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Kvarnström, Maria
Publications (10 of 11) Show all publications
Kvarnström, M., Ydrefors, J., Ekerfelt, C., Vrethem, M. & Ernerudh, J. (2013). Longitudinal interferon-β effects in multiple sclerosis: differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13. Journal of the Neurological Sciences, 325(1-2), 79-85
Open this publication in new window or tab >>Longitudinal interferon-β effects in multiple sclerosis: differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13
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2013 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 325, no 1-2, p. 79-85Article in journal (Refereed) Published
Abstract [en]

Background:

Recent studies in experimental models and in vitro indicate lowering of IL-17/Th17 as an important mechanism of interferon-beta (IFN-β) treatment in multiple sclerosis (MS).

Material and methods:

In this longitudinal study of MS patients (n = 25), spontaneous and myelin antigen-induced secretion of IL-4, IFN-γ and IL-10 (ELISPOT), mitogen stimulated secretion of IL-13 and IL-17A (ELISA) and circulating cytokine levels (Luminex) were recorded at inclusion and after 1.5, 3, 6 and 12 months of IFN-β treatment.

Results:

Early changes were noted for IL-4, while after one year of treatment the only recorded significant effects were a decrease in secreted IL-17A levels and an increase in IL-10 secreting cells. While IL-17A levels tended to be higher in non-responders (n = 8), the decrease in IL-17A levels seemed to be more pronounced in responders (n = 17) showing significantly lower IL-17A levels after one year as compared with non-responders.

Conclusion:

IFN-β treatment seems to mainly affect IL-17/IL-10-associated pathways rather than the IFN-γ/IL-4 axis.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Multiple sclerosis, Interferon-beta, Cytokines, IL-4, IL-17, IL-10, Responder
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90199 (URN)10.1016/j.jns.2012.12.001 (DOI)000315323000016 ()
Note

Funding Agencies|Biogen Idec||Network for Inflammation research||Swedish Foundation for Strategic Research||Swedish Association of Neurologically Disabled||County Council of Ostergotland||University Hospital of Linkoping and Lions Ostergotland||

Available from: 2013-04-03 Created: 2013-03-21 Last updated: 2017-12-06Bibliographically approved
Vrethem, M., Kvarnström, M., Stenstam, J., Cassel, P., Gustafsson, M., Landtblom, A.-M. & Ernerudh, J. (2012). Cytokine mapping in cerebrospinal fluid and blood in multiple sclerosis patients without oligoclonal bands. Multiple Sclerosis, 18(5), 669-673
Open this publication in new window or tab >>Cytokine mapping in cerebrospinal fluid and blood in multiple sclerosis patients without oligoclonal bands
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2012 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 18, no 5, p. 669-673Article in journal (Refereed) Published
Abstract [en]

Objective: Since there are clinical and genetic differences between MS patients with intrathecal oligoclonal bands (OCB+ ) in the cerebrospinal fluid (CSF) compared with those without (OCB-), the aim was to find out if OCB- patients showed a different pattern of cytokine immune activation compared with OCB+ patients. Methods: The study included 25 MS patients (10 OCB- and 15 OCB+ ) and 13 controls. A panel of cytokines was measured; IL-1β, IL-6, IL-8/CXCL8, IL-10, TNF and GM-CSF in serum, CSF and in supernatants from polyclonally stimulated blood mononuclear cells, where also levels of IL-12p40, IL-13, IL-15, IL-17 and IFN-γ were measured. The concentrations of soluble (s) VCAM-1 and sCD14 were measured in serum and CSF. Results: In general, there were no extensive differences in cytokine concentrations between the OCB- and OCB+ groups. Conclusion: OCB- MS patients do not seem to constitute a separate entity concerning inflammatory parameters measured as cytokine concentrations in CSF and blood.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-75970 (URN)10.1177/1352458511424903 (DOI)000303319000107 ()21965416 (PubMedID)
Note
funding agencies|Swedish Association of Neurologically Disabled||County Council of Ostergotland||University Hospital of Linkoping||Available from: 2012-03-30 Created: 2012-03-20 Last updated: 2017-12-07
Hellqvist, E., Kvarnström, M., Söderberg, A., Wrethem, M., Ernerudh, J. & Rosén, A. (2010). Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells. Haematologica, 95(4), 627-636
Open this publication in new window or tab >>Myelin protein zero is naturally processed in IgM MGUS B cells: Aberrant triggering of patient T cells
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2010 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 95, no 4, p. 627-636Article in journal (Refereed) 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.

Keywords
Monoclonal gammopathy of undetermined significance, myelin P0, peripheral neuropathy, CD5+B cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53280 (URN)10.3324/haematol.2009.015123 (DOI)000277144800017 ()
Available from: 2010-01-20 Created: 2010-01-20 Last updated: 2017-12-12
Kvarnström, M. (2005). Mechanisms in inflammatory demyelinating diseases of the nervous system: immunological and methodological aspects. (Doctoral dissertation). Linköping: Linköpings universitet
Open this publication in new window or tab >>Mechanisms in inflammatory demyelinating diseases of the nervous system: immunological and methodological aspects
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The diseases studied in this thesis, Guillain-Barré Syndrome (GBS), Multiple Sclerosis (MS) and Polyneuropathy associated with monoclonal gammopathy of uncertain significance (PNMGUS), are of autoimmune origin with myelin components as putative auto antigens. T cells are important for the pathogenesis, as well as the cytokine network and autoantibodies. For all of these diseases, the immunopathogenisis is not fully understood and even if there are treatments available, none of them are curative and there are side effects. Thus there is a need for further clues in the immune mechanisms. Contrary to PNMGUS and MS, GBS is generally self-limiting. The mechanisms of the beneficial effect of interferon-beta (IFN-ß) treatment in MS are not fully understood, (although alterations in the cytokine levels are subject to many reports). In PNMGUS, the proliferation of a monoclonal B cell clone and its antibody production are of great significance, however additional immune mechanisms are also of interest like the role of T cells and the role of B cells as antigen presenting cells.

In studies of cytokines, frozen cells are often used, sometimes for practical reasons, so also in this thesis. Therefore effects of cryopreservation on cellular expression/secretion of cytokines were studied. The expression before compared to after cryopreservation of IFN-γ, IL-4, IL-5, IL-9, IL-10 and IL-13 was analysed with ELISA, ELISPOT and/or real time RT-PCR We found that the process of cryopreservation and thawing does affect the expression of cytokines, both at the protein and the mRNA level. The most consistent fmding was that expression of IL-4 was generally decreased in spontaneous and auto-antigen/allergen induced expression in cryopreserved cells. Thus, this study points out the importance of investigation of the effects of freezing for each cytokine, stimuli and patient group before using frozen cells in studies of in vitro cytokine secretion.

The secretion of IL-4, IFN-γ, TGF-ß, IL-6, and TNF-α during the course of GBS was analysed with ELISPOT and cell-ELISA. Our findings indicate a down-regulatory role for TGF-ß and IL-4 in GBS.

The longitudinal effects over one year of IFN-ß treatment on secretion of IL-4, IFN-γ and IL-10 was analysed with the ELISPOT technique and IL-13 and IL-17 was analysed in cell supernatants with ELISA. A general finding was that surprisingly few changes occurred, and that most changes occurred early (6 weeks - 3 months). However, we found a shift in the cytokine balance towards more IL-4 and IL-10 secretion and/or less IFN-γ secretion during the treatment as the ratios of IL-4/IFN-γ as well as of IL-10/IFN-γ were increased. The interesting pro-inflammatory cytokine IL-17, associated with T cell mediated autoimmunity, has not been previously investigated during IFN-ß treatment in MS and our findings of decreased IL-17 levels after one year of treatment could be a beneficial result of the IFN-ß treatment.

