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  • 1.
    Gunnarsson, Cecilia
    et al.
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Hellqvist, Eva
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Linköpings universitet, Hälsouniversitetet.
    17β-hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer2005Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 92, nr 3, s. 547-552Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The 17β-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyses the interconversion of the weak oestrone (E1) to the more potent oestradiol (E2), whereas 17HSD type 2 catalyses the oxidation of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumour with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumour samples from 230 postmenopausal patients. For the patients with oestrogen receptor (ER)-positive breast cancer, we found a statistically significant positive correlation between recurrence-free survival and expression of 17HSD type 2 (P = 0.026). We examined the ratio of 17HSD types 2 and 1, and ER-positive patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P = 0.0047), ER positive patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P = 0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.

  • 2.
    Hellqvist, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Antigen interaction with B cells in two proliferative disorders: CLL and MGUS2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.

    The aim of the work presented in this thesis was to elucidate B cell interaction with antigen in the two B cell proliferative disorders chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In the first part we investigated the antigen specificity of CLL cells and characterized Epstein-Barr virus (EBV)-transformed CLL cell lines with regard to phenotype and genotype. The second part consists of studies on the antigen presenting capacity of myelin protein zero (P0) specific MGUS B cells and their relation to T cells and development of polyneuropathy.

    CLL cells are considered antigen experienced and different patient-derived CLL cells expressing B cell receptors (BCR) with highly homologous antigen binding sites are believed to have been selected by a common antigen at some point during the leukemogenesis. In paper I we investigated the antigen specificity of CLL-cell derived antibodies (Abs) with various IGHV gene usage and stereotyped BCR subset belonging. Identified CLL antigens included vimentin, filamin B, cofilin-1, proline rich acidic protein-1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae capsular polysaccharides. Many of the CLL Abs studied displayed an oligo- or polyreactive antigen binding pattern and the identified antigens were either associated with apoptotic cells or microbial infection. This is similar to what has been described for innate natural antibodies, possibly indicating that CLL cells are derived from a natural-antibody- producing B cell population. Further characterization of CLL homology subset-2 antigen specificity showed binding to glands in human gastric mucosa corpus tissue sections for a CLL homology subset-2 Ab with HCDR3 motif-1, suggesting that this CLL subset recognize an autoantigen much like the CLL Abs tested in Paper I.

    Characterization of EBV-transformed CLL and normal lymphoblastoid cell lines (LCLs) in paper II showed that eight of the CLL cell lines were verified to be of authentic neoplastic origin. Indication for a biclonal CLL was found in two of the cell lines and two of the presumably normal LCLs turned out to represent the malignant CLL clone. For three cell lines no conclusive evidence for CLL origin could be found emphasizing the importance of verifying the identity of cell lines used in research.

    Delarbeten
    1. A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies
    Öppna denna publikation i ny flik eller fönster >>A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies
    Visa övriga...
    2008 (Engelska)Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, nr 7, s. 3838-3848Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5+ CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-16339 (URN)10.1182/blood-2007-11-125450 (DOI)
    Tillgänglig från: 2009-01-16 Skapad: 2009-01-16 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    2. Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia
    Öppna denna publikation i ny flik eller fönster >>Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia
    Visa övriga...
    2013 (Engelska)Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, nr 8, s. 1769-1779Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

    Ort, förlag, år, upplaga, sidor
    Informa Healthcare, 2013
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-16340 (URN)10.3109/10428194.2013.764418 (DOI)000321763800032 ()
    Tillgänglig från: 2009-01-16 Skapad: 2009-01-16 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
    3. IGHV3-21 stereotyped subset-2 chronic lymphocytic leukemia cells make autoantibodies that bind to an 11.5kDa gastric mucosal antigen
    Öppna denna publikation i ny flik eller fönster >>IGHV3-21 stereotyped subset-2 chronic lymphocytic leukemia cells make autoantibodies that bind to an 11.5kDa gastric mucosal antigen
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: The immunoglobulin heavy chain variable region (IGHV) gene mutational status is an important prognostic factor in chronic lymphocytic leukemia (CLL). Patients with mutated IGHV genes show significantly longer survival than unmutated cases. CLL patients with mutated IGHV3-21 genes, however, have a shorter survival compared to other mutated CLL cases. Recently, we showed that CLL cells react with oxidized epitopes exposed on apoptotic cells and bacteria. The gastric mucosal reactivity was of special interest to further characterize in detail.

