunol & Glycobiol, Dept Lab Med, Lund, Sweden..
    Hara, Toshiro
    Kyushu Univ, Fukuoka Childrens Hosp, Fukuoka, Japan..
    Nonoyama, Shigeaki
    Natl Def Med Coll, Dept Pediat, Saitama, Japan..
    Schwenk, Jochen M.
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Hammarstrom, Lennart
    Karolinska Univ Hosp Huddinge, Dept Lab Med, Div Clin Immunol & Transfus Med, Stockholm, Sweden..
    Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies2020In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 11, article id 455Article in journal (Refereed)
    Abstract [en]

    The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.

  • 3. Forsell, M. N. E.
    et al.
    Kvastad, Linda
    KTH, School of Biotechnology (BIO), Gene Technology.
    Sedimbi, S. K.
    Andersson, J.
    Karlsson, M. C. I.
    Regulation of subunit-specific germinal center B cell responses to the HIV-1 envelope glycoproteins by antibody-mediated feedback2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, no JUN, article id 738Article in journal (Refereed)
    Abstract [en]

    The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.

  • 4. Forslund, E.
    et al.
    Guldevall, Karolin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Olofsson, Per E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Frisk, Thomas
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Christakou, Athanasia E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Wiklund, Martin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biomedical and X-ray Physics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Novel microchip-based tools facilitating live cell imaging and assessment of functional heterogeneity within NK cell populations2012In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 3, no OCT, p. 300-Article in journal (Refereed)
    Abstract [en]

    Each individual has a heterogeneous pool of NK cells consisting of cells that may be specialized towards specific functional responses such as secretion of cytokines or killing of tumor cells. Many conventional methods are not fit to characterize heterogeneous populations as they measure the average response of all cells. Thus, there is a need for experimental platforms that provide single cell resolution. In addition, there are transient and stochastic variations in functional responses at the single cell level, calling for methods that allow studies of many events over extended periods of time. This paper presents a versatile microchip platform enabling long-term microscopic studies of individual NK cells interacting with target cells. Each microchip contains an array of microwells, optimized for medium or high-resolution time-lapse imaging of single or multiple NK and target cells, or for screening of thousands of isolated NK-target cell interactions. Individual NK cells confined with target cells in small microwells is a suitable setup for high-content screening and rapid assessment of heterogeneity within populations, while microwells of larger dimensions are appropriate for studies of NK cell migration and sequential interactions with multiple target cells. By combining the chip technology with ultrasonic manipulation, NK and target cells can be forced to interact and positioned with high spatial accuracy within individual microwells.This setup effectively and synchronously creates NK-target conjugates at hundreds of parallel positions in the microchip. Thus, this facilitates assessment of temporal aspects of NK-target cell interactions, e.g., conjugation, immune synapse formation, and cytotoxic events.The microchip platform presented here can be used to effectively address questions related to fundamental functions of NK cells that can lead to better understanding of how the behavior of individual cells add up to give a functional response at the population level.

  • 5.
    Guldevall, Karolin
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brandt, Ludwig
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forslund, Elin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Sweden.
    Olofsson, Karl
    Frisk, Thomas W.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Olofsson, Per E.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gustafsson, Karin
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Manneberg, Otto
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Vanherberghen, Bruno
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Karre, Klas
    Uhlin, Michael
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Microchip screening Platform for single cell assessment of NK cell cytotoxicity2016In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 7, article id 119Article in journal (Refereed)
    Abstract [en]

    Here, we report a screening platform for assessment of the cytotoxic potential of individual natural killer (NK) cells within larger populations. Human primary NK cells were distributed across a silicon-glass microchip containing 32,400 individual microwells loaded with target cells. Through fluorescence screening and automated image analysis, the numbers of NK and live or dead target cells in each well could be assessed at different time points after initial mixing. Cytotoxicity was also studied by time-lapse live-cell imaging in microwells quantifying the killing potential of individual NK cells. Although most resting NK cells (approximate to 75%) were non-cytotoxic against the leukemia cell line K562, some NK cells were able to kill several (>= 3) target cells within the 12-h long experiment. In addition, the screening approach was adapted to increase the chance to find and evaluate serial killing NK cells. Even if the cytotoxic potential varied between donors, it was evident that a small fraction of highly cytotoxic NK cells were responsible for a substantial portion of the killing. We demonstrate multiple assays where our platform can be used to enumerate and characterize cytotoxic cells, such as NK or T cells. This approach could find use in clinical applications, e.g., in the selection of donors for stem cell transplantation or generation of highly specific and cytotoxic cells for adoptive immunotherapy.

