Multiple Sclerosis Current Status and Strategies for the Future (2001) / Chapter Skim
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5 Strategies for Future Research on Disease Mechanisms
5 Strategies for Future Research on Disease Mechanisms
Pages 241-276
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From page 241... ...
Unclerstancling Injury of Neurons Even the earliest descriptions of multiple sclerosis mentioned axonal degeneration. Recent studies, using contemporary methods such as magnetic resonance imaging (MRI)
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From page 242... ...
FICORE 5.1 DemyeUn~Uon Ed ~on~1 degener~Uon in multiple sclerosis (A) In ~ Norma myeUn~d anon, me Dacron popgun (disbud Bong Novak, Aim high velocity and reU~ib~, to me pos~yn~Uc neuron.
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From page 243... ...
The available evidence suggests that demyelination may produce significant molecular changes in the neuronal cell body, including changes in gene activation.9 Since these changes are likely to interfere with neuronal function, they should be studied. Details of the molecular mechanisms underlying various pathological changes in neurons in MS remain to be elucidated.
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) , macrophages, and resident microglia at the site of inflammation in the white matter of the central nervous system causes release of glutamate.
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Given the critical role that sodium channels play in restoration of conduction in demyelinated axons and the intimate spatial relationship that develops between astrocytes and demyelinated axons, there is a need to understand the role of astrocytic sodium channels, and thus of astrocytes, in MS. Mechanisms of Recovery The nervous system exhibits a remarkable degree of plasticity, and it seems likely that reorganization at several levels, ranging from the molecular to the circuit level, contributes to remissions.
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From page 246... ...
Following loss of the overlying myelin insulation, electrical current is lost through this sodium channel-poor membrane, and the density of current through sodium channel-rich parts of the axon membrane falls. As a result, the conduction of action potentials is impaired and, in some cases, abolished.98 It has been well demonstrated in a number of animal models that in some chronically demyelinated axons, the denuded axon membrane, however, can acquire a higher-than-normal number of sodium channels, which is sufficient to support conduction.~0202~2965 Experimental methods for demonstrating this sodium channel plasticity require access to demyelinated tissue, and to date, most demonstrations of this phenomenon have been confined to laboratory models of MS.
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From page 247... ...
For example, after a long-term deafferentation of the nerve supply to the upper limb (several years) or after amputation, neurons in the primary somatosensory cortex that normally responded to the missing arm discharge after stimulation to the face.74 77~79 This phenomenon reflects a substantial reorganization in the response properties of neocortical neurons distributed over many millimeters (a long distance in cortex)
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From page 248... ...
In relation to MS, the question is, How do neurons change their responses in the presence of lesions, and how can the potential for positive neuronal change be harnessed to promote restorative recovery of function? Although the lesions in MS are clearly related primarily to glial cells, it is now accepted that axonal damage accompanies the lesions, which will impact on neural function.
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This procedure also results in a change in synaptic strength because the conditioned cell often responds to the nonpreferred stimulus. Changes in Morphology of Neurons-Axonal Growth or Sprouting.
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More detail about this family of neurotrophic and gliotrophic molecules is given in other sections. On the other side, proteoglycans such as chondroitin sulfate are molecules that appear to block axonal growth and may prevent successful attempts at reorganization.8 i~ 27 In summary, all the manifestations of neural plasticity described above hold the potential to be harnessed for recovery of function in diseases such as MS.
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, or by cytokines and neurotransmitters. Axons and neuronal cell bodies can be induced to express MHC class I and thus, in principle, could be recognized by cytotoxic T cells (CTLs)
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Myelin basic protein (MBP) specific, class II restricted CD4 T cells, for example, bind recombinant complexes of appropriate MHC class II and peptide to their membrane receptors, and this binding can be visualized by fluorescence staining.
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Phage display libraries have been used to directly test potentially binding target autoantigens of B-cell-derived autoantigens.~7 In the case of T cells, which recognize peptide segments embedded in suitable MHC class I or class II products rather than native proteins, modified approaches must be developed. One example is the screening of large-scale libraries of synthetic peptide variants, which implies laborious determination of T-cell responses in multiple microcultures.38 In any
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The entire field of regulation and suppression is still subject to debate. Although it is likely that downregulation of autoimmune responses takes place in the immune tissues, the location of T-cell activation, for example by exposure to autoantigen, is less established.
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Thus, one hypothesis is that dendritic cells engulf apoptotic brain cells, then migrate out of the CNS into the peripheral immune system (lymph nodes) , where they present protein components of these engulfed cells as autoantigens to specific autoreactive T cells.
