A switch in pathogenic mechanism in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in IFN-γ-inducible lysosomal thiol reductase-free mice.

IFN-γ-inducible lysosomal thiol reductase (GILT) is an enzyme located in the Lamp-2-positive compartments of APC. GILT(-/-) mice are phenotypically normal, but their T cells exhibit reduced proliferation to several exogenously administered Ags that include cysteine residues and disulfide bonds. We undertook the present studies to determine if GILT(-/-) mice would process exogenously administered myelin oligodendrocyte glycoprotein (MOG), which contains disulfide bonds, to generate experimental autoimmune encephalomyelitis (EAE) to the endogenous protein.

Microglial Fc receptors mediate physiological changes resulting from antibody cross-linking of myelin oligodendrocyte glycoprotein.

Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been implicated in Multiple Sclerosis demyelination through activation of complement and/or macrophage-effector processes. We presented a novel mechanism, whereby MOG on oligodendrocytes, when cross-linked with anti-MOG and secondary antibody resulted in its repartitioning into lipid rafts, and changes in protein phosphorylation and morphology. Here, we show that similar events occur when anti-MOG is cross-linked with Fc receptors (FcRs) present on microglia but not with complement.

Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology.

Antibodies to myelin components are routinely detected in multiple sclerosis patients. However, their presence in some control subjects has made it difficult to determine their contribution to disease pathogenesis. Immunization of C57BL/6 mice with either rat or human myelin oligodendrocyte glycoprotein (MOG) leads to experimental autoimmune encephalomyelitis (EAE) and comparable titers of anti-MOG antibodies as detected by ELISA.

Signaling cascades activated upon antibody cross-linking of myelin oligodendrocyte glycoprotein: potential implications for multiple sclerosis.

Antibody-induced demyelination is an important component of pathology in multiple sclerosis. In particular, antibodies to myelin oligodendrocyte glycoprotein (MOG) are elevated in multiple sclerosis patients, and they have been implicated as mediators of demyelination. We have shown previously that antibody cross-linking of MOG in oligodendrocytes results in the repartitioning of MOG into glycosphingolipid-cholesterol membrane microdomains ("lipid rafts"), followed by changes in the phosphorylation of specific proteins, including dephosphorylation of beta-tubulin and the beta subunit of the trimeric G protein and culminating in rapid and dramatic morphological alterations.

Proteomic mapping provides powerful insights into functional myelin biology.

Myelin is a dynamic, functionally active membrane necessary for rapid action potential conduction, axon survival, and cytoarchitecture. The number of debilitating neurological disorders that occur when myelin is disrupted emphasizes its importance. Using high-resolution 2D gel electrophoresis, mass spectrometry, and immunoblotting, we have developed an extensive proteomic map of proteins present in myelin, identifying 98 proteins corresponding to at least 130 of the approximately 200 spots on the map.

Morphological changes of myelin sheaths in rats intracranially injected with apotransferrin.

Previous findings from our laboratories indicate that the intracranial injection of apotransferrin (aTf) in neonatal rats produces an accelerated oligodendrocyte maturation and an enhanced production and deposition of myelin membranes in the brain. To evaluate the anatomical distribution and the morphological characteristics of the myelin in these rats, we analyzed the optic nerves, cerebellum, and selected areas of brain sections from aTf-treated and control rats by both light and electron microscopy. Microscopic identification of myelin using a specific staining procedure, showed that in aTf-injected rats, in coincidence with previous biochemical studies, there was an increased deposition of myelin in selected areas of the nervous system.

Molecular mechanisms involved in the actions of apotransferrin upon the central nervous system: Role of the cytoskeleton and of second messengers.

Apotransferrin (aTf), intracranially administered into newborn rats, produces increased myelination with marked increases in the levels of myelin basic protein (MBP), phospholipids and galactolipids, and mRNAs of MBP and 2', 3' cyclic nucleotide 3'-phosphohydrolase (CNPase). Cytoskeletal proteins such as tubulin, actin, and microtubule-associated proteins are also increased after aTf injection. In contrast, almost no changes are observed in myelin proteolipid protein (PLP) or in its mRNA or cholesterol.

Apotransferrin decreases migration and enhances differentiation of oligodendroglial progenitor cells in an in vitro system.

We have previously shown that a single intracranial injection of apotransferrin (aTf) in neonatal rats produces an accelerated mylinogenesis and increases the expression of certain myelin proteins such as myelin basic protein (MBP). In the present work, we studied the effects of aTf upon oligodendrocyte progenitor cell (Opc) cultures. In the presence of aTf, cells developed a multipolar morphology and showed an increased expression of O(4), MBP, O(1) and myelin-associated glycoprotein compared to controls.