IL-10 and IFN-γ in Guillain–Barré syndrome

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Abstract

Guillain–Barré syndrome (GBS) is an acute inflammatory disease affecting myelin and axons of the peripheral nervous system (PNS). GBS is considered to be caused by breakdown of tolerance to autoantigens of the PNS. The involvement of cytokines in GBS and in relation to treatment with high dose intravenous immunoglobulin (IvIg) is incompletely known. We studied the temporal profiles of IL-10 and IFN-γ-secreting blood mononuclear cells (MNC) over the course of GBS, using enzyme-linked immunospot (ELISPOT) assays. Pretreatment levels of blood MNC spontaneously secreting IL-10 were higher in the acute phase of GBS than in control patients with aseptic meningitis, other neurological diseases, diabetic neuropathy and healthy subjects. Levels of IFN-γ-secreting blood MNC were not increased over the course of GBS. Patients treated with IvIg had lower numbers of IL-10-secreting MNC compared to untreated patients. High levels of IL-10-secreting MNC correlated with serum anti-ganglioside IgM antibody levels, and with neurophysiological signs of axonal damage. The present data suggests that IFN-γ is not involved in GBS pathogenesis, and IL-10 being up-regulated in the early phase of GBS and associated with axonal damage, may have a pathogenetic role in GBS.

Introduction

Several studies have confirmed the inflammatory nature of Guillain–Barré syndrome (GBS) [for review see Hartung et al. (1995)]. T cell activation in GBS is evident by the increased numbers of circulating T cells secreting IL-2 (Chalen and Sindic, 1993). Serum concentrations of Th1 cytokines such as TNF-α and IL-6 are elevated during the acute phase of GBS (Maimone et al., 1993, Sharief et al., 1993). Serum TNF-α and IL-2R concentrations correlate with disease severity (Bansil et al., 1991, Exley et al., 1994). The proinflammatory role of IFN-γ has been clearly demonstrated in experimental allergic neuritis (EAN), an animal model of GBS (Hartung et al., 1995). The role of IFN-γ in GBS is less well defined. One study of IFN-γ levels in serum in the acute phase of GBS revealed no difference compared to controls (Exley et al., 1994) while, in another study, high serum concentrations of IFN-γ were detected in the acute stage of GBS (Hohnoki et al., 1998).

Cytokines generally considered as anti-inflammatory have been found to be up-regulated in the recovery phase of GBS. High serum concentrations of TGF-β (Creange et al., 1998), and elevated numbers of circulating IL-4-secreting mononuclear cells (MNC) (Dahle et al., 1997), were reported in patients examined during the recovery phase of GBS. The involvement of IL-10 in GBS is as yet unclear. Elevated IL-10 concentrations in serum (Hohnoki et al., 1998), but not cerebrospinal fluid (CSF) (Gallo et al., 1994) are reported in patients examined during the acute phase of GBS.

High-dose intravenous immunoglobulin (IvIg) is frequently used to treat GBS. How this treatment influences cytokines in patients with GBS is less well defined. Aukrust et al. (1994) reported increased TNF-α concentrations in plasma after a bolus injection of IvIg to a patient with idiopathic thrombocytopenic purpura (ITP). Andersson et al. (1996) showed a reduction of both pro- and anti-inflammatory cytokines including IL-10 after exposing blood MNC in culture to IvIg. IvIg treatment of patients with GBS, decreased TNF-α but not IL-10 concentrations in serum (Sharief et al., 1999).

Studies of cytokine levels in body fluids are hampered by the short half-life (often minutes) of individual cytokines and by their action and binding to receptors mainly at sites of production. This may explain some of the occurrence of inconsistancies in results observed when circulating cytokines are measured by e.g. ELISA. An alternative approach to detect cytokine abnormalities is the use of enzyme-linked immunospot (ELISPOT) assays that allow detection and enumeration in body fluids of cells secreting a certain cytokine. The only up to date published study of cytokines in GBS using ELISPOT is a study describing high levels of IL-4-secreting blood MNC in the recovery phase of the disease (Dahle et al., 1997).

Our objectives were to study the involvement of IL-10 and IFN-γ-secreting MNC and effects of IvIg treatment on levels of such cells over the course of GBS using ELISPOT assays.

Section snippets

Patients

A multi-center network of neurologists was set up in Sweden in order to maximise the number of patients to be recruited for the present study. Forty-one patients (18 females) fulfilling the Asbury criteria (Asbury et al., 1978) for GBS were included (35 patients were included at the Huddinge University Hospital and six patients were included in the study by the other network members). The mean age of the patients with GBS was 53±13 years. CSF analysis and neurophysiological studies were

Statistics

The non-parametric Kruskal Wallis test together with the Dunn’s multiple comparison test and the Spearman rank correlation test were used.

Levels of IL-10-secreting blood MNC over the course of GBS

When examined during the acute phase of GBS (phase A), the numbers of IL-10-secreting MNC did not differ when considering the whole group of GBS patients compared to the control groups (Fig. 1a). Considering patients examined during phase A, untreated patients with GBS (i.e. subgroups A-1 plus A-3) had higher levels of IL-10-secreting MNC in blood compared to patients treated with IvIg (i.e. subgroup A-2) ( P=0.002). Untreated patients examined during the acute phase of GBS had also higher

Discussion

The acute progressive nature of GBS, reflecting a dynamic series of events within the immune system affecting the PNS, and the importance of early initiation of immuno-modulating treatment, complicate the design of studies dealing with immunological aspects of GBS pathogenesis. The three factors proposed to be in need of standardization in such studies are the definition of the duration of the acute progressive phase of GBS, the duration of disease prior to blood sampling in the acute phase,

Acknowledgements

This work was supported by the Swedish Medical Research Council, the Swedish Association of Neurologically Disabled (NHR) and by funds from the Karolinska Institute.

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    Members of the Swedish Epidemiological Study Group: Dr. Bo Ekstedt (Neurology Department, Örebro Hospital); Dr. Magnus Andersson (Neurology Department, Karolinska Hospital); Dr. Jan Toft and Dr. Anders Larsson (Department of Internal Medical, Borås Hospital); Dr. Håkan Askmark (Neurology Department, Uppsala Akademiska Hospital) and Dr. Lena Wallrup (Department of Internal Medicine, Falun Hospital).

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