  • 6.
    Idborg, Helena
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Zandian, Arash
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Ossipova, Elena
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Wigren, Edvard
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Preger, Charlotta
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Mobarrez, Fariborz
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden.;Uppsala Univ, Akad Hosp, Dept Med Sci, Uppsala, Sweden..
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Sohrabian, Azita
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Pucholt, Pascal
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Sandling, Johanna K.
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Fernandes-Cerqueira, Catia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Ronnelid, Johan
    Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Oke, Vilija
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Kvarnstrom, Marika
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Larsson, Anders
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden..
    Syvanen, Ann-Christine
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden..
    Ronnblom, Lars
    Uppsala Univ, Dept Med Sci, Rheumatol, Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Persson, Helena
    KTH Royal Inst Technol, Sci Life Lab, Drug Discovery & Dev, Stockholm, Sweden.;KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden..
    Graslund, Susanne
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Jakobsson, Per-Johan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden..
    Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed)
    Abstract [en]

    Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (p(adjusted) = 3 x 10(-9), 3 x 10(-6), and 5 x 10(-6) respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

  • 7.
    Joshi, Rubin Narayan
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Unit Computat Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Stadler, Charlotte
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Lehmann, Robert
    King Abdullah Univ Sci & Technol, Comp Elect & Math Sci & Engn Div, Biol & Environm Sci & Engn Div, Thuwal, Saudi Arabia..
    Lehtio, Janne
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Solna, Sweden..
    Tegner, Jesper
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Unit Computat Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden.;King Abdullah Univ Sci & Technol, Comp Elect & Math Sci & Engn Div, Biol & Environm Sci & Engn Div, Thuwal, Saudi Arabia..
    Schmidt, Angelika
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Unit Computat Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden.;Ludwig Maximilians Univ Munchen, Inst Immunol, Biomed Ctr, Munich, Germany..
    Vesterlund, Mattias
    Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, Solna, Sweden..
    TcellSubC: An Atlas of the Subcellular Proteome of Human T Cells2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2708Article in journal (Refereed)
    Abstract [en]

    We have curated an in-depth subcellular proteomic map of primary human CD4+ T cells, divided into cytosolic, nuclear and membrane fractions generated by an optimized fractionation and HiRIEF-LC-MS/MS workflow for limited amounts of primary cells. The subcellular proteome of T cells was mapped under steady state conditions, as well as upon 15 min and 1 h of T cell receptor (TCR) stimulation, respectively. We quantified the subcellular distribution of 6,572 proteins and identified a subset of 237 potentially translocating proteins, including both well-known examples and novel ones. Microscopic validation confirmed the localization of selected proteins with previously known and unknown localization, respectively. We further provide the data in an easy-to-use web platform to facilitate re-use, as the data can be relevant for basic research as well as for clinical exploitation of T cells as therapeutic targets.

  • 8. Kirik, Ufuk
    et al.
    Persson, Helena
    KTH, School of Biotechnology (BIO), Protein Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Levander, Fredrik
    Greiff, Lennart
    Ohlin, Mats
    Antibody Heavy Chain variable Domains of Different Germline Gene Origins Diversify through Different Paths2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 1433Article in journal (Refereed)
    Abstract [en]

    B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes.

  • 9.
    Persson, Helena
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kirik, Ufuk
    Lund Univ, Dept Immunotechnol, Lund, Sweden.;Univ Copenhagen, Novo Nordisk Fdn, Ctr Prot Res, Copenhagen, Denmark..
    Thörnqvist, Linnea
    Lund Univ, Dept Immunotechnol, Lund, Sweden..
    Greiff, Lennart
    Lund Univ, Dept Clin Sci, Lund, Sweden.;Skane Univ Hosp, Dept Otorhinolaryngol Head & Neck Surg, Lund, Sweden..
    Levander, Fredrik
    Lund Univ, Dept Immunotechnol, Lund, Sweden..
    Ohlin, Mats
    Lund Univ, Dept Immunotechnol, Lund, Sweden.;Lund Univ, Sci Life Lab, Human Antibody Therapeut Drug Discovery & Dev Pla, Lund, Sweden..
    In Vitro Evolution of Antibodies Inspired by In Vivo Evolution2018In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 1391Article in journal (Refereed)
    Abstract [en]

