Central Nervous System White Matter Research Articles

Schwann Cell Transplantation for CNS Repair

Demyelination occurs in several central nervous system (CNS) disorders, including multiple sclerosis, viral infection and spinal cord injury and can result in severe functional impairment. Therefore there is great interest in developing therapies promoting repair in CNS demyelinating diseases and trauma. Cell replacement therapy is an attractive approach for myelin repair, and experimental transplantation has provided convincing evidence of the repair potential of grafted myelin-forming cells. Schwann cells (SCs), oligodendrocyte progenitors, olfactory ensheathing cells and embryonic and neural stem cells have been shown to form myelin after transplantation into the demyelinated CNS. SCs are among the most promising candidates for autologous grafting. They can remyelinate spinal cord lesions after experimental demyelination, leading in some cases to functional recovery in rodent and primate models. However, SCs do not normally enter the CNS, and migration of SCs transplanted in CNS white matter is inhibited by astrocytes. As SC migration and myelination is mediated by interactions of sets of extracellular matrix molecules with cell surface molecules, genetic engineering of SCs to alter aspects of these interactions is a possible way forward. Thus efforts towards the development of SC-based therapies are focused in enhancing their migration and functional integration into the lesioned CNS. In addition, efforts are being made to use these cells as gene delivery vehicles for an array of molecules with repair potential. In this review we summarize data from the recent literature regarding the use of SCs in CNS repair and discuss the prospects for future therapeutic applications.

Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis

FTY720 [2-amino-2-[2-(4-octylphenyl) ethyl]propane-1,3-diol hydrochloride] is an oral sphingosine-1-phosphate receptor modulator under development for the treatment of multiple sclerosis (MS). The drug is phosphorylated in vivo by sphingosine kinase 2 to its bioactive form, FTY720-P. Although treatment with FTY720 is accompanied by a reduction of the peripheral lymphocyte count, its efficacy in MS and experimental autoimmune encephalomyelitis (EAE) may be due to additional, direct effects in the central nervous system (CNS). We now show that FTY720 localizes to the CNS white matter, preferentially along myelin sheaths. Brain trough levels of FTY720 and FTY720-P in rat EAE are of the same magnitude and dose dependently increase; they are in the range of 40 to 540 ng/g in the brain tissue at efficacious doses and exceed blood concentrations severalfold. In a rat model of chronic EAE, prolonged treatment with 0.03 mg/kg was efficacious, but limiting the dosing period failed to prevent EAE despite a significant decrease in blood lymphocytes. FTY720 effectiveness is likely due to a culmination of mechanisms involving reduction of autoreactive T cells, neuroprotective influence of FTY720-P in the CNS, and inhibition of inflammatory mediators in the brain.

MR diffusion changes correlate with ultra-structurally defined axonal degeneration in murine optic nerve

Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) are widely used to investigate central nervous system (CNS) white matter structure and pathology. Changes in principal diffusivities parallel and perpendicular to nerve fibers or axonal tracts have been associated with axonal pathology and de/dysmyelination respectively. However, the ultra-structural properties and the pathological alterations of white matter responsible for diffusivity changes have not been fully elucidated. We examined the relationship between the directional diffusivities and ultra-structural properties in mouse optic nerve using healthy animals, and mice with optic neuritis (ON) that exhibited marked inflammatory changes and moderately severe axonal pathology. Progressive axonal degeneration in ON resulted in a 23% reduction of parallel diffusivity as detected by diffusion MRI (P<10(-5)), but no change in perpendicular diffusivity. Parallel diffusion changes were highly correlated with the total axolemmal cross-sectional area in the pre-chiasmal portion of the optic nerve (r=0.86, P<0.001). This study provides quantitative evidence that reduced parallel diffusivity in the optic nerve correlates significantly with axolemmal cross-sectional area reductions. MRI-based assessment of axonal degeneration in murine ON is feasible and potentially useful for monitoring of neuro-protective therapies in preclinical trials in animals.

