Multiple Sclerosis Current Status and Strategies for the Future (2001) / Chapter Skim
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2 Clinical and Biological Features
2 Clinical and Biological Features
Pages 29-114
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From page 29... ...
by only about 10-15 years, and about half of the patients survive 30 years or more from onset.~° THE CLINICAL PICTURE: SYMPTOMS, DISEASE COURSE, VARIATION, AND DIAGNOSIS Disease Activity and Progression MS, as defined by ongoing central nervous system (CNS) lesion formation and increasing cumulative damage, is now recognized as a disease that is active in most patients most of the time.
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From page 30... ...
Natural history studies of untreated relapsing MS indicate 50% of patients will be secondary progressive at 10 years and almost 90% by 25 years. This form of MS shows a lower rate of inflammatory lesion activity than relapsing MS, yet the total burden of disease continues to increase.
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From page 31... ...
Clinical disease activity and progression are judged by observation and necrologic examination. Subclinical components refer to pathological changes that are not observable in a clinical examination but are observed using a variety of laboratory tests, predominantly neuroimaging parameters.
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From page 32... ...
Relapses also occur in patients with progressive relapsing disease and in a number of patients with secondary progressive disease. The only clinical disease subtype in which relapses never occur is primary progressive MS.
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From page 33... ...
They reflect a temporary disruption in nerve conduction, rather than the formation of a new lesion. Approximately 85 percent of MS patients begin with relapsing-remitting disease.222 MS relapses can involve a single neural system, as in optic neuritis, or several anatomically distinct systems at the same time, for example, combined motor and sensory problems.
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From page 34... ...
In the second form, 10 percent have either primary progressive MS and never experience acute disease attacks or progressive relapsing MS (5 percent) , and have occasional subsequent attacks.
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Changes in normal-appearing brain tissue are generally pronounced in MS patients with severe impairment. As a group, secondary progressive MS patients show more abnormalities in normal white matter and brain tissue than relapsing patients.
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From page 36... ...
Disease Markers At the present time, neuroimaging provides the best assessment of disease activity in MS (Box 2.1, Figure 2.31. Ne maim aging A bn arm alities A number of neuroimaging techniques can measure distinct pathologic changes and thereby provide markers for different aspects of the MS disease
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From page 37... ...
(A) An MRI image shows multiple ovoid and confluent hyperintense lesions in the white matter surrounding the ventricles (the ventricles appear in the center of this image as a dark butterfly shape; they are the spaces through which cerebrospinal fluid [CSF]
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From page 38... ...
Correlates with disability. Atrophy is detectable in both brain and spinal cord of MS patients.
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From page 39... ...
Reduced NAA is found not only within MS lesions but also in the normal-appearing white matter of relapsing-remitting, secondary progressive, and primary progressive MS patients. The reduction in NAA is more severe in secondary progressive MS than in relapsing MS.
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From page 40... ...
Lower MTR values occur with disease worsening in relapsing, secondary progressive, and primary progressive MS patients and even in patients with clinically isolated MS syndromes. In primary progressive patients who have a relatively small T2 burden of disease, MTR is significantly reduced, suggesting that axon damage is significantly greater in this clinical subtype.
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From page 41... ...
Cerebrospinal Fluicl Cerebrospinal fluid (CSF) is the fluid that circulates around and within the brain and spinal cord.
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From page 42... ...
Urine disease markers have included myelin basic protein-like material, free light chains, neopterin, gliotoxin, and neuron-specific enolase. Mucosal fluid cells and immunoglobulins have also been studied.
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From page 43... ...
The results of that meeting, however, were not available at the time of this writing. The failure of the Poser criteria to incorporate primary progressive MS has recently been addressed by revised criteria that define definite, probable, and possible levels of diagnostic certainty.209 These criteria are based on clinical findings, CSF abnormalities, brain and spinal cord MRI abnormalities, and evoked potentials.
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From page 44... ...
(IgG, IgM) T cells White blood cells responsible for cell-mediated immune responses to antigens, including viral infections.
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From page 45... ...
Neural cell A modulator of axon outgrowth and cell adhesion that adapts its adhesion structure to requirements during development by alternative splicing and posttranslational modifications Ciliary neurotrophic factor (CNTF) CNTF appears to promote remyelination, as well as formation of oligodendroctyes.
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From page 46... ...