    Methods: We collected corpus biopsies from seven Helicobacter pylori (H.p.)+ study subjects withnon-atrophic gastritis, six subjects with H.p.- atrophic gastritis, eight subjects with H.p.+ atrophicgastric and from eight controls without gastritis. The binding pattern of CLL subset-2 IGHV3-21antibodies was analyzed by immunohistochemistry and the antigen was biochemically purified byaffinity chromatography.

    Results: The subset-2 IGHV3-21 Abs bound to mucosal glands in 18 of 29 cases regardless of H.p.status or diagnosis. It also showed staining of connective tissue in all of the biopsies. The antigen waspurified and a protein of 11.5 kDa MW was isolated.

    Conclusion: The results from this study indicate that IGHV3-21 subset-2 CLL Abs bind an 11.5kDaprotein present in gastric mucosal glands or connective tissue. This autoantigen has no associationwith H.p. since it is present in normal, non-atrophic H.p.+ and atrophic H.p.+/H.p.- gastric mucosafrom corpus. The exact nature of the 11.5 kDa protein is currently under detailed structure massspectrometry analysis in order to reveal whether bacterial mimicry is the mechanism behind theinduction of this particular autoantibody.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-53279 (URN)
    Tillgänglig från: 2010-01-20 Skapad: 2010-01-20 Senast uppdaterad: 2010-01-20Bibliografiskt granskad
    4. Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells
    Öppna denna publikation i ny flik eller fönster >>Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells
    Visa övriga...
    2010 (Engelska)Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 95, nr 4, s. 627-636Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background and Objectives: Monoclonal gammopathy of undetermined significance (MGUS) of IgM isotype is a condition with clonally expanded B cells, recently suggested having an infectious origin. MGUS is frequently associated with polyneuropathy and antibodies against myelin protein zero (P0), whereas the role of the T cells remains largely unknown. Here we have analyzed P0-specific B cells, as antigen-presenting cells, and their capacity to activate T helper cells.

    Design and Methods: We used a well-characterized MGUS-derived B cell line, TJ2, expressing anti-P0 IgM. The ability of TJ2 cells to bind, endocytose, process, and present P0 was investigated by receptor-clustering and immunofluorescence. The activation of P0-specific autologous T cells was studied by measuring IL2 and IFNγ with flow cytometry, immunobeads, and ELISPOT.

    Results: Surface-receptor clustering and endocytosis of receptor-ligand (IgM/P0) complexes were pronounced after P0 exposure. Naturally processed or synthetic P0 peptide (194-208)-pulsed TJ2 cells significantly induced IL2 secretion from autologous T cells compared to control antigen pulsed cells (p<0 .001). The numbers of IFNγ producing T helper cells, including CD4+/CD8+ cells, were also significantly increased (p=0.0152). Affinity-isolated naturally processed myelin peptides were potent IFNγ stimulators for autologous PBMCs, but not for control PBMCs.

    Interpretation and conclusions: We show for the first time that myelin P0 is naturally processed in IgM MGUS B cells, acting as aberrant antigen-presenting cells in activation of patients T helper cells. Our findings cast new light on the important role of autoreactive P0-specific B cells in he induction of the pathogenic T cell responses found in nerve lesions of MGUS patients with peripheral neuropathy.

    Nyckelord
    Monoclonal gammopathy of undetermined significance, myelin P0, peripheral neuropathy, CD5+B cells
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-53280 (URN)10.3324/haematol.2009.015123 (DOI)000277144800017 ()
    Tillgänglig från: 2010-01-20 Skapad: 2010-01-20 Senast uppdaterad: 2017-12-12
  • 3.
    Hellqvist, Eva
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Kvarnström, Maria
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet.
    Söderberg, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Wrethem, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Neurologi. Linköpings universitet, Hälsouniversitetet.
    Ernerudh, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk immunologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells2010Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 95, nr 4, s. 627-636Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Objectives: Monoclonal gammopathy of undetermined significance (MGUS) of IgM isotype is a condition with clonally expanded B cells, recently suggested having an infectious origin. MGUS is frequently associated with polyneuropathy and antibodies against myelin protein zero (P0), whereas the role of the T cells remains largely unknown. Here we have analyzed P0-specific B cells, as antigen-presenting cells, and their capacity to activate T helper cells.

    Design and Methods: We used a well-characterized MGUS-derived B cell line, TJ2, expressing anti-P0 IgM. The ability of TJ2 cells to bind, endocytose, process, and present P0 was investigated by receptor-clustering and immunofluorescence. The activation of P0-specific autologous T cells was studied by measuring IL2 and IFNγ with flow cytometry, immunobeads, and ELISPOT.

    Results: Surface-receptor clustering and endocytosis of receptor-ligand (IgM/P0) complexes were pronounced after P0 exposure. Naturally processed or synthetic P0 peptide (194-208)-pulsed TJ2 cells significantly induced IL2 secretion from autologous T cells compared to control antigen pulsed cells (p<0 .001). The numbers of IFNγ producing T helper cells, including CD4+/CD8+ cells, were also significantly increased (p=0.0152). Affinity-isolated naturally processed myelin peptides were potent IFNγ stimulators for autologous PBMCs, but not for control PBMCs.

    Interpretation and conclusions: We show for the first time that myelin P0 is naturally processed in IgM MGUS B cells, acting as aberrant antigen-presenting cells in activation of patients T helper cells. Our findings cast new light on the important role of autoreactive P0-specific B cells in he induction of the pathogenic T cell responses found in nerve lesions of MGUS patients with peripheral neuropathy.

  • 4.
    Hellqvist, Eva
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Morad, Vivian
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Borch, Kurt
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    IGHV3-21 stereotyped subset-2 chronic lymphocytic leukemia cells make autoantibodies that bind to an 11.5kDa gastric mucosal antigenManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: The immunoglobulin heavy chain variable region (IGHV) gene mutational status is an important prognostic factor in chronic lymphocytic leukemia (CLL). Patients with mutated IGHV genes show significantly longer survival than unmutated cases. CLL patients with mutated IGHV3-21 genes, however, have a shorter survival compared to other mutated CLL cases. Recently, we showed that CLL cells react with oxidized epitopes exposed on apoptotic cells and bacteria. The gastric mucosal reactivity was of special interest to further characterize in detail.

    Methods: We collected corpus biopsies from seven Helicobacter pylori (H.p.)+ study subjects withnon-atrophic gastritis, six subjects with H.p.- atrophic gastritis, eight subjects with H.p.+ atrophicgastric and from eight controls without gastritis. The binding pattern of CLL subset-2 IGHV3-21antibodies was analyzed by immunohistochemistry and the antigen was biochemically purified byaffinity chromatography.

    Results: The subset-2 IGHV3-21 Abs bound to mucosal glands in 18 of 29 cases regardless of H.p.status or diagnosis. It also showed staining of connective tissue in all of the biopsies. The antigen waspurified and a protein of 11.5 kDa MW was isolated.

    Conclusion: The results from this study indicate that IGHV3-21 subset-2 CLL Abs bind an 11.5kDaprotein present in gastric mucosal glands or connective tissue. This autoantigen has no associationwith H.p. since it is present in normal, non-atrophic H.p.+ and atrophic H.p.+/H.p.- gastric mucosafrom corpus. The exact nature of the 11.5 kDa protein is currently under detailed structure massspectrometry analysis in order to reveal whether bacterial mimicry is the mechanism behind theinduction of this particular autoantibody.

  • 5.
    Klasson, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Ahrén, Maria
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten.
    Hellqvist, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Söderlind, Fredrik
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Fysikalisk Kemi. Linköpings universitet, Tekniska fakulteten.
    Rosén, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Tekniska högskolan.
    Käll, Per-Olov
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Fysikalisk Kemi. Linköpings universitet, Tekniska högskolan.
    Uvdal, Kajsa
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär ytfysik och nanovetenskap. Linköpings universitet, Tekniska fakulteten.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Medicinsk radiologi. Linköpings universitet, Tekniska högskolan. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Positive MRI Enhancement in THP-1 Cells with Gd2O3 Nanoparticles2008Ingår i: Contrast Media and Molecular Imaging, ISSN 1555-4309, Vol. 3, nr 3, s. 106-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There is a demand for more efficient and tissue-specific MRI contrast agents and recent developments involve the design of substances useful as molecular markers and magnetic tracers. In this study, nanoparticles of gadolinium oxide (Gd2O3) have been investigated for cell labeling and capacity to generate a positive contrast. THP-1, a monocytic cell line that is phagocytic, was used and results were compared with relaxivity of particles in cell culture medium (RPMI 1640). The results showed that Gd2O3-labeled cells have shorter T1 and T2 relaxation times compared with untreated cells. A prominent difference in signal intensity was observed, indicating that Gd2O3 nanoparticles can be used as a positive contrast agent for cell labeling. The r1 for cell samples was 4.1 and 3.6 s-1 mm-1 for cell culture medium. The r2 was 17.4 and 12.9 s-1 mm-1, respectively. For r1, there was no significant difference in relaxivity between particles in cells compared to particles in cell culture medium, (pr1 = 0.36), but r2 was significantly different for the two different series (pr2 = 0.02). Viability results indicate that THP-1 cells endure treatment with Gd2O3 nanoparticles for an extended period of time and it is therefore concluded that results in this study are based on viable cells.

