OVA-immunized wild type (e,h) and Fc/ (f,i) mice received a unilateral injection of OVA into the striatum and tissue was analysed for CD3 (d,e,f) or CD11b (g,h,i) immunoreactivity at 7days. parenchyma and SKF-86002 indirectly induce neuronal tissue damage through recruitment and activation of microglia via Fc receptors. These observations may have important implications for the development of therapeutic antibodies directed against neuronal antigens used for therapeutic intervention in neurological diseases. Keywords:Fc receptor, Antibody, Immunotherapy, Microglial activation == Introduction == An inevitable consequence of an ageing population is an increased incidence of neurodegeneratative diseases, such as Alzheimers disease, Parkinsons disease and age-related macular degeneration. Recent experimental and clinical studies have provided evidence for both innate and adaptive immune activation in the pathogenesis of these debilitating disorders. For example, microglia activation is typically associated with any neuropathology and there is increasing evidence that (auto)-antibodies against brain-reactive antigens are associated with clinical symptoms [11,28]. Genome wide association studies (GWAS) in AD [21] and AMD [35] provide further evidence for the involvement of the immune system in disease pathogenesis. The young and healthy CNS is an immune privileged site where immune surveillance and inflammation is usually tightly regulated [4,15]. The presence of an intact bloodbrain barrier (BBB) combined with the unique microenvironment of the brain, ensures that the reactions to an inflammatory challenge, such as endotoxin (LPS) or cytokines, are attenuated [30]. We and others have shown that this healthy CNS parenchyma is able to modify leucocyte responses to acute injury [2,3], but it is usually less clear if, and how, the brain controls antibody-mediated responses, and whether these responses are altered under neuroinflammatory conditions or age-related pathology. Antibodies may mediate tissue damage when they form immune complexes and recruit cytotoxic effector cells, such as macrophages via their Fc receptors (FcRs) or by activating complement [34]. The conversation with FcRs stimulates cell signalling in the effector cell that ultimately results in phagocytosis and/or release of inflammatory or cytotoxic mediators. These responses are well described in peripheral tissues, using the (reversed) Arthus reaction, a well accepted experimental model of antibody-mediated inflammation [10]. In the presence of an intact BBB, IgG is only present in the healthy brain at very low levels relative to plasma levels [32] and the effector cells, such as microglia and perivascular macrophages, express detectable but low levels of FcRs [31]. However, expression of SKF-86002 FcRs is usually enhanced on microglia following treatment with IFN-, TNF- and LPS in vitro [26], after intracerebral injection of LPS [17] and, as we have recently shown, during experimental chronic neurodegeneration [27]. Despite these observations we have limited knowledge of the consequences of immune complex formation in the CNS, the associated inflammatory response and the function of the different FcRs in the CNS. The growing incidence of neurodegenerative conditions in the human population, and the interest in the use of antibody-based immunotherapy to treat these diseases, IFITM1 highlights the need to understand the possible consequences of antibody-mediated inflammation in the CNS parenchyma. Davidoff et al. [12] were the first to describe antibody-mediated inflammation in the brain and showed that this Arthus reaction in the rabbit brain resembled that seen in the skin and other peripheral tissues. However, it is likely that the relatively crude SKF-86002 techniques used in this study significantly disturbed the unique vasculature and microenvironment of the brain making it difficult to interpret the results. More recently, Lister and Hickey [25] reported that immune complexes can be formed in the microvasculature of the brain, resulting in complement activation, increased microvascular permeability and leucocyte adhesion. However, this study was restricted to the role of immune complexes in the meningeal compartment and not in the brain parenchyma. The aim SKF-86002 of the current study was to investigate the acute and long-term consequences of immune complex formation in the brain parenchyma, using a model antigen widely used in the study of peripheral antibody-mediated responses. We show that immune complex formation in the brain parenchyma results in neuroinflammatory and behavioural changes that depend on FcR interactions. Apart from further understanding of antibody-mediated responses in the brain in general,.