TABLE 2.7 MRI Criteria for Definite MS Paty et al.l63 · Four or more white matter lesions · Lesions >6 mm in diameter · Presence of at least one lesion in the periventricular region adjacent to the body of the lateral ventrical, corpus callosum, or infratentorial · Ovoid lesions or oval-shaped lesions near the lateral ventricles with the long axis of the lesion 90 degrees to the plane of the lateral ventricle Barkhof et al.l4 . At least one gadolinium-enhancing lesion Juxtacortical location (at least one lesion)
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From page 47... ...
, spinal cord, wrists or and the knees thalamus, and knees (peroneal sensory cortex nerve) The use of evoked potentials as a diagnostic tool has greatly declined since the advent of the MRI, which provides a more comprehensive picture of disease activity.
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For example, Theiler's murine encephalomyelitis virus, the demyelinating disease that afflicts mice, is mainly a spinal cord disease. There is an apparent overrepresentation of specific phenotypes in certain geographic regions.
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From page 49... ...
s.c. three times decreased white blood cells, elevated liver a week enzymes T-CELL THERAPIES Glatiramer acetate 20 mg s.c.
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In both studies, early treatment with a diseasemodifying agent significantly delayed onset of a second clinical attack over the two-year study period. Patients who received treatment also showed significantly less MRI disease activity over the next two years.
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From page 51... ...
The European study, which showed a treatment effect on progression in contrast to the two negative studies, included secondary progressive patients who had a shorter disease duration, were still experiencing relapses, and had contrastenhancing brain MRI lesions. Considered as a whole, these studies suggest that in the earlier stages of MS, when there is still a significant inflammatory component (reflected in clinical relapses and gadolinium-enhancing lesion activity)
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From page 52... ...
The most common side effect of glatiramer acetate is irritation at the injection site, although it is typically mild. The most common side effects of beta-interferon are flu-like symptoms, and these usually resolve after three to six months.
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From page 53... ...
The estimated costs of beta-interferon treatment per gain in QALY for relapsing-remitting MS range from 809,000 British pounds ($1,140,000 U.S. to 2,038,400 British pounds ($2,870,000 U.S.~.~52 The estimates are considerably lower in Canada (406,000 to 490,000 Canadian dollars, or $270,000-$330,000 U.S.~.~59 For secondary progressive MS, the estimated costs of beta-interferon treatment per gain in QALY range from 874,600 British pounds ($1,230,000 U.S.~52 to 1,024,000 British pounds ($1,440,000 U.S.~.73 While disease-related expenditures are relatively easy to calculate, the benefits of these expenditures are not so easy to calculate, particu
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From page 54... ...
that are carried to other neurons via axons, the cable-like fibers that extend from neuron cell bodies. Many axons within the brain and spinal cord are myelinated.
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From page 55... ...
The internodal axon is normally surrounded by myelin sheaths whose thicknesses are related to the caliber of the ensheathed axon.2~9 In FIGURE 2.4 Oligodendrocyte making myelin. The processes of a given oligodendrocyte wrap themselves around portions of the surrounding axons.
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From page 56... ...
are uncovered. Myelinatecl Axons Exhibit Complex Molecular Architecture Prior to the last decade, axonal dysfunction in demyelinating diseases was considered to be due entirely to the loss of the myelin insulation.
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From page 57... ...
Potassium channels, on the other hand, tend to be located in the internodal parts of the axon membrane, beneath the myelin sheath; as a result of this, they are masked by the FIGURE 2.5 Pathogenesis. Current concept of pathogenesis of neurological dysfunction associated with acute multiple sclerosis lesion in relapsing-remitting MS patient.
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From page 58... ...
It is now clear that demyelinated axons possess a remarkable capability to rebuild themselves at the molecular level. In the weeks following demyelination, demyelinated axons acquire, within regions where myelin has been lost, a density of sodium channels that is high enough to support action potential conduction even in the absence of insulating myelin.
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From page 59... ...
According to this schema, axonal transection during (A) is a consistent feature of inflammatory demyelinating lesions.
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A plaque is characterized by loss of myelin sheath and infiltration by macrophages (which show myelin basic protein and myelin-associated glycoprotein immunoreactivities)
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From page 61... ...
Possible mechanisms include a direct toxic effect of tumor necrosis factor (TNF) on myelin (upper panel)
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From page 62... ...
Axonal damage might be a pathological correlate of irreversible neurological deficits that occur in patients with progressive MS.5~2~22~3220 In individuals with chronic MS, plaques are often sharply demarcated with scattered lipid-containing macrophages and little evidence of ongoing myelin destruction. Demyelination can be incomplete.
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From page 63... ...
CLINICAL AND BIOLOGICAL FEATURES 63 FIGURE 2. X The blood-brain barrier.
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From page 64... ...
Finally, although gliosis is generally considered harmful, there is also evidence that the gliotic ensheathment of demyelinated axons might favor the restoration of nerve conduction.22i
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From page 65... ...
Some of the lessons from studies of the repair of spinal cord injury are likely to be relevant here. i33 Moreover, because abnormal patterns of ion channels have been found within neurons whose axons are undergoing demyelination,22 it will be important to understand the factors that influence the regulation of these channels.2~9 These lines of research, involving strategies that protect axons from degeneration or promote repair,8i i33 and those agents that can restore conduction in demyelinated axons represent opportunities to restore functions and could have significant implications for therapy.2~9 Similarly, future therapeutic approaches might involve replacement of oligodendroglia with pluripotent stem cells (discussed further in Chapter 6~.
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From page 68... ...
When T and B lymphocytes are activated by a specific antigen, they undergo proliferation, producing more cells with their same antigen specificity. This serves to amplify the immune response against the foreign antigen.
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From page 69... ...
Rasmussen's Epileptic seizures and encephalitis neurological dysfunction Immune response against topoisomerase I leads to increased formation of collagen in the skin and internal organs Destruction of thyroid cells Demyelination of peripheral nerve fibers Muscle weakness Demyelination and/or axonal degeneration of peripheral nerve fibers Antibodies against presynaptic calcium channel of the neuromuscular junction (NMJ) disrupt function Antibodies against postsynaptic acetylcholine receptor of the NMJ disrupt function Muscular twitching, cramps, Antibodies against potassium channel at the stiffness, and weakness NMJ cause increased muscle activity Antibodies against subunit of ionotropic glutamate receptor lead to degeneration of one cerebral hemisphere Stiff man Axial and limb rigidity; Antibodies block production of GAB A syndrome spasms (~-aminobutyric acid)
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From page 70... ...
NOTE: MBP = myelin basic protein. SOURCE: Steinman and Oldstone, 1997.2°6 Reprinted with permission.
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From page 71... ...
First, elevations in certain types of autoreactive T cells were not unique to MS patients. Second, and more critically, T cells were necessary but not sufficient to cause demyelinating disease in animal models.
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From page 72... ...
Clinical studies were shaped by research on experimental allergic encephalomyelitis (EAE) , the classic animal model of demyelinating disease.
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From page 73... ...
It is also important to investigate whether different subtypes of MS, which are distinguished by divergent clinical, genetic, and morphological features, are associated with enhanced T-cell responses against different target autoantigens.~27 Thus far, research has spotlighted one class of T cells those with a TCR termed odd.* ocp T cells are the major class of immune cells centrally involved in adaptive immune responses against infections and tumors.
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From page 74... ...
The increased immunoglobulin is due to production by only a few different clones of B cells that have been induced to proliferate. B cells from the CSF of MS patients have been reported to contain mutations in the DNA sequences that encode antibodies, which is consistent with the notion of an antigen-driven selection of antibodies with high-affinity antigen-binding sites.~70 Such events are commonly observed in immune responses against foreign antigens such as bacterial infections, as well as in humoral autoimmune responses.~7i However, no foreign antigen or autoantigen responsible for the generation of oligoclonal bands in MS has yet been identified.
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From page 75... ...
Much of our present understanding of cytokine action in demyelinating disease comes from studies of animal models, including EAE. A large body of research is being compiled on the expression and possible function of cytokines as pro- and anti-inflammatory mediators in MS.
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Local glial cells can be stimulated by proinflammatory cytokines to express immunologically active molecules, such as the major histocompatability complex (MHC) products, cytokines, and chemokines required for local immune responses.
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From page 77... ...
As in other autoimmune diseases, women are much more likely to get MS than men, suggesting that hormonal or genetic factors are involved. The ratio of women to men with MS is about 2:1.57 Among both sexes, the age of onset for
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From page 78... ...