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Nerve growth factor seems to be one mediator involved in this regulation.67 Conversely, areas with failing neuronal function preferentially attract immune cells and favor local inflammatory responses, as in Alzheimer's disease and other cases of neurodegeneration. Research into the interactions between neurons and immune cells thus may shed light on the generation of MS lesions and generate new therapeutic targets.
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From page 257... ...
Vaccinations with inactivated, "mitigated" autoreactive T-cell lines5 or peptide segments representing their antigen receptors were tested.94 There have also been attempts to "blindfold" pathogenic T cells, for example, by injecting either peptide antagonists that bind to restricting MHC loci or soluble MHC class II proteins complexed with autoantigenic peptide. More recently, researchers have attempted to modify the pathogenic potential of autoreactive T cells by exposing them to altered peptide ligands.
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From page 258... ...
It is well established that the blood-brain barrier becomes more permeable during inflammatory attacks in MS, yet the cytokines, chemokines, and other molecular mechanisms underlying enhanced permeability are just beginning to be defined.33 Greater understanding of key events that initiate blood-brain barrier permeability and trafficking of immune cells into the CNS may lead to means for preventing the development of MS lesions or controlling the degree of inflammation once an MS attack is in progress. Fresh experimental and clinical studies are required to identify the best therapeutic targets.
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From page 259... ...
The precise roles of various Cytokine and cytokine-related molecules in dampening the inflammatory process and initiating restorative mechanisms in the MS plaque is a fertile area for future research. Cytokine Production as a Systemic Marker of Disease Activity Cytokine levels and the production of cytokines by circulating peripheral blood cells have reportedly been increased in MS patient sera and CSF.
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From page 260... ...
In the absence of completely effective disease course-modifying agents, the availability of anticytokine therapies with the ability to interrupt the acute disease process would be desirable. ~ DENTIFICATION OF ~ NFECTIOUS AGENTS IN MS Standard and conventional approaches to the isolation of pathogens in MS have failed to find any consistent and convincing result.
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The identification of markers of disease phenotype would also permit one to identify these forms prior to full clinical expression and to determine the effectiveness of therapy. Improved identification of different disease subtypes could be derived from clinical observations, neuroimaging, and genetic or acquired biological markers.
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Biological Markers One would like to develop markers that reflect or serve as surrogates for the actual biology of the disease process. We do not yet know what the critical biological mediators of the disease process are.
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T-Cell-Relatecl Markers The molecular events associated with antigen presentation, cell activation, and migration have increasingly been defined. Studies of disease-specific immune responses the measurement of antigen reactive T cells are dependent on having a candidate disease-relevant antigen.
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The ability to link multiple MHC class I/peptide complexes together allows for identification of specific receptor-bearing T cells by flow cytometry. In addition, investigators can use tetramers to quickly and efficiently purify a specific T-cell population using fluorescent activated cell sorting (FACS)
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From page 265... ...
and disease phenotype (for example, lymphocyte migration rate and IFN~ production are increased in primary progressive patients with high lesion volume compared to primary progressive patients with low lesion volume) .75 B-Cell-Relatecl Markers In terms of disease-specific immune responses, the direct approach has been to look for the presence of antibodies in the serum or CSF that may directly participate in the MS disease process.
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From page 266... ...
and by detection of immune products such as those of the complement cascade and immune complexes that participate in antibodymediated immune responses. Neurobiological Markers These can be considered in terms of molecules produced by resident cells of the CNS that reflect interaction with the constituents of the immune system and in terms of molecules that reflect the tissue injury or repair process.
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From page 267... ...
In the EAE mouse model, this technique could allow researchers to watch immune cells migrate to the CNS long before any obvious damage occurs. With improved methods of targeting, they might be able to determine which immune cells lead the attack on myelin and the remyelination process.
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Susceptibility is likely to be mediated by the MHC class II genes themselves (DR, DQ, or both) and is most likely related to the known function of these molecules in the normal immune response, antigen-binding, and T-cell repertoire determination.
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From page 269... ...
to look at the coordinated expression, in both the CNS and the periphery, of ensembles of critical genes encoding cytokines, adhesion molecules, metalloproteinases, molecules involved in apoptosis, and molecules participating in myelin destruction and repair will contribute to our understanding of how these genes influence susceptibility and pathogenesis in MS. As gene chip methodologies mature, there is also the opportunity to perform wider
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270 MULTIPLE SCLEROSIS "whole-genome" analyses of gene expression unbiased by the selection of known candidate genes (see Box 5.1~.
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1981. Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein.
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1990. Changed distribution of sodium channels along demyelinated axons.
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1995. An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis.
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T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis.
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1989. Immunization with a synthetic T-cell receptor Vregion peptide protects against experimental autoimmune encephalomyelitis.
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