Symposium on ‘Live cell imaging of neuronal and glial signalling’

In July 2006 the Institute of Biomedical and Biomolecular Sciences at the University of Portsmouth hosted a symposium on ‘Live cell imaging of neuronal and glial signalling’, in conjunction with the Anatomical Society of Great Britain and Ireland. The symposium was organized by Professor Arthur Butt and here we present articles arising from the presentations given in the symposium. The six papers presented here address the issue of how live cell imaging techniques have helped transform the prevailing neurocentric view of information processing in the central nervous system (CNS) to include glial cells. In the past, glia were considered to be passive structural elements, but the development of calcium-sensitive dyes and transgenic mice in which specific glial cell types express fluorescent proteins has demonstrated that glia are dynamic cells and actively participate in neurotransmitter signalling. Ricardo Scott addresses the issue from the neuronal viewpoint, describing how visualization of activity in individual CNS synapses has helped resolve the mechanisms of use-dependent control of presynaptic Ca2+ signalling in grey matter neurons. Evidence that astroglia are integral cellular elements at grey matter synapses is introduced by Frank Kirchhoff and Alex Verkhratsky, who describe how transgenic mouse models facilitate brain analysis of glutamate-mediated communications between astroglia and neurons at CNS synapses. Astroglia not only sense neurotransmitters released at synapses by virtue of their NMDA- and AMPA-type receptors, but also release neurotransmitters and are thereby able to communicate back to neurons and influence synaptic activity. Arthur Butt and colleagues (Wigley et al.) introduce a novel population of NG2-glia, which are active at grey matter synapses, in addition to astroglia. Intriguingly, neurotransmitters are also released along white matter axons and these stimulate Ca2+ excitability in NG2-glia and astrocytes. The physiological functions of neuron-glial signalling are the focus of these three papers, but neurotransmitters are also important in CNS pathology, and this is the focus of papers by Chvatal, Fern and Matute. Alexandr Chvataldiscusses the dramatic and dynamic changes in astroglial cell three-dimensional morphology visualized by imaging of living astrocytes in grey matter brain slices during osmotic stress and ischaemia. Robert Fern describes live cell imaging of white matter glia and shows that glutamate mediates the loss of astrocytes and myelin during ischaemia in CNS white matter. This theme is continued by Carlos Matute, who discusses the evidence that neurotransmitters mediate excitotoxic damage in white matter glia, and their roles in ischaemia and the demyelinating disease multilpe sclerosis. These articles demonstrate the diverse properties of glial cells. Thus, the ability to image neurons and glia in living brain slices allows us to study their integrated function, which is essential if we are to have a true understanding of nervous system physiology and pathology.

Toward accurate diagnosis of white matter pathology using diffusion tensor imaging

Diffusion tensor imaging (DTI) has been widely applied to investigate injuries in the central nervous system (CNS) white matter (WM). However, the underlying pathological correlates of diffusion changes have not been adequately determined. In this study the coregistration of histological sections to MR images and a pixel-based receiver operating characteristic (ROC) analysis were used to compare the axial (lambda( parallel)) and radial (lambda( perpendicular)) diffusivities derived from DTI and histological markers of axon (phosphorylated neurofilament, SMI-31) and myelin (Luxol fast blue (LFB)) integrity, respectively, in two different patterns of injury to mouse spinal cord (SC) WM. In contusion SC injury (SCI), a decrease in lambda( parallel) matched the pattern of axonal damage with high accuracy, but lambda( perpendicular) did not match the pattern of demyelination detected by LFB. In a mouse model of multiple sclerosis (MS), lambda( perpendicular) and lambda( parallel) did not match the patterns of demyelination or axonal damage, respectively. However, a region of interest (ROI) analysis suggested that lambda( perpendicular)-detected demyelination paralleled that observed with LFB, and lambda( parallel) decreased in both regions of axonal damage and normal-appearing WM (NAWM) as visualized by SMI-31. The results suggest that directional diffusivities may reveal abnormalities that are not obvious with SMI-31 and LFB staining, depending on the type of injury.

NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating polyneuropathy, associated with deafness exclusively found in Gypsies and resulting from a homozygous R148X mutation in the N-myc downstream-regulated gene 1 ( NDRG1). We report the detailed phenotypic study of a family without Gypsy ancestry, who presented with severe demyelinating polyneuropathy, deafness, subcortical white matter abnormalities on brain magnetic resonance imaging studies, and the R148X mutation in NDRG1. For the first time, central nervous system white matter lesions are demonstrated in CMT4D. This report extends the clinical knowledge of CMT4D and indicates that the role of the R148X mutation in NDRG1 in the central nervous system should be further studied.