The ratio of males to females with primary progressive MS is approximately 1:1. Epidemiological studies have provided conflicting data as to whether an infectious agent (viral or bacterial)
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From page 79... ...
Researchers continue to look for causative infectious agents. 83 (See section below on infectious causes of MS for further discussion.)
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From page 80... ...
In addition to MS, similar issues are present in other autoimmune diseases such as diabetes mellitus that are genetically complex, and common research tools will be needed to decipher specific disease genes in these different conditions. Major Histocompatibility Complex.
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From page 82... ...
Another locus on chromosome l9q22 near apolipoprotein C1 has been linked to MS in several genomic screens, but the estimated ~s is only 1.4. A polymorphism near the gene for myelin basic protein on chromosome 21 was reported to be linked to MS in a family from Finland, but not in other populations.
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From page 83... ...
In contrast, a more restricted form of MS in which optic nerve and/or spinal cord involvement predominate ("Asian MS") is not associated with DR2.
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From page 84... ...
Animal diseases that resemble MS are discussed under animal models. CNS demyelinating diseases include those mediated by immune responses, infection, and toxins, as well as inherited disorders.
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From page 85... ...
PML is caused by the JC virus, which infects and destroys oligodendrocytes with minimal associated immune response. It typically occurs in immunosuppressed or immunocompromised individuals and is common in AIDS.
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From page 86... ...
Immune system disturbances, which are known to occur following measles virus infection,~04 might underlie the immunopathological response of postinfectious encephalomyelitis. A new direction for studies of PIE involves the possibility of establishing a model for this disease in transgenic mice that express the CD46 measles virus receptor.~58 Molecular cross-reactivity, or molecular mimicry, has been demonstrated between myelin antigens and an array of viruses.
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From page 87... ...
The pathogenesis of HAM/TSP remains unclear. There are numerous CD8+ T cells that recognize the virus, suggesting that this immune response might foster white matter disease.20 Infected glial cells are a possible source of inflammatory pathogenic cytokines and might also be the target for these cytolytic T cells.~40 In addition, there is some evidence that molecular mimicry plays a role in disease pathogenesis.
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From page 88... ...
, or the release of myelin antigens can stimulate an immune response that is directed against white matter antigens and becomes more broad over time (epitope spreading)
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From page 89... ...
Members of this group of viruses remain attractive candidates as etiologic agents in MS since they are common pathogens that are known to persist and reactivate from a latent stage (and therefore could trigger the attacks and remissions seen in MS) and in some cases can induce focal demyelination in animals (see discussion of animal models of virusinduced demyelination)
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From page 90... ...
Although HHV-6 may not induce the white matter lesions of MS, it remains a possibility that HHV-6 contributes to the demyelination seen in some cases of MS. The recent identification of CD46 as a cellular receptor for HHV-6~9i and the availability of transgenic mice that carry CD46~58 provide an opportunity to develop an experimental model of HHV-6-induced CNS disease pathogenesis.
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From page 91... ...
As an alternative approach, B-cell "monoclonal" mice have recently been generated by gene replacement transgenesis Humanized models Genetic engineering is used to produce animals that express particular human genes hypothesized to be involved in MS Virus-induced A variety of viruses can induce CNS demyelination, including demyelinating disease Theiler's murine encephalomyelitis virus, mouse hepatitis virus, and herpes simplex virus Most of our present knowledge of myelin-specific autoimmunity and, more generally, of immune reactivity within the CNS emanates from experimental animal models. It should, however, be noted that there is a diversity of distinct models, defined by the animal species, the target autoantigen, and the mode of induction.
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From page 92... ...
Knowledge of the extensive heterogeneity in disease susceptibility and modifier genes in these MS models should provide targets for study in human MS. Even within genetically identical littermates, the immune response following immunization with whole myelin is heterogeneous, with different antigenic targets dominating in different individuals.
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From page 93... ...
B cells are the best-characterized effectors of this function. Large, confluent inflammatory demyelinated lesions can be produced in rats by transferring encephalitogenic T cells along with a monoclonal antibody against myelin oligodendrocyte glycoprotein.
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From page 94... ...
It has recently been shown that a chronic relapsing EAE in a primate, the common marmoset, is more like MS than other EAE models.~74 This form of EAE, induced in marmosets by immunization with MOG, produces lesions that are almost indistinguishable from fresh, acute human MS plaques.78 In both the human disease and this animal model, a zone of myelin destruction is seen at the margins of lesions; within the lesions, myelin sheaths are replaced by vesiculated membranous elements. MOG-specific antibodies, thought to be related to the deposition of antigen-specific antibody, are present over the vesiculated myelin.
