title: Polyclonal immunoglobulins (IVIg) modulate nitric oxide production and microglial functions in vitro via Fc receptors.
abstract: 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.
authors: Department of Neurology, Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. mstangel@zedat.fu-berlin.de
authors: M
authors: M
authors: Stangel
authors: A
authors: A
authors: Compston
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D010587:Phagocytosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011961:Receptors, Fc / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016756:Immunoglobulins, Intravenous; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma