Chemokines direct tissue invasion by specific leukocyte populations. Thus, chemokines may play a role in multiple sclerosis (MS), an idiopathic disorder in which the central nervous system (CNS) inflammatory reaction is largely restricted to mononuclear phagocytes and T cells. We asked whether specific chemokines were expressed in the CNS during acute demyelinating events by analyzing cerebrospinal fluid (CSF), whose composition reflects the CNS extracellular space. During MS attacks, we found elevated CSF levels of three chemokines that act toward T cells and mononuclear phagocytes: interferon-γ-inducible protein of 10 kDa (IP-10); monokine induced by interferon-γ (Mig); and regulated on activation, normal T-cell expressed and secreted (RANTES). We then investigated whether specific chemokine receptors were expressed by infiltrating cells in demyelinating MS brain lesions and in CSF. CXCR3, an IP-10/Mig receptor, was expressed on lymphocytic cells in virtually every perivascular inflammatory infiltrate in active MS lesions. CCR5, a RANTES receptor, was detected on lymphocytic cells, macrophages, and microglia in actively demyelinating MS brain lesions. Compared with circulating T cells, CSF T cells were significantly enriched for cells expressing CXCR3 or CCR5. Our results imply pathogenic roles for specific chemokine-chemokine receptor interactions in MS and suggest new molecular targets for therapeutic intervention.

IntroductionOxidized LDL is present in human atherosclerotic lesions, but the mechanisms responsible for oxidation in In the last decade strong evidence has accumulated supporting the concept that oxidative processes, acting on the lipids and proteins of LDL in the vessel wall, participate in the progression of atherosclerotic disease ( 1-4). Evidence from in situ studies has demonstrated that oxidized LDL, macrophages, and 15-lipoxygenase colocalize within human atherosclerotic lesions (5). We therefore chose to determine whether 15-lipoxygenase was acting upon the available lipid substrate within the lesions to cause its oxidation in vivo.Early studies by Hamberg and Samuelsson (6) demonstrated that the oxidation of polyunsaturated fatty acids PUFAs'by soybean 15-lipoxygenase was stereospecific. Kuhn et al. (7) later developed a convenient chiral phase HPLC method and used it to analyze the PUFA oxidation products from a variety of lipoxygenase enzymes, confirming that stereospecificity was a fingerprint of lipoxygenase activity. These investigators found that mammalian lipoxygenase enzymes also specifically produce the S enantiomer at the target positions of oxidation on their PUFA substrates (7). In contrast, nonenzymatic PUFA oxidation results in products positionally the same as those catalyzed by lipoxygenases but with equal quantities of both stereoisomers (R and S) at all positions of oxidation. We have recently shown that esterified, oxidized linoleate is the major oxidized PUFA in monocyte-oxidized LDL (8). Esterified, oxidized PUFA products, predominantly from linoleate, have previously been reported to be present in lesions of atherosclerosis (9-14). Kuhn et al. (14) have analyzed the oxidized PUFA products in atherosclerotic lesions using chiral phase HPLC and have recently reported detection of stereospecific oxidation in a rabbit model of the disease. Herein we report the results of our analysis of the chirality of the oxidation products in human lesions, to determine whether PUFA oxidation is catalyzed by a lipoxygenase. The quantity of cholesteryl linoleate and its oxidation products in aortae have been shown to increase with progression of vascular disease (9,10,13,15

Background: We introduce the Basic Immune Simulator (BIS), an agent-based model created to study the interactions between the cells of the innate and adaptive immune system. Innate immunity, the initial host response to a pathogen, generally precedes adaptive immunity, which generates immune memory for an antigen. The BIS simulates basic cell types, mediators and antibodies, and consists of three virtual spaces representing parenchymal tissue, secondary lymphoid tissue and the lymphatic/humoral circulation. The BIS includes a Graphical User Interface (GUI) to facilitate its use as an educational and research tool.

We have characterized the immune system involvement in the disease processes of idiopathic pulmonary fibrosis in novel ways. To do so, we analyzed lung tissue from 21 cases of idiopathic pulmonary fibrosis and 21 (non-fibrotic, non-cancerous) controls for immune cell and inflammation-related markers. The immunohistochemical analysis of the tissue was grouped by patterns of severity in disease pathology. There were significantly greater numbers of CD68+ and CD80+ cells, and significantly fewer CD3+, CD4+, and CD45RO+ cells in areas of relatively (histologically) normal lung in biopsies from idiopathic pulmonary fibrosis patients compared to controls. In zones of active disease, characterized by epithelial cell regeneration and fibrosis, there were significantly more cells expressing CD4, CD8, CD20, CD68, CD80, CCR6, S100, IL-17, tumor necrosis factor-α, and retinoic acid-related orphan receptors compared to histologically normal lung areas from idiopathic pulmonary fibrosis patients. Inflammation was implicated in these active regions by the cells that expressed retinoid orphan receptor-α, -β, and -γ, CCR6, and IL-17. The regenerating epithelial cells predominantly expressed these pro-inflammatory molecules, as evidenced by co-expression analyses with epithelial cytokeratins. Macrophages in pseudo-alveoli and CD3+ T cells in the fibrotic interstitium also expressed IL-17. Co-expression of IL-17 with retinoid orphan receptors, and epithelial cytoskeletal proteins, CD68, and CD3 in epithelial cells, macrophages, and T-cells, respectively, confirmed the production of IL-17 by these cell types. There was little staining for Foxp3, CD56, or CD34 in any idiopathic pulmonary fibrosis lung regions. The fibrotic regions had fewer immune cells overall. In summary, our study shows participation of innate and adaptive mononuclear cells in active-disease regions of idiopathic pulmonary fibrosis lung, where the regenerating epithelial cells appear to propagate inflammation. The regenerative mechanisms become skewed to ultimately result in lethal, fibrotic restriction of lung function.