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Th2 shift in mononeuritis multiplex and increase of Th2 cells in chronic inflammatory demyelinating polyneuropathy: an intracellular cytokine analysis

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Abstract

To elucidate the T helper 1 (Th1)/T helper 2 (Th2) balance in various inflammatory neuropathies, we measured the ratio of intracellular interferon-γ (IFN-γ)-positive to IL-4-positive cells (intracellular IFN-γ/IL-4 ratio) by flow cytometry in peripheral blood CD4+ T cells of 14 patients with mononeuritis multiplex (MNM), 12 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 patients with Guillain–Barré syndrome (GBS), 23 patients with neurodegenerative disorders and 36 healthy controls by intracellular labeling. The patients with MNM showed a significantly lower intracellular IFN-γ/IL-4 ratio (P<0.05) and higher IL-4+/IFN-γ cell percentages (P<0.05) than the controls. The increase of IL-4+/IFN-γ cell percentages was especially prominent in MNM of unknown etiology (P<0.005). The patients with CIDP also showed significantly higher IL-4+/IFN-γ cell percentages (P<0.05) than the controls. The IL-4+/IFN-γ cell percentages were increased in some patients with GBS, but the difference was not significant compared with the controls. Thus, our results suggest that a Th2 shift is a characteristic of MNM and may play an important role in the development of the disease.

Introduction

Naive CD4+ T cells can be differentiated into two distinct subsets of helper T cells, that are designated T helper 1 (Th1) and T helper 2 (Th2) [1]. Th1 cells secrete interleukin-2 (IL-2) and interferon-γ (IFN-γ) while Th2 cells secrete IL-4, IL-5, IL-6 and IL-13 [1]. The former cells are considered to induce organ-specific autoimmune diseases through the IFN-γ-mediated macrophage activation whereas the latter cells induce allergic diseases through the production of allergen-specific IgE. Thus, the Th1/Th2 balance is crucial in the development of human immune-mediated disorders.

We recently reported heightened IgE responses in the acute phase of various inflammatory neuropathies, such as Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP) and mononeuritis multiplex (MNM) [2], that suggested the existence of Th2 hyperactivity in these conditions.

To clarify the Th1/Th2 balance, it is necessary to simultaneously analyze both Th1 and Th2 cytokines. Such analyses in inflammatory neuropathies have revealed that both Th1 and Th2 cytokines were increased in sera from GBS patients [3], and the ELISPOT method determined that Th2 cytokine responses of peripheral blood lymphocytes to neuritogenic myelin peptides predominate in the plateau phase of GBS patients [4]. In these previous studies, IL-4 responses were considered to be beneficial through down-regulation of Th1 responses. The Th1/Th2 balance has never been studied in MNM, and such studies are scant in CIDP. We therefore designed a study to simultaneously measure intracellular Th1 and Th2 cytokine production of CD4+ helper T cells in various inflammatory neuropathies, in order to clarify Th1/Th2 balance. We found a distinct pattern of Th1/Th2 balance in each inflammatory neuropathy.

Section snippets

Subjects

The subjects consisted of 14 patients with MNM (mean age±S.D.=40±14 years, range 13–65 years), i.e. cryoglobulinemia in 1, Lyme disease in 1, polyarteritis nodosa in 2 and idiopathic MNM in 10; 10 patients with GBS (mean age±S.D.=41±17 years, range 24–78 years) who fulfilled the diagnostic criteria for GBS [5]; 12 patients with CIDP (mean age±S.D.=47±15 years, range 20–70 years) based on the criteria of the American Academy of Neurology AIDS Task Force [6]; and 23 with neurodegenerative

Results

The percentages of IL-4+/IFN-γ cells were significantly higher in MNM (P=0.0126) as well as in CIDP (P=0.0116) than in the controls Fig. 1, Fig. 2. The increase was especially prominent in MNM of unknown etiology (P=0.004). The increase of IL-4+/IFN-γ cells was not statistically significant in GBS in comparison to the healthy controls. None of the other cell percentages showed any statistically significant changes in any disease groups compared with the controls. The intracellular IFN-γ/IL-4

Discussion

In the present study, by intracellular labeling of two distinct cytokines, IFN-γ and IL-4, we have for the first time found a Th2 shift in patients with MNM, especially in MNM with unknown etiology. Although it has been reported that Th1 response may play an important role in the development of GBS and CIDP [3], [4], [8], the present study demonstrated that the Th1/Th2 balance in the patients with CIDP and GBS was not shifted to the Th1 side, at least in the peripheral blood. In fact, we found

Acknowledgements

We thank M. Oyamada (Otsuka Pharmaceutical), T. Miyazaki and T. Kohsaka (Otsuka Tokyo Assay Laboratories) for their technical assistance. This work was supported in part by grants from the Ministry of Education, Science and Culture of Japan, a Neuroimmunological Disease Research Committee grant and a Research on Brain Science grant from the Ministry of Health and Welfare of Japan.

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