    In vitro generation of antibodies often requires variable domain sequence evolution to adapt the protein in terms of affinity, specificity, or developability. Such antibodies, including those that are of interest for clinical development, may have their origins in a diversity of immunoglobulin germline genes. Others and we have previously shown that antibodies of different origins tend to evolve along different, preferred trajectories. Apart from substitutions within the complementary determining regions, evolution may also, in a germline gene-origin-defined manner, be focused to residues in the framework regions, and even to residues within the protein core, in many instances at a substantial distance from the antibody's antigen-binding site. Examples of such germline origin-defined patterns of evolution are described. We propose that germline gene-preferred substitution patterns offer attractive alternatives that should be considered in efforts to evolve antibodies intended for therapeutic use with respect to appropriate affinity, specificity, and product developability. We also hypothesize that such germline gene-origin-defined in vitro evolution hold potential to result in products with limited immunogenicity, as similarly evolved antibodies will be parts of conventional, in vivo-generated antibody responses and thus are likely to have been seen by the immune system in the past.

  • 10.
    Poux, Candice
    et al.
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    Dondalska, Aleksandra
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    Bergenstråhle, Joseph
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Palsson, Sandra
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    Contreras, Vanessa
    CEA, Inst Biol Francois Jacob, UMR1184, IDMIT Dept,DRF, Fontenay Aux Roses, France..
    Arasa, Claudia
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    Jarver, Peter
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    Albert, Jan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Busse, David C.
    Imperial Coll London, Dept Infect Dis, London, England..
    LeGrand, Roger
    CEA, Inst Biol Francois Jacob, UMR1184, IDMIT Dept,DRF, Fontenay Aux Roses, France..
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Tregoning, John S.
    Imperial Coll London, Dept Infect Dis, London, England..
    Spetz, Anna-Lena
    Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, Stockholm, Sweden..
    A Single-Stranded Oligonucleotide Inhibits Toll-Like Receptor 3 Activation and Reduces Influenza A (H1N1) Infection2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2161Article in journal (Refereed)
    Abstract [en]

    The initiation of an immune response is dependent on the activation and maturation of dendritic cells after sensing pathogen associated molecular patterns by pattern recognition receptors. However, the response needs to be balanced as excessive pro-inflammatory cytokine production in response to viral or stress-induced pattern recognition receptor signaling has been associated with severe influenza A virus (IAV) infection. Here, we use an inhibitor of Toll-like receptor (TLR)3, a single-stranded oligonucleotide (ssON) with the capacity to inhibit certain endocytic routes, or a TLR3 agonist (synthetic double-stranded RNA Polyl:C), to evaluate modulation of innate responses during H1N1 IAV infection. Since IAV utilizes cellular endocytic machinery for viral entry, we also assessed ssON's capacity to affect IAV infection. We first show that IAV infected human monocyte-derived dendritic cells (MoDC) were unable to up-regulate the co-stimulatory molecules CD80 and CD86 required for T cell activation. Exogenous TLR3 stimulation did not overcome the IAV-mediated inhibition of co-stimulatory molecule expression in MoDC. However, TLR3 stimulation using Polyl:C led to an augmented pro-inflammatory cytokine response. We reveal that ssON effectively inhibited Polyl:C-mediated pro-inflammatory cytokine production in MoDC, notably, ssON treatment maintained an interferon response induced by IAV infection. Accordingly, RNAseq analyses revealed robust up-regulation of interferon-stimulated genes in IAV cultures treated with ssON. We next measured reduced IAV production in MoDC treated with ssON and found a length requirement for its anti-viral activity, which overlapped with its capacity to inhibit uptake of Polyl:C. Hence, in cases wherein an overreacting TLR3 activation contributes to IAV pathogenesis, ssON can reduce this signaling pathway. Furthermore, concomitant treatment with ssON and IAV infection in mice resulted in maintained weight and reduced viral load in the lungs. Therefore, extracellular ssON provides a mechanism for immune regulation of TLR3-mediated responses and suppression of IAV infection in vitro and in vivo in mice.

