Subject(s)
Autoantibodies/cerebrospinal fluid , Kleine-Levin Syndrome/diagnosis , Receptors, N-Methyl-D-Aspartate/immunology , Adolescent , Antimanic Agents/therapeutic use , Electroencephalography/methods , Humans , Kleine-Levin Syndrome/cerebrospinal fluid , Kleine-Levin Syndrome/drug therapy , Kleine-Levin Syndrome/immunology , Limbic Encephalitis/cerebrospinal fluid , Limbic Encephalitis/diagnosis , Lithium Carbonate/therapeutic use , Male , Receptors, Glutamate/immunology , Receptors, N-Methyl-D-Aspartate/analysis , Treatment OutcomeABSTRACT
CC chemokine ligand 2 (CCL2)/monocyte chemotactic protein-1, a member of the CC chemokine family, is a chemoattractant for monocytes and T cells through interaction with its receptor CCR2. In the present study, we examined a T helper cell type 1 (Th1)-dependent disease, proteolipid protein-induced experimental autoimmune encephalomyelitis, in a transgenic mouse line that constitutively expressed low levels of CCL2 in the central nervous system (CNS) under control of the astrocyte-specific glial fibrillary acidic protein promoter. CCL2 transgenic mice developed significantly milder clinical disease than littermate controls. As determined by flow cytometry, mononuclear cell infiltrates in the CNS tissues of CCL2 transgenic and littermate-control mice contained equal numbers of CD4+ and CD8+ T cells, and the CCL2 transgenic mice showed an enhanced number of CNS-infiltrating monocytes. CNS antigen-specific T cells from CCL2 transgenic mice produced markedly less interferon-gamma. Overexpression of CCL2 in the CNS resulted in decreased interleukin-12 receptor expression by antigen-specific T cells. Collectively, these results indicate that sustained, tissue-specific expression of CCL2 in vivo down-regulates the Th1 autoimmune response, culminating in milder clinical disease.
Subject(s)
Central Nervous System/immunology , Chemokine CCL2/genetics , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Animals , Central Nervous System/metabolism , Chemokine CCL2/biosynthesis , Chemokine CCL2/immunology , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/immunology , Gene Expression Regulation/immunology , Mice , Mice, Transgenic , Myelin Proteolipid Protein/chemistry , Myelin Proteolipid Protein/immunology , Peptide Fragments/chemistry , Peptide Fragments/immunology , RNA, Messenger/genetics , RNA, Messenger/immunology , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
CCL2 is a member of the CC chemokine family that mediates the migration and recruitment of monocytes and T cells and has been identified in the central nervous system (CNS) during several neuroinflammatory diseases. In order to examine the biological effect of constitutive CCL2 expression in the CNS, the authors engineered a mouse that expressed CCL2 in the CNS under control of the human glial fibrillary acidic protein (hGFAP) promoter. The results demonstrated that transgenic expression of CCL2 in the CNS resulted in diffuse CNS monocyte infiltration and accumulation. Transgenic CCL2 expression did not alter normal development, differentiation, or function of T cells. There was no evidence of overt CNS disease or other pathologic phenotype when mice were left unchallenged with antigen or uninfected. However, when CCL2 transgenic mice were given a peripheral challenge of lipopolysaccharide (LPS), an inflammatory infiltrate with organized perivascular lesions developed. Infection of the transgenic mice with Theiler's murine encephalomyelitis virus (TMEV) resulted in accelerated onset and increased severity of clinical and histological disease. These results suggest that CCL2 expression in the CNS is a major pathogenic factor that drives macrophage accumulation in the development of CNS inflammatory disease.