B cell clones from a patient with PNMGUS were successfully established by isolating B cells with myelin protein zero (P0) coated magnetic beads and subsequently transforming with Epstein-Barr virus (EBV). The clones were characterised and for instance they strongly expressed HLA-DR and CD80, compatible with antigen-presenting properties. The cell lines may provide useful tools in studies of PNMGUS.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2005. p. 86
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 892
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24541 (URN)6700 (Local ID)91-85299-02-2 (ISBN)6700 (Archive number)6700 (OAI)
Public defence
2005-05-04, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-03Bibliographically approved
Kvarnström, M., Jenmalm, M. & Ekerfelt, C. (2004). Effect of cryopreservation on expression of Th1 and Th2 cytokines in blood mononuclear cells from patients with different cytokine profiles, analysed with three common assays: an overall decrease of interleukin-4: An overall decrease of interleukin-4. Cryobiology, 49(2), 157-168
Open this publication in new window or tab >>Effect of cryopreservation on expression of Th1 and Th2 cytokines in blood mononuclear cells from patients with different cytokine profiles, analysed with three common assays: an overall decrease of interleukin-4: An overall decrease of interleukin-4
2004 (English)In: Cryobiology, ISSN 0011-2240, E-ISSN 1090-2392, Vol. 49, no 2, p. 157-168Article in journal (Refereed) Published
Abstract [en]

Studies on cytokine expression in blood cells are commonly performed on cryopreserved cells. Previous studies show that cryopreservation affects cytokine expression, but the findings are not consistent. This may be due to divergent effects of freezing on different cytokines, different stimuli, and different patient groups or to the use of different assays in the studies. This study was designed to investigate the effect of freezing on spontaneous, auto-antigen, allergen, and mitogen induced cytokine secretion from peripheral blood mononuclear cells from several groups of patients expressing different cytokine profiles; multiple sclerosis, atopic children, non-atopic children, and pregnant women. The expression of IFN-γ, IL-4, IL-5, IL-9, IL-10, and IL-13 was analysed with ELISA, ELISPOT and/or real time RT-PCR. Our data provide evidence that the process of cryopreservation and thawing does affect the expression of cytokines, both at the protein and the mRNA level. Moreover, the effect varied among different cytokines, different stimuli, and different patient groups, which partly may be explained by differences in optimal freezing conditions for non-activated and activated cells. An increase of allergen and PHA stimulated IFN-γ secretion in atopic children was found following cryopreservation, but no such increase in auto-antigen induced IFN-γ was seen in MS-patients. The most consistent finding was that expression of IL-4 was generally decreased in spontaneous and auto-antigen/allergen induced expression in cryopreserved cells. In conclusion, this study points out the importance of investigation of the effects of freezing for each cytokine, stimuli and patient group before using frozen cells in studies of in vitro cytokine secretion.

Keywords
Cryopreservation, cytokine, IL-4, ELISA, ELISPOT, Real time RT-PCR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22345 (URN)10.1016/j.cryobiol.2004.06.003 (DOI)1546 (Local ID)1546 (Archive number)1546 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
Dahle, C., Kvarnström, M., Ekerfelt, C., Samuelsson, M. & Ernerudh, J. (2003). Elevated number of cells secreting transforming growth factor β in Guillain-Barré syndrome. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 111(12), 1095-1104
Open this publication in new window or tab >>Elevated number of cells secreting transforming growth factor β in Guillain-Barré syndrome
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2003 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 111, no 12, p. 1095-1104Article in journal (Refereed) Published
Abstract [en]

We used ELISPOT and cell ELISA to study secretion of IL-4, IFN-γ, TGF-β, IL-6, and TNF-α by circulating mononuclear cells during the course of Guillain-Barré syndrome (GBS). Compared to healthy controls, patients with GBS had higher numbers of TGF-β-secreting cells and the number of individuals with myelin-peptide-induced IL-4 and TGF-β secretion was higher in the GBS group. No significant differences were seen concerning the predominantly pro-inflammatory cytokines IFN-γ, IL-6 or TNF-α. Our findings indicate a down-regulatory role for TGF-β and IL-4 in GBS.

