Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis

Abstract

We have recently described the induction of anti-cytokine autoantibodies (Aabs) in the serum as a novel mechanism for cytokine regulation during bacterial infections. Here we use the infant rat-model of Haemophilus influenzae type b (Hib) meningitis to examine the induction of five potentially important cytokines and their autoantibody responses in the CSF. Protein levels of the cytokines interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), IL-4 and IL-10 were detected at day 3 post-inoculation (p.i.) with maximum induction at day 8. Thereafter, these levels of cytokines had become undetectable. Increased Aab titres to these cytokines, except IL-4, were registered with peak levels between days 7 and 9. Upon re-inoculation with Hib at day 30, regeneration of Aabs was recorded 7 days later (i.e. at day 37). To control the specificity of these Aabs, preincubation of the CSF with a cytokine inhibited the binding effects of that particular cytokine, but not those of any other cytokine. Aabs dose-dependently inhibited IFN-gamma-induced MHC expression by peritoneal macrophages and TNF-alpha-mediated L929 cytotoxicity. Our data demonstrate for the first time the existence of the anti-cytokine antibodies in the CSF of the meningitis Hib model. Furthermore, the data present a role for the Aabs in cytokine regulation, which is consistent with the previously demonstrated effects of the Aabs in the serum.

Fig. 1

(a) IFN-γ levels in the CSF in U/ml. Bars denote means ± s.d. and readings refer to the left ordinate. The right ordinate represents the anti-IFN-γ autoantibody (Aab) responses in CSF in ng/ml. •, Means ± s.d. of IgG response in the CSF; ○, means ± s.d. of controls. (b) Effects of CSF from day 8 p.i. on MHC expression on rat peritoneal macrophages induced by IFN-γ. The data are from representative experiments, which were repeated twice with similar results.

Fig. 3

IL-4 (a), IL-10 (b) and transforming growth factor-beta (TGF-β) (c) levels in the CSF in U/ml. Bars denote means ± s.d. and readings refer to the left ordinate. The right ordinate represents the anti-IL-4 (a), anti-IL-10 (b) and anti-TGF-β (c) autoantibody (Aab) responses in CSF in ng/ml. •, Means ± s.d. of IgG responses in the CSF; ○, means ± s.d. of controls.

Fig. 2

(a) Tumour necrosis factor-alpha (TNF-α) levels in the CSF in U/ml. Bars denote means ± s.d. and readings refer to the left ordinate. The right ordinate represents the anti-TNF-α autoantibody (Aab) responses in CSF in ng/ml. •, Means ± s.d. of IgG response in the CSF; ○, means ± s.d. of controls. (b) Effects of different dilutions of the CSF from day 8 p.i. on TNF-α-mediated L929 cytotoxicity. The data are from representative experiments, which were repeated twice with similar results.