The human monoclonal antibody rHIgM22 enhances remyelination following spinal cord demyelination in a virus-induced murine model of multiple sclerosis. Using three-dimensional T2-weighted in vivo spinal cord magnetic resonance imaging (MRI), we have therefore assessed the extent of spinal cord demyelination, before and after 5 weeks of treatment with rHIgM22, to determine whether antibody enhanced remyelination can be detected by MRI. A significant decrease was seen in T2 high signal lesion volume following antibody treatment. Histologic examination of the spinal cord tissue reveals that this decrease in lesion volume correlates with antibody promoted remyelination. To show that rHIgM22 enters the spinal cord and colocalizes with demyelinating lesions, we used ultrasmall superparamagnetic iron oxide particle (USPIO)-labeled antibodies. This may be considered as additional evidence to the hypothesis that rHIgM22 promotes remyelination by local effects in the lesions, likely by binding to CNS cells. The reduction in high signal T2-weighted lesion volume may be an important outcome measure in future clinical trials in humans.

We developed a novel MRI technique to image immune cell location and homing in vivo to the central nervous system (CNS). Superparamagnetic antibodies specific for cell surface markers allowed imaging of CD4+ T cells, CD8+ T cells, and Mac1+ cells in the CNS of mice infected with Theiler's murine encephalomyelitis virus (TMEV) and in mice with experimental autoimmune encephalomyelitis (EAE). Superparamagnetic antibodies have excellent T2, T2*, and good T1 relaxation properties, which makes them ideal MRI contrast materials. Immunohistochemistry of corresponding sections confirmed the specificity of the technique to detect immune cell types in the CNS. This powerful technique has potential to image any cell with unique surface antigens. Because superparamagnetic antibodies similar to those used in the study are approved for human use, the in vivo MRI technique we have described could be developed for human use.

A major area of investigation in neurovirology is directed toward understanding the factors that participate in neuronal viral clearance versus viral persistence. Clearance of virus from the infected central nervous system (CNS) is unique because of the intact blood-brain barrier, the relative absence of major histocompatibility complex (MHC) molecules on neuronal cells, and the lack of well-established lymphatic drainage. Nevertheless, once viruses replicate in the CNS, there is a vigorous immune response directed toward the clearance of virus antigen from infected cells. Antibody plays a critical role in neutralizing extracellular viral particles and also has been proposed to participate in the clearance of intracellular virus (4, 21). However, the manner in which antibody enters cells or interacts with surface cellular receptors to prevent viral persistence in neurons is not well understood.The classical way in which intracellular virus is eliminated is by cytotoxic T cells that are restricted by class I MHC. The control of MHC expression on neurons is dependent upon electrical activity (36). Neurons with normal electrical activity suppress MHC expression, whereas silent or injured neurons up-regulate class I MHC expression, an activity that makes them susceptible to class I MHC-mediated injury. Disruption of electrical activity induces class II MHC expression on microglia and astrocytes (36). Following virus infection in the CNS, class I MHC is rapidly up-regulated (1, 26) in neuronal cells. In particular, soluble factors such as alpha/beta interferon (IFN-␣/␤) (39) are required for the up-regulation of MHC in most CNS cells, including neurons. Cytotoxic T-cell responses in brain infiltrating mononuclear inflammatory cells have been demonstrated (23,24,25,28) and have been shown to participate in viral clearance. However, the consequences to the CNS are a "double-edged sword." Virus is cleared at the expense of the destruction of neurons that are not renewable and whose death results in permanent functional deficits. For example, cytotoxic T cells have been shown to transect neurites expressing class I MHC (31). Therefore, this vigorous cytotoxic response may participate directly in immune-mediated pathology.However, there are examples where viruses are cleared from the CNS without significant destruction of brain parenchyma (2). In these situations, the hypothesis proposed is that factors secreted by cytotoxic lymphocytes participate in viral clearance without cytotoxicity. Of the factors that are secreted by immune cells and that are thought to play a critical role in viral clearance, IFN-␥ has received the most attention (33). IFN-␥ is a 50-kDa N-glycosylated noncovalent homodimer composed of two identical 17-kDa polypeptides. It is produced by activated NK cells and T cells. IFN-␥ induces many immunomodulatory effects on CNS cells, including activation of macrophages, promotion of leukocyte adhesion to allow trafficking of cells to the * Corresponding author. Mailing address:

We evaluated the role of interleukin-6 (IL-6) in neuronal injury after CNS infection. IL-6-/- and IL-6+/+ mice of resistant major histocompatibility complex (MHC) H-2b haplotype intracerebrally infected with Theiler's virus cleared the infection normally without development of viral persistence, lethal neuronal infection, or late phase demyelination. In contrast, infection of IL-6-/- mice on a susceptible H-2q haplotype resulted in frequent deaths and severe neurologic deficits within 2 weeks of infection as compared with infected IL-6+/+ H-2q littermate controls. Morphologic analysis demonstrated dramatic injury to anterior horn neurons of IL-6-/- H-2q mice at 12 d after infection. Infectious viral titers in the CNS (brain and spinal cord combined) were equivalent between IL-6-/- H-2q and IL-6+/+ H-2q mice. In contrast, more viral RNA was detected in the spinal cord of IL-6-/- mice compared with IL-6+/+ H-2q mice. Virus antigen was localized predominantly to anterior horn cells in infected IL-6-/- H-2q mice. IL-6 deletion did not affect the humoral response directed against virus, nor did it affect the expression of CD4, CD8, MHC class I, or MHC class II in the CNS. Importantly, IL-6 was expressed by astrocytes of infected IL-6+/+ mice but not in astrocytes of IL-6-/- mice or uninfected IL-6+/+ mice. Furthermore, expression of various chemokines was robust at 12 d after infection in both H-2b and H-2q IL-6-/- mice, indicating that intrinsic CNS inflammatory responses did not depend on the presence of IL-6. Finally, in vitro analysis of virus-induced death in neuroblastoma-spinal cord-34 motor neurons and primary anterior horn cell neurons showed that IL-6 exerted a neuroprotective effect. These data support the hypothesis that IL-6 plays a critical role in protecting specific populations of neurons from irreversible injury.

The authors studied the MRI findings of three patients with Möbius syndrome. Möbius syndrome is a rare congenital disorder characterized by complete or partial facial diplegia accompanied by other cranial nerve palsies. MRI demonstrated brainstem hypoplasia with straightening of the fourth ventricle floor, indicating an absence of the facial colliculus. These MRI features suggest the diagnosis of Möbius syndrome and correlate with the clinical and neurophysiologic findings.