Keywords
Cytokines, ELISPOT, Guillain-Barré, IL-4, Syndrome, TGF-ß
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-46369 (URN)10.1111/j.1600-0463.2003.apm1111204.x (DOI)
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
Jansson, A., Ernerudh, J., Kvarnström, M., Ekerfelt, C. & Vrethem, M. (2003). Elispot assay detection of cytokine secretion in multiple sclerosis patients treated with interferon-β1a or glatiramer acetate compared with untreated patients. Multiple Sclerosis, 9(5), 440-445
Open this publication in new window or tab >>Elispot assay detection of cytokine secretion in multiple sclerosis patients treated with interferon-β1a or glatiramer acetate compared with untreated patients
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2003 (English)In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 9, no 5, p. 440-445Article in journal (Refereed) Published
Abstract [en]

The mechanisms behind the beneficial effects of interferon-β1a (IFN-β1a) and glatiramer acetate (GA) in the treatment of multiple sclerosis (MS) are still uncertain. Altered cytokine patterns have been suggested including inhibition of proinflammatory cytokines like interferon-γ (IFN-γ) and enhancement of anti-inflammatory cytokines such as interleukin-4 (IL-4). Twenty-nine patients with MS (10 untreated, nine treated with IFN-β1a and 10 with GA) were investigated with elispot of peripheral blood mononuclear cells. Spontaneous and myelin induced (myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG)-14-39 and MOG 63-87) IFN-γ, IL-4, IL-5 and IL-10 secretion was studied. We found a significant reduction of spontaneous IFN-γ, IL-4 and IL-5, but no difference in IL-10 secreting cells in both groups of treated patients compared with the untreated patients. Myelin-specific responses showed a significant decrease of IFN-γ and an increase of IL-5, but no change in IL-4 and IL-10 secreting cells in treated compared with untreated patients. Both treatment groups revealed similar cytokine secretion patterns except for a more pronounced decrease of both spontaneous and MOG 14-39 induced IL-4 secretion in the IFN-β1a treated group. Thus, immunological effects of IFN-β1a and GA were similar showing that disease promoting Th1 (IFN-γ) cells were reduced while the potentially beneficial Th2 response (IL-4) was maintained.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26416 (URN)10.1191/1352458503ms951oa (DOI)10958 (Local ID)10958 (Archive number)10958 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
Kvarnström, M., Sidorova, E., Nilsson, J., Ekerfelt, C., Vrethem, M., Söderberg, O., . . . Ernerudh, J. (2002). Myelin protein P0-specific IgM producing monoclonal B cell lines were established from polyneuropathy patients with monoclonal gammopathy of undetermined significance (MGUS). Clinical and Experimental Immunology, 127(2), 255-262
Open this publication in new window or tab >>Myelin protein P0-specific IgM producing monoclonal B cell lines were established from polyneuropathy patients with monoclonal gammopathy of undetermined significance (MGUS)
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2002 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 127, no 2, p. 255-262Article in journal (Refereed) Published
Abstract [en]

