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Studies on T cells and cytokines in Guillain-Barré syndrome and experimental allergic neuritis
Linköping University, Department of Molecular and Clinical Medicine, Clinical Immunology. Linköping University, Department of Neuroscience and Locomotion, Neurology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-28074Local ID: 12838ISBN: 91-7373-151-X (print)OAI: oai:DiVA.org:liu-28074DiVA: diva2:248625
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
List of papers
1. T lymphocyte subset abnormalities in peripheral blood from patients with the Guillain-Barré syndrome
Open this publication in new window or tab >>T lymphocyte subset abnormalities in peripheral blood from patients with the Guillain-Barré syndrome
1994 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 53, no 2, 219-225 p.Article in journal (Refereed) Published
Abstract [en]

T lymphocytes are probably of pathogenic importance in many autoimmune diseases. Recently, deviations of circulating T-helper (CD4+) subpopulations have been noticed. Blood samples from 12 patients with Guillain-Barré syndrome (GBS) were studied with flow cytometry during their disease to define circulating T cell populations. The proportion of T-helper cells (CD4+) was decreased (mean value 41±15%, P = 0.01) and the proportion of T cytotoxic/suppressor cells (CD8+) was increased (35±18%, P = 0.0006) as compared to the control group of healthy blood donors (47±8% and 26±7% respectively). The CD4+ population is divided into the helper/inducer (CD4+ CD29+) and suppressor/inducer (CD4+ CD45RA+) subsets. which normally are equally distributed (mean values in our control group were 45±15% and 44±15%, respectively). In patients with GBS, the helper/inducer (CD4+ CD29+) subset was increased (54±10%, P = 0.05) and the suppressor/inducer (CD4+ CD45RA+) subset was decreased (31±9, P = 0.005) compared to the controls. The proportion of activated HLA-DR-expressing T cells was increased (7±8%, P = 0.005) as compared to control (3±3%). The total proportions of T cells (CD2+), B cells (CD19+) and natural killer (NK) cells (CD56+) were similar in pateints and controls. The CD4+ and CD8+ populations, as well as the activated HLA-DR+ T cells, normalized during the disease course. The derivations within the CD4+ population also tended to normalize, but even at follow up after 6–33 (mean 23) months, some abnormalities remained. In conclusion, we confirm previous reports of T cell activation in peripheral blood from patients with GBS. A new finding is the derivation of T helper subpopulations with an increased helper/inducer (CD4+ CD29+) subset and a decreased suppressor/inducer (CD4+ CD45RA+) subset, which indicates a possible autoimmune character of GBS.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80191 (URN)10.1016/0165-5728(94)90032-9 (DOI)
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07Bibliographically approved
2. T helper type 2 like cytokine responses to peptides from P0 and P2 myelin proteins during the recovery phase of Guillain-Barré syndrome
Open this publication in new window or tab >>T helper type 2 like cytokine responses to peptides from P0 and P2 myelin proteins during the recovery phase of Guillain-Barré syndrome
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1997 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 153, no 1, 54-60 p.Article in journal (Refereed) Published
Abstract [en]

T-lymphocytes are probably involved in the pathogenesis of Guillain-Barré syndrome (GBS). T-helper-1 (Th1) cytokines activate macrophages and induce a delayed type hypersensitivity (DTH) inflammatory response, consistent with the morphology of the demyelination in GBS. Th2 cytokines encourage antibody production and downregulate Th1 responses. To study the Th1/Th2 cytokines in relation to the clinical course of GBS an ELISPOT method for determination of single cells secreting interferon-γ, IFN-γ (Th1) or interleukin-4, IL-4 (Th2) was used. We serially investigated antigen-induced cytokine secretion from circulating T-cells stimulated with human peptides from the P0 and P2 proteins in seven patients and compared to results from seven serially investigated healthy controls. Most patients (five of seven) showed IL-4 responses during the plateau- or recovery-phase as compared to controls. One patient with a prolonged disease course, on the other hand, had an IFN-γ dominated reactivity. We suggest that the IL-4 responses are beneficial in GBS, and may have a role in terminating the disease process in this self-limiting inflammatory disease.

Keyword
Guillain-Barré syndrome, Myelin, P0, P2, T cells, IFN-γ, IL-4
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80193 (URN)10.1016/S0022-510X(97)00178-0 (DOI)
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07Bibliographically approved
3. Elevated number of cells secreting transforming growth factor β in Guillain-Barré syndrome
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, 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.

Keyword
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: 2013-08-29Bibliographically approved
4. Transfer of myelin-specific cells deviated in vitro towards IL-4 production ameliorates ongoing experimental allergic neuritis
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, 112-118 p.Article 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: 2013-08-29Bibliographically approved

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