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From page 95... ...
The DA strain of TMEV produces an inflammatory demyelinating disease of the spinal cord with lesions that resemble MS. A variety of experimental studies of TMEV-induced demyelination suggest that as in MS, the immune system fosters demyelination.
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From page 96... ...
paresis associated with an inflammatory demyelinating disease of the spinal cord. Although the titers of DA virus decrease over the first few weeks, virus persists in the central nervous system for the life of the mouse.
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From page 97... ...
It is clear that viral persistence in the oligodendrocytes and microglia is critical to the development of TMEV-induced demyelination; that is, an ongoing virus infection is always associated with the white matter disease. It is also clear that the immune system contributes to the late demyelinating disease, but exactly how remains poorly understood.
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From page 98... ...
DA virus infection induces demyelination in both CD4+ and CD8+ Tcell knockout mice, suggesting that both CD4+ and CD8+ T cells mediate the late demyelinating disease.~49 The targets for these immunopathogenic CD4+ and the CD8+ T cells are unknown. There is some evidence for epitope spreading, in which an increasing number of myelin antigenic epitopes become the target for a CD4+ T-cell response.~4i However, epitope spreading appears to begin after demyelination has become established, so it is unclear how important this mechanism of immunopathology is to DA-induced demyelination, especially early in the white matter disease.
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From page 99... ...
PIE is of special interest since recurrences following this acute inflammatory white matter disease are so similar to MS attacks that the two diseases are indistinguishable, indicating a close relationship between PIE and MS. The availability of transgenic mice that carry a receptor for measles virus might provide an experimental model for the study of PIE.
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From page 100... ...
Genetically Engineerecl Moclels Molecular genetic manipulation has become one of the most important tools for evaluating gene function in living organisms.52 79 i47 These tools of molecular biology have extended the reach of researchers to a new level of understanding of neurodegeneration mechanisms. The development of animal models for neurodegenerative disorders by means of genetic engineering has revolutionized experimental neurology.27 The identification and cloning of genes involved in diseases such as Alzheimer's, Huntington's, and amyotropic lateral sclerosis provided the keys to develop mice that overexpress the human genes involved in these diseases (reviewed in 1999 by Brusa27~.
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From page 101... ...
In reverse genetics, mutant strains of mice that either overexpress or lack specific genes are generated through a variety of techniques. The classic approach to creating transgenic mice is to inject a foreign gene ("transgene")
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From page 102... ...
The development of inducible systems will become an important tool in the many diverse aspects of research on the disease mechanisms and possibilities for repair in MS, including the potential administration of gene therapy. Transgenic Mice and Demyelinating Disease.
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From page 103... ...
These models should facilitate the development of rational therapies and the transfer of knowledge from animal models to the prevention and treatment of human disease.226 However, although temporally regulated targeting controlled by the administration of an environmental inducer has become feasible with high efficiency for some organs, it remains to be further improved for other tissues, particularly the brain.~47 New generations of inducible promoters will more faithfully mimic the in vivo kinetics and dynamics of cytokine production. Knock-in mice, in which
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From page 104... ...
1998. Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy.
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From page 105... ...
1987. Macromolecular structure of axonal membrane during acute experimental allergic encephalomyelitis in rat and guinea pig spinal cord.
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From page 106... ...
1999. The immunobiology of multiple sclerosis: an autoimmune disease of the central nervous system.
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From page 107... ...
2000. Assessment of spinal cord damage in MS using MRI.
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From page 108... ...
1996. TCR usage in human and experimental demyelinating disease.
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From page 109... ...
T cells and RANTES in virus-induced central nervous system inflammation and demyelination. J Virol.;74:1415-24.
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2000. Spinal cord magnetic resonance imaging in suspected multiple sclerosis.
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From page 111... ...
2000. Astrocyte-targeted expression of IL-12 induces active cellular immune responses in the central nervous system and modulates experimental allergic encephalomyelitis.
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1995. Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity.
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From page 113... ...
2000. The contribution of spinal cord MRI to the diagnosis and differential diagnosis of multiple sclerosis.
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From page 114... ...
1994. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis.
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