Monoclonal expansion of B cells and plasma cells, producing antibodies against ‘self’ molecules, can be found not only in different autoimmune diseases, such as peripheral neuropathy (PN), but also in malignancies, such as Waldenström’s macroglobulinaemia and B-type of chronic lymphocytic leukaemia (B-CLL), as well as in precancerous conditions including monoclonal gammopathy of undetermined significance (MGUS). About 50% of patients with PN-MGUS have serum antibodies against peripheral nerve myelin, but the specific role of these antibodies remains uncertain. The aims of the study were to establish, and characterize, myelin-specific B cell clones from peripheral blood of patients with PN-MGUS, by selection of cells bearing specific membrane Ig-receptors for myelin protein P0, using beads coated with P0. P0-coated magnetic beads were used for selection of cells, which subsequently were transformed by Epstein–Barr virus. The specificity of secreted antibodies was tested by ELISA. Two of the clones producing anti-P0 antibodies were selected and expanded. The magnetic selection procedure was repeated and new clones established. The cells were CD5+ positive, although the expression declined in vitro over time. The anti-P0 antibodies were of IgM-λ type. The antibodies belonged to the VH3 gene family with presence of somatic mutations. The IgM reacted with P0 and myelin-associated glycoprotein (MAG), and showed no evidence for polyreactivity, in contrast to other IgM CD5+ clones included in the study as controls. The expanded clones expressed CD80 and HLA-DR, which is compatible with properties of antigen-presenting cells. The immunomagnetic selection technique was successfully used for isolation of antimyelin protein P0-specific clones. The cell lines may provide useful tools in studies of monoclonal gammopathies, leukaemia, and autoimmune diseases, including aspects of antigen-presentation by these cells followed by T cell activation.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25117 (URN)10.1046/j.1365-2249.2002.01739.x (DOI)9550 (Local ID)9550 (Archive number)9550 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
Schöier, J., Öllinger, K., Kvarnström, M., Söderlund, G. & Kihlström, E. (2001). Chlamydia trachomatis -induced apoptosis occurs in uninfected McCoy cells late in the developmental cycle and is regulated by the intracellular redox state. Microbial Pathogenesis, 31(4), 173-184
Open this publication in new window or tab >>Chlamydia trachomatis -induced apoptosis occurs in uninfected McCoy cells late in the developmental cycle and is regulated by the intracellular redox state
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2001 (English)In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 31, no 4, p. 173-184Article in journal (Refereed) Published
Abstract [en]

Infections with the obligate intracellular bacterium Chlamydia trachomatis are characterized by avoidance of fusion between chlamydia-containing endosomes and lysosomes, bacterial persistence and development of post-infectious sequelae. In this report we show that C. trachomatis induces apoptosis in McCoy and HeLa cells. Apoptosis was monitored by three different techniques; enzyme-linked immunoassay (EIA) of fragmented nucleosomes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and flow cytometry of propidium iodide-stained cells. Apoptosis occurred in uninfected cells, was induced late in the chlamydial developmental cycle, beyond 24 h post-infection and was dependent on bacterial protein synthesis. Apoptosis was not significantly increased in infected, inclusion-containing cells. Treatment of cells with the antioxidants ascorbic acid (10 μM) and α-tocopherol (10 μM) reduced the degree of apoptosis. These results suggest that host cells infected with C. trachomatis generate proapoptotic stimuli that induce apoptosis in uninfected, neighbouring cells and that the redox state of the cell is a regulator in chlamydia-induced apoptosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25989 (URN)10.1006/mpat.2001.0460 (DOI)10441 (Local ID)10441 (Archive number)10441 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
Ekerfelt, C., Dahle, C., Weissert, R., Kvarnström, M., Olsson, T. & Ernerudh, J. (2001). Transfer of myelin-specific cells deviated in vitro towards IL-4 production ameliorates ongoing experimental allergic neuritis. Clinical and Experimental Immunology, 123(1), 112-118
Open this publication in new window or tab >>Transfer of myelin-specific cells deviated in vitro towards IL-4 production ameliorates ongoing experimental allergic neuritis
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2001 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 123, no 1, p. 112-118Article in journal (Refereed) Published
Abstract [en]

A causal role of IL-4 (Th2) production for recovery in experimental allergic neuritis (EAN) was indicated by experiments where Th1-like autoreactive cell populations, taken from the induction phase of the disease, were deviated to extensive secretion of IL-4 in a selective fashion, by ex vivo stimulation with autoantigen in the presence of IL-4. The deviated cells were adoptively transferred to EAN rats at a time just prior to the onset of clinical signs. This treatment ameliorated EAN compared with sham treatment. This therapeutic approach, with generation of autoreactive IL-4-secreting cells ex vivo followed by subsequent adoptive transfer, may become a new selective treatment of organ-specific autoimmune diseases since, in contrast to previous attempts, it is done in a physiological and technically easy way.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25887 (URN)10.1046/j.1365-2249.2001.01424.x (DOI)10328 (Local ID)10328 (Archive number)10328 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
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