  • 6.
    Klasson, Anna
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Medicinsk radiologi. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Hellqvist, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
    Käll, Per-Olov
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Fysikalisk Kemi.
    Uvdal, Kajsa
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Sensorvetenskap och Molekylfysik.
    Engström, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Medicinsk radiologi. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Cell tracking with positive contrast using Gd2O3 nanoparticles2006Ingår i: ESMRMB,2006, 2006Konferensbidrag (Övrigt vetenskapligt)
  • 7.
    Lanemo Myhrinder, Anna
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Hellqvist, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Sidorova, Ekaterina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderberg, Anita
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Baxendale, Helen
    Infectious Disease & Microbiology Unit, Institute of Child Health, University of London Medical School, London, United Kingdom.
    Dahle, Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Willander, Kerstin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Tobin, Gerard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Bäckman, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Söderberg, Ola
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hörkko, Sohvi
    Department of Pharmacology and Toxicology and Biocenter Oulu, University of Oulu, and Clinical Research Center, Oulu University Hospital, Oulu, Finland.
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies2008Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, nr 7, s. 3838-3848Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5+ CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.

  • 8.
    Myhrinder, Anna Lanemo
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Hellqvist, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Jansson, Mattias
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Nilsson, Kenneth
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Hultman, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Jonasson, Jon
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, SE-781 85 Uppsala, Sweden.
    Rosén, Anders
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia2013Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, nr 8, s. 1769-1779Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

  • 9.
    Rosén, Anders
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Bergh, Ann-Charlotte
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Gogok, Peter
    Karolinska Institutet; Stockholm, Sweden.
    Evaldsson, Chamilly
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Lanemo Myhrinder, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hellqvist, Eva
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rasul, Abu
    Karolinska Institutet; Stockholm, Sweden.
    Björkholm, Magnus
    Karolinska University Hospital; Stockholm, Sweden.
    Jansson, Mattias
    Uppsala University; Uppsala, Sweden.
    Mansouri, Larry
    Uppsala University; Uppsala, Sweden.
    Liu, Anquan
    Karolinska Institutet; Stockholm, Sweden.
    Tean Teh, Bin
    Van Andel Research Institute; Grand Rapids, MI USA.
    Rosenquist, Richard
    Uppsala University; Uppsala, Sweden.
    Klein, Eva
    Karolinska Institutet; Stockholm, Sweden.
    Lymphoblastoid cell line with B1 cell characteristics established from a chronic lymphocytic leukemia clone by in vitro EBV infection2012Ingår i: OncoImmunology, ISSN 2162-402X, Vol. 1, nr 1, s. 18-27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) cells express the receptor for Epstein-Barr virus (EBV) and can be infected in vitro. Infected cells do not express the growth-promoting set of EBV-encoded genes and therefore they do not yield LCLs, in most experiments. With exceptional clones, lines were obtained however. We describe a new line, HG3, established by in vitro EBV-infection from an IGHV1–2 unmutated CLL patient clone. All cells expressed EBNA-2 and LMP-1, the EBV-encoded genes pivotal for transformation. The karyotype, FISH cytogenetics and SNP-array profile of the line and the patient's ex vivo clone showed biallelic 13q14 deletions with genomic loss of DLEU7, miR15a/miR16–1, the two micro-RNAs that are deleted in 50% of CLL cases. Further features of CLL cells were: expression of CD5/CD20/CD27/CD43 and release of IgM natural antibodies reacting with oxLDL-like epitopes on apoptotic cells (cf. stereotyped subset-1). Comparison with two LCLs established from normal B cells showed 32 genes expressed at higher levels (> 2-fold). Among these were LHX2 and LILRA. These genes may play a role in the development of the disease. LHX2 expression was shown in self-renewing multipotent hematopoietic stem cells, and LILRA4 codes for a receptor for bone marrow stromal cell antigen-2 that contributes to B cell development. Twenty-four genes were expressed at lower levels, among these PARD3 that is essential for asymmetric cell division. These genes may contribute to establish precursors of CLL clones by regulation of cellular phenotype in the hematopoietic compartment. Expression of CD5/CD20/CD27/CD43 and spontaneous production of natural antibodies may identify the CLL cell as a self-renewing B1 lymphocyte.

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