Azetidine-2-Carboxylic Acid-Induced Oligodendrogliopathy: Relevance to the Pathogenesis of Multiple Sclerosis.

The naturally occurring imino acid azetidine-2-carboxylic acid (Aze) is consumed by humans and can be misincorporated in place of proline in myelin basic protein (MBP) in vitro. To determine Aze effects on the mammalian CNS in vivo, adult CD1 mice were given Aze orally or intraperitoneally. Clinical signs reminiscent of MBP-mutant mice occurred with 600 mg/kg Aze exposure.

Anti-Myelin Proteolipid Protein Peptide Monoclonal Antibodies Recognize Cell Surface Proteins on Developing Neurons and Inhibit Their Differentiation.

Using a panel of monoclonal antibodies (mAbs) to myelin proteolipid protein (PLP) peptides, we found that in addition to CNS myelin, mAbs to external face but not cytoplasmic face epitopes immunostained neurons in immature human CNS tissues and in adult hippocampal dentate gyrus and olfactory bulbs, that is neural stem cell niches (NSCN). To explore the pathobiological significance of these observations, we assessed the mAb effects on neurodifferentiation in vitro. The mAbs to PLP 50-69 (IgG1κ and IgG2aκ), and 178-191 and 200-219 (both IgG1κ) immunostained live cell surfaces and inhibited neurite outgrowth of E18 rat hippocampal precursor cells and of PC12 cells, which do not express PLP.

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species.

Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf). It is an evolutionarily conserved polytopic integral membrane protein and a potential autoantigen in multiple sclerosis (MS). To analyze antibody recognition of PLP epitopes in situ, monoclonal antibodies (mAbs) specific for different regions of human PLP (50-69, 100-123, 139-151, 178-191, 200-219, 264-276) were generated and used to immunostain CNS tissues of representative vertebrates.

Interferon-beta counteracts inflammatory mediator-induced effects on brain endothelial cell tight junction molecules-implications for multiple sclerosis.

To elucidate mechanisms of endothelial cell (EC) dysfunction in CNS inflammatory responses and beneficial effects of interferon-beta (IFN-gamma) in multiple sclerosis (MS), we analyzed effects of individual and combinations of soluble inflammatory mediators on the intracellular localization of the EC tight junction-associated molecules zonula occludens-1 and -2 (ZO-1 and ZO-2) in human brain ECs. The cytoplasm in the majority of cells in control EC cultures was clear; ZO-1 and ZO-2 were localized peripherally near sites of cell contact and associated with submembranous cytoplasmic filaments. H2O2 induced reversible time- and concentration-dependent translocation of ZO-1 and ZO-2 to a random distribution within EC cytoplasm and retraction of EC borders.

Endothelial cell class II major histocompatibility complex molecule expression in stereotactic brain biopsies of patients with acute inflammatory/demyelinating conditions.

To determine if central nervous system (CNS) microvessel endothelial cells express class II major histocompatibility complex (MHC) molecules in early demyelinating lesions in humans, cerebral white matter (WM) biopsies from patients with acute inflammatory/demyelinating conditions, including 4 with multiple sclerosis (MS), were immunostained for class II MHC and other antigens. Eight of 9 biopsies showed focal MHC class II-positive endothelial cells; there were none in the CNS of 1 of the MS patients at autopsy. There were more vessels with class II-positive endothelial cells in areas with intact WM and gliosis than in areas with active demyelination or control WM; class II-positive endothelial cells in small venules and capillaries were adjacent to transmigrating and perivascular CD4-positive cells.