Controlled trials in
multiple sclerosis (MS) and case reports in acute demyelinating
encephalomyelitis (ADEM) have shown that
intravenous immunoglobulins (
IVIg) are of therapeutic benefit in central nervous system (CNS) inflammatory diseases. Studies in
experimental autoimmune encephalomyelitis (EAE) have suggested these effects are mediated by modulation of the
cytokine network and T cell responses. However, there are no data on the influence of
IVIg on the local immune reaction in the CNS, the site of
inflammation in EAE. We have therefore studied the effect of
IVIg on cultured rat microglia, the main immune cell in the CNS.
IVIg increased
nitric oxide (NO) production in a dose-dependent manner in microglia stimulated with IFNgamma. The increase was only marginal in LPS-treated cells, and no effect was seen in untreated microglia or after stimulation with
TNFalpha or PMA. This enhancement of NO production depended on the Fc portion of
IVIg and could be abrogated by the pharmacological inhibition of Syk and
phosphatidylinositol 3-kinase, two
enzymes involved in the signalling cascade of
Fc receptors.
TNFalpha secretion was dose-dependently stimulated by
IVIg in both untreated microglia and after stimulation with LPS or IFNgamma. Again, this effect was mediated through the Fc portion. Finally, we showed that
Fc receptor-mediated phagocytosis was inhibited by
IVIg, presumably by blockade of the
Fc receptor. These different effects may protect oligodendrocytes from antibody mediated phagocytosis and on the other hand could terminate the immune reaction by induction of apoptosis in infiltrating T cells via NO and
TNFalpha. We propose that
IVIg, in addition to known effects on the peripheral immune system, may also modulate the local immune reaction in CNS inflammatory disease.