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Elevated number of cells secreting transforming growth factor β in Guillain-Barré syndrome
Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-3993-9985
Neurology Unit, Örebro University Hospital, Sweden.
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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, 1095-1104 p.Article 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.

Place, publisher, year, edition, pages
2003. Vol. 111, no 12, 1095-1104 p.
Keyword [en]
Cytokines, ELISPOT, Guillain-Barré, IL-4, Syndrome, TGF-ß
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-46369DOI: 10.1111/j.1600-0463.2003.apm1111204.xOAI: oai:DiVA.org:liu-46369DiVA: diva2:267265
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Studies on T cells and cytokines in Guillain-Barré syndrome and experimental allergic neuritis
Open this publication in new window or tab >>Studies on T cells and cytokines in Guillain-Barré syndrome and experimental allergic neuritis
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Guillain-Barrésyndrome (GBS) is an inflammatory disease of peripheral nerves, characterised by muscle weakness. The nerves are attacked and destroyed by the immune system. The symptoms usually progress over a few weeks and many patients become severely disabled. However, in contrast to many other organspecific autoimmune diseases, GBS is self-limiting and most patients recover. Individuals of all ages can be affected. The incidence is about 1/100 000 per year. An infection often precedes the onset of neurological symptoms and probably triggers the immune-mediated attack.

Activation of T cells and the resulting release of cytokines are decisive for the regulation of antigen-specific inflammation. Different cytokine patterns promote different types of responses. Interferon-y (lFN-γ) has a key role in Th type 1 responses, and is thought to be a driving force in many organ-specific autoimmune diseases. Interleukin-4 (IL-4) promotes Th type 2 responses, characterised by the production of certain antibodies and activation of mastcells and eosinophils. Th type 1 and Th type 2 responses down-regulate one another and the balance between them is important for the immune homeostasis. TGF-ß is an important cytokine with strong down-regulatory properties.

Flow cytometry studies showed that circulating T cells were activated in patients with GBS as determined by expression of HLA-DR on T cells, increased proportion of activated memory phenotype (CD4+CD29+), and decreased proportion of naive phenotype (CD4+CD45RA+). A sensitive Ell-spot method was used to determine cytokine secretion from circulating mononuclear cells with or without stimulation with immunogenic peptides from myelin proteins P2 and PO. Both spontaneous and myelin-specific cytokine secretion were increased in patients compared with controls. Increased numbers of myelin-specific cells secreting IL-4 and TGF-ß were found in the majority of the patients, indicating a Th2 type and down-regulatory cytokine profile, in line with the self-limiting character of the disease.

An animal model of GBS, experimental allergic neuritis (EAN), is known to be inducible by myelin-specific T cells, supporting the pathogenetic role of T cells. A Th1 deviated, IFN-y-producing cell population from EAN, was in vitro stimulated with autoantigen and IL-4, thereby obtaining a Th2 cytokine profile. These myelin-specific cells were subsequently transferred to rats with EAN, and were found to ameliorate the disease course.

In conclusion, Circulating T cells are activated in patients with GBS. Most patients have myelin-specific T cells that mainly secrete down-regulatory cytokines such as IL-4 and TGF-ß, which probably have a beneficial role in regulating the disease process. In vitro deviation of myelin-specific T cells into Th2 phenotype and subsequent transfer of these cells ameliorated the disease course in EAN.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 62 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 704
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-28074 (URN)12838 (Local ID)91-7373-151-X (ISBN)12838 (Archive number)12838 (OAI)
Public defence
2001-12-06, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-08-22Bibliographically approved
2. Mechanisms in inflammatory demyelinating diseases of the nervous system: immunological and methodological aspects
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. 86 p.
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

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Dahle, CharlotteKvarnström, MariaEkerfelt, ChristinaErnerudh, Jan

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