Haemorrhagic acute disseminated encephalomyelitis: an unusual case of blindness in an HIV-infected patient

Acute disseminated encephalomyelitis (ADEM) is a monophasic, polysymptomatic, immune-mediated demyelinating disorder involving central nervous system (CNS) white matter. It is usually seen in association with exanthematous viral illnesses, systemic infections or vaccinations. The haemorrhagic form of ADEM is rarer and follows a more fulminant course. We describe a case of haemorrhagic ADEM in an HIV-infected patient presenting solely with acute onset bilateral blindness and normal retina. ADEM was diagnosed from clinical, laboratory and radiological findings. Although ADEM has been seen with HIV seroconversion illness and in chronic infection, the haemorrhagic form has never been reported in association with HIV. Acute onset blindness is extremely rare in HIV-positive patients. A Medline search revealed very few reports. The importance of considering haemorrhagic ADEM as aetiology of blindness in such a scenario is discussed.

Insulin resistance, inflammation, and cognition in Alzheimer's Disease: Lessons for multiple sclerosis

Insulin resistance (reduced ability of insulin to stimulate glucose utilization) is common in North American and Europe, where as many as one third of all older adults suffer from prodromal or clinical type 2 diabetes mellitus. It has long been known that insulin-resistant conditions adversely affect general health status. A growing body of findings suggests that insulin contributes to normal brain functioning and that peripheral insulin abnormalities increase the risk for memory loss and neurodegenerative disorders such as Alzheimer's disease. Potential mechanisms for these effects include insulin's role in cerebral glucose metabolism, peptide regulation, modulation of neurotransmitter levels, and modulation of many aspects of the inflammatory network. An intriguing question is whether insulin abnormalities also influence the pathophysiology of multiple sclerosis (MS), an autoimmune disorder characterized by elevated inflammatory biomarkers, central nervous system white matter lesions, axonal degeneration, and cognitive impairment. MS increases the risk for type 1 diabetes mellitus. Furthermore, the lack of association between MS and type 2 diabetes may suggest that insulin resistance affects patients with MS and the general population at the same alarming rate. Therefore, insulin resistance may exacerbate phenomena that are common to MS and insulin-resistant conditions, such as cognitive impairments and elevated inflammatory responses. Interestingly, the thiazolidinediones, which are used to treat patients with type 2 diabetes, have been proposed as potential therapeutic agents for both Alzheimer's disease and MS. The agents improve insulin sensitivity, reduce hyperinsulinemia, and exert anti-inflammatory actions. Ongoing studies will determine whether thiazolidinediones improve cognitive functioning for patients with type 2 diabetes or Alzheimer's disease. Future studies are needed to examine the effects of thiazolidinediones on patients with MS.

Molecular mechanisms involved in T cell migration across the blood–brain barrier

In the healthy individuum lymphocyte traffic into the central nervous system (CNS) is very low and tightly controlled by the highly specialized blood-brain barrier (BBB). In contrast, under inflammatory conditions of the CNS such as in multiple sclerosis or in its animal model experimental autoimmune encephalomyelitis (EAE) circulating lymphocytes and monocytes/macrophages readily cross the BBB and gain access to the CNS leading to edema, inflammation and demyelination. Interaction of circulating leukocytes with the endothelium of the blood-spinal cord and blood-brain barrier therefore is a critical step in the pathogenesis of inflammatory diseases of the CNS. Leukocyte/endothelial interactions are mediated by adhesion molecules and chemokines and their respective chemokine receptors. We have developed a novel spinal cord window preparation, which enables us to directly visualize CNS white matter microcirculation by intravital fluorescence videomicroscopy. Applying this technique of intravital fluorescence videomicroscopy we could provide direct in vivo evidence that encephalitogenic T cell blasts interact with the spinal cord white matter microvasculature without rolling and that alpha4-integrin mediates the G-protein independent capture and subsequently the G-protein dependent adhesion strengthening of T cell blasts to microvascular VCAM-1. LFA-1 was found to neither mediate the G-protein independent capture nor the G- protein dependent initial adhesion strengthening of encephalitogenic T cell blasts within spinal cord microvessel, but was rather involved in T cell extravasation across the vascular wall into the spinal cord parenchyme. Our observation that G-protein mediated signalling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo suggested the involvement of chemokines in this process. We found functional expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in CNS venules surrounded by inflammatory cells in brain and spinal cord sections of mice afflicted with EAE suggesting that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue might be involved in T lymphocyte migration into the immuneprivileged CNS during immunosurveillance and chronic inflammation. Here, I summarize our current knowledge on the sequence of traffic signals involved in T lymphocyte recruitment across the healthy and inflamed blood-brain and blood-spinal cord barrier based on our in vitro and in vivo investigations.

Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR2 in the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR2 expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR2 wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR2 KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR2 activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein–induced EAE caused more severe inflammatory gene expression in the CNS of PAR2 WT animals (P < 0.05), together with enhanced T cell proliferation and interferon γ production (P < 0.05), compared with KO littermates. Indeed, PAR2 WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR2 KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR2 expression and neuroinflammation with ensuing demyelination and axonal injury.

Hypoglycemia influences oligodendrocyte development and myelin formation

Damage to central nervous system white matter is observed following hypoglycemia, raising the possibility that hypoglycemia influences oligodendrocytes and myelination. To examine effects of hypoglycemia on oligodendrocytes and myelin formation, we studied cultured oligodendrocyte precursor cells and cerebellar slice cultures. We observed that with decreasing concentrations of glucose, oligodendrocyte precursor cell proliferation, maturation, and migration decreased. We also observed that hypoglycemia induced apoptotic cell death and activation of caspase-3 in oligodendrocyte precursor cells. Slice culture studies showed that glucose is required for myelinated fiber formation, as with reduction in the glucose concentration, the density of myelinated fibers decreased. Collectively, these data show that hypoglycemia inhibits oligodendrocyte development and myelination and that hypoglycemia triggers apoptotic cell death in oligodendrocyte precursor cells.

Oligodendroglial Dysplasia in Two Bullmastiff Dogs

Leukodystrophies are inherited neurological disorders involving central nervous system white matter. They are uncommon in animals but a few, breed-specific entities have been described. In 2002, two young-adult, purebred Bullmastiff dogs from central New York State presented to their referring veterinarians displaying moderate to severe ataxia of all limbs, spastic tetraparesis that was worse in the pelvic limbs, and a diffuse, action-related, whole-body tremor. Clinical signs were insidious in onset and slowly progressive. Anatomic diagnoses considered were a C1-C5 lesion or, based on the whole-body tremor, a diffuse central nervous system disorder. No gross lesions were apparent in the brain or spinal cord. Histopathologically, numerous, multifocal, sharply demarcated, small, ovoid to angular areas of myelin pallor (plaques) were present throughout the major white matter tracts of the brainstem and spinal cord. These plaques, which often were traversed by axons, did not stain with luxol fast blue for myelin and were associated with minimal astrocytosis. Ultrastructural findings include occasional hypertrophic glia in white matter, rare unmyelinated segments of axons, and focal proliferation of tubule-containing cytoplasmic glial cell processes (oligodendroglial). The described clinical and morphological findings and age of onset are similar to the well-characterized, presumably hereditary, bovine syndrome known as Charolais ataxia or oligodendroglial dysplasia. This article presents the first description of a leukodystrophy in the Bullmastiff breed and the first report of oligodendroglial dysplasia in animals other than Charolais cattle.

Surviving Anoxia: A Tale of Two White Matter Tracts

Successful axon function is vital to the overall performance of the central nervous system (CNS). White matter (WM) axons are dependent on constant supply of oxygen and glucose to transmit signals with high fidelity. The optic nerve is a pure WM tract composed of completely myelinated axons while corpus callosum (CC) slices contain both gray and WM portions of the brain with a mixture of myelinated and unmyelinated axons. Axon function in both WM tracts is resistant to anoxia with a subset of axons able to survive exclusively on energy generated by glycolysis. In mouse optic nerves (MONs), removal of glucose during anoxia causes complete loss of axon function, implicating glucose as the sole source of energy. In contrast, in rat optic nerve (RON), anoxia causes rapid and complete loss of function. Because RON is about twice the diameter of MON, glucose diffusion during anoxia is inadequate. Increasing bath glucose concentration restores the ability of RON axons to persist during anoxia. Although in 10 mM glucose, MONs and CC slices exhibit identical resistance to anoxia, 30 mM glucose unmasks the greater resistance of CC axons suggesting unmyelinated axons and/or the smallest axons with the thinnest myelin sheath are resistant to anoxia. These results reveal that CNS WM is remarkably tolerant of anoxia although there is regional variability in their ability to function and survive anoxia. To achieve optimal protection of the CNS in various neurological diseases, it is critical to understand the properties of regional energy metabolisms and injury mechanisms for successful therapeutic approaches.

