Cerebrospinal fluid interleukin 6 in amyotrophic lateral sclerosis: immunological parameter and comparison with inflammatory and non-inflammatory central nervous system diseases
Introduction
IL-6 is a B cell differentiation factor that was first described by Hirano et al. (1985). Although usually T-cell derived, it can be produced by other cells including astrocytes and microglia in the central nervous system (CNS) (Benveniste et al., 1990, Frei et al., 1989, Woodroofe et al., 1991). Cerebrospinal fluid (CSF) levels of IL-6 are consistently elevated in herpes simplex virus encephalitis and other bacterial and viral CNS infections (Houssiau et al., 1988, Frei et al., 1988). In contrast, variable results have been reported in non-infectious CNS inflammatory diseases. IL-6 was detected in experimental allergic encephalomyelitis CSF (Gijbels et al., 1990) and systemic lupus erythematosus with central nervous system involvement (Hirohata and Miyamoto, 1990), but IL-6 was not detected in multiple sclerosis (MS) (Houssiau et al., 1988, Frei et al., 1988, Araga et al., 1991) (or detected no more frequently than in neurological disease controls) (Hauser et al., 1990). Reports of IL-6 in non-inflammatory CNS disease prompted the present study of CSF in patients with amyotrophic lateral sclerosis (ALS). We found a higher frequency of detection and higher levels of IL-6 in ALS than in the other neurological disease control group. In contrast, there was no significant difference in CSF IL-6 in either MS or HAM patients compared to other neurological disease controls, and there was no correlation of CSF immune parameters and IL-6 levels. These results are consistent with the hypothesis that CSF IL-6 in ALS has an non-immune origin, occurring as a neurotrophic response to nerve cell damage.
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Patients
Diagnostic criteria used were for ALS (Mulder, 1982) MS (Poser et al., 1983) and HAM (Osame et al., 1987). All 19 ALS patients from Japan had progressive weakness without significant sensory disturbance, upper or lower motor neuron signs, muscle atrophy with fasciculation, and a neurogenic pattern on electromyography. Eight CSF ALS samples and two non-neurological disease controls were obtained from the National Neurological Research Bank (VA Wadsworth Medical Center, Los Angeles, CA). All HAM
Results
Table 1 shows CSF of patients in the ALS, MS, HAM, and OND groups. A mild pleocytosis was present in the MS and HAM groups and the protein was mildly elevated in the MS group. The highest mean values of both total IgG and percent IgG were in the HAM group.
As shown in Fig. 1, there was considerable overlap in IL-6 levels in all patient groups. A Kruskal-Wallis test comparing the five groups (3 experimental and 2 controls) was significant overall (P=0.0012).
Table 2 shows IL-6 detection in 78% of
Discussion
We found a modest, but statistically significant elevation of CSF IL-6 in ALS patients (Fig. 1). A published study using this same assay technique found no difference between 15 ALS patient and 20 controls with psychiatric or neurodegenerative disease (Krieger et al., 1992). In comparing these studies, a similar percentage of ALS patients had undetectable CSF IL-6 (6/27 versus 2/15); but 37% of our patients had IL-6 levels greater than 10 pg/ml compared to only 7% in the published study. The
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