  • 11.
    Radestad, Emelie
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden..
    Sundin, Mikael
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Pediat, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Hematol Immunol HSCT Sect, Stockholm, Sweden..
    Torlen, Johan
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Thunberg, Sara
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences (SCI), Applied Physics.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ljungman, Per
    Karolinska Univ Hosp, Cell Therapy & Allogene Stem Cell Transplantat, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Watz, Emma
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Div Transplantat Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Mattsson, Jonas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Princess Margaret Canc Ctr, Div Med Oncol & Hematol, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics.
    Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 189Article in journal (Refereed)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of alpha beta T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The alpha beta T-cell depleted cell products were characterized by flow cytometry. The median log depletion of alpha beta T-cells was -4.3 and the median yield of gamma delta T-cells was 73.5%. The median CD34+ cell dose was 4.4 x 10(6)/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of alpha beta T-cell depleted products as stem cell boosters with encouraging results.

  • 12.
    Sayitoglu, Ece Canan
    et al.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Georgoudaki, Anna-Maria
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.;Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Chrobok, Michael
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
    Ozkazanc, Didem
    Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey..
    Josey, Benjamin J.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Arif, Muhammad
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kusser, Kim
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Hartman, Michelle
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Chinn, Tamara M.
    Nova Southeastern Univ, Dr Kiran C Patel Coll Osteopath Med, Ft Lauderdale, FL 33314 USA..
    Potens, Renee
    Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
    Pamukcu, Cevriye
    Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey..
    Krueger, Robin
    Nova Southeastern Univ, Translat Res & Econ Dev, Ft Lauderdale, FL 33314 USA..
    Zhang, Cheng
    Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London, England..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Alici, Evren
    Temple, Harry Thomas
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Dept Surg, Ft Lauderdale, FL 33314 USA..
    Sutlu, Tolga
    Bogazici Univ, Dept Mol Biol & Genet, Istanbul, Turkey..
    Duru, Adil Doganay
    Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.;Karolinska Inst, Dept Med Solna, Sci Life Lab, Stockholm, Sweden..
    Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D2020In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 11, article id 40Article in journal (Refereed)
    Abstract [en]

    Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

  • 13. Sternberg-Simon, M.
    et al.
    Brodin, P.
    Pickman, Y.
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics.
    Kärre, K.
    Malmberg, K. -J
    Höglund, P.
    Mehr, R.
    Natural killer cell inhibitory receptor expression in humans and mice: A closer look2013In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 4, no March, p. 65-Article in journal (Refereed)
    Abstract [en]

    The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the "product rule (PR)," i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.

  • 14. Stikvoort, Arwen
    et al.
    Chen, Yang
    Radestad, Emelie
    Torlen, Johan
    Lakshmikanth, Tadepally
    Bjorklund, Andreas
    Mikes, Jaromir
    Achour, Adnane
    Gertow, Jens
    Sundberg, Berit
    Remberger, Mats
    Sundin, Mikael
    Mattsson, Jonas
    Brodin, Petter
    Uhlin, Michael
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cellular Biophysics. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease2017In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, article id 717Article in journal (Refereed)
    Abstract [en]

    Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets.

  • 15. Tauriainen, Johanna
    et al.
    Gustafsson, Karin
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Göthlin, Mårten
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gertow, Jens
    Buggert, Marcus
    Frisk, Thomas W.
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Karlsson, Annika C.
    Uhlin, Michael
    Önfelt, Björn
    KTH, School of Engineering Sciences (SCI), Applied Physics, Cell Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Single-cell characterization of in vitro migration and interaction dynamics of T cells expanded with IL-2 and IL-72015In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 6, article id 196Article in journal (Refereed)
    Abstract [en]

    T cells are pivotal in the immune defense against cancers and infectious agents. To mount an effector response against cancer cells, T cells need to migrate to the cancer-site, engage in contacts with cancer cells, and perform their effector functions. Adoptive T cell therapy is an effective strategy as treatment of complications such as relapse or opportunistic infections after hematopoietic stem cell transplantations. This requires a sufficient amount of cells that are able to expand and respond to tumor or viral antigens. The cytokines interleukin (IL)-2 and IL-7 drive T cell differentiation, proliferation, and survival and are commonly used to expand T cells ex vivo. Here, we have used microchip-based live-cell imaging to follow the migration of individual T cells, their interactions with allogeneic monocytes, cell division, and apoptosis for extended periods of time; something that cannot be achieved by commonly used methods. Our data indicate that cells grown in IL-7 + IL-2 had similar migration and contact dynamics as cells grown in IL-2 alone. However, the addition of IL-7 decreased cell death creating a more viable cell population, which should be beneficial when preparing cells for immunotherapy.

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