Inflammation in white matter: Clinical and pathophysiological aspects

While the central nervous system (CNS) is generally thought of as an immunopriviledged site, immune-mediated CNS white matter damage can occur in both the perinatal period and in adults, and can result in severe and persistent neurological deficits. Periventricular leukomalacia (PVL) is an inflammatory white matter disease of premature infants that frequently results in cerebral palsy (CP). Clinical and experimental studies show that both hypoxic/ischemic and innate immune mechanisms contribute to the destruction of immature oligodendroglia and of axons in the deep cerebral white matter in PVL. No data are yet available as to whether there is any genetic predisposition to PVL or to its neurological sequelae. Multiple sclerosis (MS) is an inflammatory white matter disease that often begins in young adulthood, causes multifocal destruction of mature oligodendroglia and of axons, and eventually leads to substantial cumulative neurological disability. Certain genetic polymorphisms contribute to susceptibility to MS, and adaptive immune responses to myelin-associated self antigens, or to exogenous antigens that mimic these self antigens, play a central role in the pathophysiology of this disease.

Central Nervous System Involvement in Hereditary Neuropathy With Liability to Pressure Palsies

To describe a large family with hereditary neuropathy with liability to pressure palsies associated with central nervous system demyelination. We examined the 18 members of a pedigree. Genetic analysis was performed on 15 subjects, standard nerve conduction studies on 10 subjects, and brain magnetic resonance imaging studies on 8 subjects. Hereditary neuropathy with liability to pressure palsies was confirmed in 9 patients of the pedigree. Brain magnetic resonance imaging findings showed multiple areas of demyelination in 6 of 6 affected members and were normal in 2 of 2 healthy relatives. Magnetic resonance imaging abnormalities were predominantly located in the subcortical frontal white matter. All patients had acute and recurrent nerve palsies, while clinical features of central nervous system involvement were not a characteristic of this pedigree. We demonstrate that this association, previously reported in sporadic cases, is not coincidental. Therefore, patients with hereditary neuropathy with liability to pressure palsies can present central nervous system white matter lesions, and the role of the PMP22 (peripheral myelin protein 22) gene deletion in the central nervous system should be further studied.

Polymorphisms in the interleukin‐4 and IL‐4 receptor genes and multiple sclerosis: a study in Spanish‐Basque, Northern Irish and Belgian populations

Cytokine gene polymorphisms are known to influence susceptibility and disease course of many autoimmune diseases. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. We analysed both the well-known intronic variable number of tandem repeat (VNTR) and +33 C/T single-nucleotide polymorphisms (SNP) in the IL-4 gene, as well as the functional Q551R SNP in the IL4-R gene in a cohort of three distinct populations comprising sporadic cases and controls from the northern Spanish Basque Country and Northern Ireland, as well as family trios from Belgium. The IL-4 +33 TT genotype was decreased in primary progressive (PP) versus relapsing-remitting (RR) patients in the Northern Irish population (OR = 0.14; 95% CI = 0.018-1.09). Two-marker haplotype distribution of the VNTR and +33 C/T SNP in PP patients differed from that seen in RR patients in Northern Ireland (P = 0.03). The R allele of the Q551R SNP was significantly under-transmitted in the Belgian trio families (P = 0.003), although this effect was not seen in the Northern Irish and Basque data sets. We did not identify IL-4-IL4-R gene-gene interaction in determining susceptibility or clinical parameters of MS. Disease or genetic heterogeneity or both may be responsible for the observed lack of reproduction in different populations. Our data reinforce recent findings for a role of IL4-R in susceptibility to MS.

MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system

The classical view of MS as a chronic inflammatory demyelinating disease leading to the formation of focal central nervous system (CNS) white matter (WM) lesions has been recently challenged by pathological studies and by the extensive application of modern MRI-based techniques. There is now overwhelming evidence supporting the following statements: MS causes widespread tissue damage in the normal-appearing white matter (NAWM) of the brain and spinal cord, whose extent and severity is more strictly associated to the clinical manifestations of the disease than the extent of focal pathology. Discrete, macroscopic lesions are just the tip of the iceberg of MS pathology. Grey matter (GM) damage is a consistent feature of all MS phenotypes, which is progressive from the start of the relapsing-remitting phase of the disease. As is the case for WM, GM damage is also a mixture of focal lesions and diffuse pathology. High-field strength MR scanners are improving our ability to image focal GM lesions and modern MR-based techniques are enabling us to quantify in vivo the extent and severity of GM pathology, which have been shown to correlate only moderately with the amount of WM changes. At least part of GM pathology in MS is not secondary to retrograde degeneration of fibers traversing WM lesions. The neurodegenerative component of the disease is not a late phenomenon and it is not completely driven by inflammatory demyelination. In fact, neurodegeneration occurs very early in the course of MS and the correlation between MRI measures of inflammation and neurodegeneration is weak in all disease phases. The interplay of inflammation and neurodegeneration is a complex and still poorly understood phenomenon. At least part of MS-related neurodegeneration is not directly driven by Wallerian degeneration. Functional cortical changes can be seen in virtually all MS patients and are likely to play a central role in the ability of the MS brain to respond to tissue injury and, hence, limit the functional consequences of structural damage. MS disability is not just the result of tissue destruction but rather a balance between tissue destruction, tissue repair and adaptive cortical reorganization. All of this calls for the concept of MS as a focal, inflammatory demyelinating, WM disease to be reexamined and to start viewing MS as a diffuse CNS disease with an important neurodegenerative component. This is central for identifying novel and effective treatment strategies.

The CTLA4 + 49 A/G* G– CT60* G haplotype is associated with susceptibility to multiple sclerosis in Flanders

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. The cytotoxic T lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analysed the CTLA4 +49A/G and CT60 polymorphisms in a cohort of 120 MS trio families recruited from the Flanders region in Belgium. Both polymorphisms were genotyped by polymerase chain reaction—restriction fragment length polymorphism (RFLP). The +49 G-allele was significantly more transmitted to affected probands ( P = 0.005). No transmission distortion was observed for the CT60 polymorphism. Haplotype analysis revealed significant overtransmission of the + 49 A/G* G–CT60* G haplotype ( P = 0.0025), and undertransmission of the + 49 A/G* A–CT60* G haplotype ( P = 0.015). The CTLA4 gene has been the focus of intense investigation in MS. Of 15 recently published papers, only six reported significant associations of various CTLA4 polymorphisms with MS, with the remainder being negative. Ours is the first report investigating the CT60 polymorphism in MS. Our data highlight a need for further scrutiny of the CTLA4 gene in MS.

Complementary Contribution of CD4 and CD8 T Lymphocytes to T-Cell Infiltration of the Intact and the Degenerative Spinal Cord

The central role of T cells in inflammatory reactions of the central nervous system (CNS) is well documented. However, there is little information about the few T cells found within the noninflamed CNS. In particular, the contribution of CD4+ and CD8+ T cells to the lymphocyte pool infiltrating the intact CNS, the location of these cells in CNS white and gray matter, and changes in the cellular composition of T-cell infiltrates coinciding with degeneration are primarily undefined. To address these points, we studied T cells in the intact and degenerative rat spinal cord. In the intact spinal cord, T cells were preferentially located within the gray matter. CD8+ T cells were more numerous than CD4+ lymphocytes. In cases of neuroaxonal degeneration or myelin degeneration/oligodendrocyte death, T cells were predominantly seen in areas of degeneration and were present in increased numbers. These effects were more pronounced for the CD4+ than for the CD8+ T-cell subset. Collectively, these data provide evidence for a clear cellular and compartmental bias in T-cell infiltration of the intact and degenerative spinal cord. This could indicate that CD4+ and CD8+ T cells might fulfill complementary roles in the intact and the diseased organ.

Multiple sclerosis

Multiple sclerosis (MS) is a complex genetic disease associated with inflammation in the central nervous system (CNS) white matter and is thought to be mediated by autoimmune processes. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. The association of the disease with major histocompatibility complex genes, the inflammatory white matter infiltrates, similarities with animal models, and the observation that MS can be treated with immunomodulatory and immunosuppressive therapies support the hypothesis that autoimmunity plays a major role in the disease pathology. This review discusses the immunopathology of MS with particular focus given to regulatory T cells and the role of B cells and antibodies, immunomodulatory therapeutics, and finally new directions in MS research, particularly new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understandings and therapies for this disease.