Rodriguez, Moses

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler’s virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2 q /SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T H 1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.

Stimulation of remyelination in multiple sclerosis lesions may be one possible therapeutic approach. However, since the pathology and pathogenesis of multiple sclerosis may be heterogeneous, it is important to analyze in what patients and at what stages of the disease such a therapy can be reasonable and feasible. Spontaneous remyelination is pronounced in some MS patients. The extent of remyelination correlates well with the presence of oligodendrocytes in the lesions. Yet, the source and origin of the remyelinating cells is still unclear. These may be derived from either undifferentiated progenitor cells or, in part from mature oligodendrocytes, that have escaped destruction during lesional activity. Complete remyelination of plaques is possible, leading to the formation of 'shadow plaques'. No reliable data are available at present on the frequency of remyelination in different forms of MS. However, most studies agree that remyelination is especially prominent at the early stages of the disease, whereas it is sparse after several years of disease duration. In addition, very little remyelination is found in cases of primary progressive MS.

Studies in both humans and experimental animals indicate that there is potential for full remyelination following CNS demyelination, but the factors that control the degree of myelin repair are unknown. In the Theiler's virus model of demyelination CNS remyelination can be promoted either by global immunosuppression or by selective immunoglobulin therapy. In this paper we discuss whether immunoglobulin-mediated remyelination is a characteristic of immune-mediated demyelination, or whether immunoglobulin-mediated remyelination also occurs in the toxic-traumatic model of lysolecithin-induced demyelination. Our data support the hypothesis that even in a non-primary immune model of demyelination, manipulating the immune system can be beneficial in myelin repair.

Studies in both human and experimental models demonstrate that myelin repair occurs in the central nervous system and is a normal physiologic response to myelin injury. However, remyelination in MS is often incomplete and limited. The outcome of an actively demyelinating lesion depends on the balance between factors promoting myelin destruction and myelin repair. Experimental models of CNS demyelination provide an opportunity to investigate the morphologic, cellular and molecular mechanisms involved in remyelination. This review focuses on experiments using the Theiler's virus model of demylination which indicate that manipulation of the immune response has the potential to promote endogenous CNS remyelination and functional recovery in MS.

Summary Natural antibodies are produced by B lymphocytes in the absence of external antigen stimulation. With their ability to recognize self, altered self and foreign antigens, they comprise an important first-line defence against invading pathogens, but are also important for tissue homeostasis. By recognizing oligosaccharides expressed on tumour cells and modified cell surface structures accompanying necrosis, natural antibodies have an important anti-tumorigenic function. IVIg contains a wide spectrum of specificities presented in normal plasma including natural antibodies and has been shown to exert inhibitory effects on tumour cells through a subfraction of anti-vascular endothelial growth factor immunoglobulin (Ig)G antibodies with anti-angiogenic properties. IgA antibodies also have potent immunomodulatory properties, being able to both induce and suppress immune responses. IgA-mediated inhibitory function is able to inhibit several inflammatory diseases including asthma and glomerulonephritis. Autoantibodies of the IgM type, on the other hand, have shown promising results in the treatment of multiple sclerosis. These autoantibodies promote remyelination rather than modulating inflammation. Oxidation-specific epitopes, as found in atherosclerotic lesions and on apoptotic cells, comprise one important target of natural antibodies. By recognizing these epitopes, natural antibodies neutralize proinflammatory responses and mediate atheroprotection.

ABSTRACTThe RNA-dependent RNA polymerase 3Dpolis required for the elongation of positive- and negative-stranded picornavirus RNA. During the course of investigating the effect of the transgenic expression of viral genes on the host immune response, we evaluated the viral load present in the host after infection. To our surprise, we found that 3D transgenic expression in genetically susceptible FVB mice led to substantially lower viral loads after infection with Theiler's murine encephalomyelitis virus (TMEV). As a result, spinal cord damage caused by chronic viral infection in the central nervous system was reduced in FVB mice that expressed 3D. This led to the preservation of large-diameter axons and motor function in these mice. The 3D transgene also lowered early viral loads when expressed in FVB-Dbmice resistant to persistent TMEV infection. The protective effect of 3D transgenic expression was not altered in FVB-Rag−/−.3D mice that are deficient in T and B cells, thus ruling out a mechanism by which the overexpression of 3D enhanced the adaptive immune clearance of the virus. Understanding how endogenously overexpressed 3D polymerase inhibits viral replication may lead to new strategies for targeting therapies to all picornaviruses.