Destruction Of Oligodendrocytes Research Articles

Polyomavirus JC infection inhibits differentiation of oligodendrocyte progenitor cells.

Reactivation of the human polyomavirus JC (JCV) in the CNS results in a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). The lytic destruction of oligodendrocytes, which occurs at the terminal stage of the viral infection cycle, is considered a critical factor in the development of demyelination and the pathogenesis of PML. However, knowledge is limited about interaction of JCV with oligodendrocytes and its impact on the denudation of axons at the early stage of viral reactivation and prior to the destruction of the infected cells. We have developed an in vitro neuroprogenitor cell culture using human fetal brain that can be differentiated to the oligodendrocyte lineage to investigate interactions of JCV with its host cells. Results show that infection with JCV delays oligodendrocyte maturation as shown by reduced levels of oligodendrocytic markers, including myelin basic protein, proteolipid protein, and platelet-derived growth factor receptor-α. Furthermore, replication of JCV in these cells caused substantial dysregulation of several chemokines, including CCL5/RANTES, GRO, CXCL1/GROα, CXCL16, CXCL8/IL-8, CXCL5/ENA-78, and CXCL10/IP-10, all of which play a role in cell growth and differentiation.

JCV agnoprotein‐induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons

An indispensable role for oligodendrocytes in the protection of axon function and promotion of neuronal survival is strongly supported by the finding of progressive neuron/axon degeneration in human neurological diseases that affect oligodendrocytes. Imaging and pathological studies of the CNS have shown the presence of neuroaxonal injury in progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the CNS, resulting from destruction of oligodendrocytes upon productive replication of the pathogenic neurotropic polyomavirus JC. Here, we examined the extracellular factors involved in communication between oligodendrocytes and neurons. Culturing cortical neurons with conditioned medium (CM) from rat CG4 oligodendrocytic cells that express the JCV agnoprotein showed that CXCL5/LIX, which is a chemokine closely related to the human CXCL5/ENA78 and CXCL6/GCP-2 chemokines, is essential for neuronal cell survival. We found that in CM from agnoprotein-producing CG-4 cells level of CXC5/LIX is decreased compared to control cells. We also demonstrated that a reduced expression of CXCL5/LIX by CG4 GFP-Agno cells triggered a cascade of signaling events in cortical neurons. Analysis of mitogen-activated protein kinases (MAPK) and glycogen synthase kinase (GSK3) pathways showed that they are involved in mechanisms of neuronal apoptosis in response to the depletion of CXCL5/LIX signaling. These data suggest that agnoprotein-induced dysregulation of chemokine production by oligodendrocytes may contribute to neuronal/axonal injury in the pathogenesis of PML lesions.

NKG2 Receptors Acquired by Activated Human CD4 T Cells Are Involved in Oligodendrocyte Destruction in the Context of MS (P07.086)

Objective: To characterize novel mechanisms by which CD4 T cells can injure human oligodendrocytes, and identify these cells in patients with Multiple Sclerosis (MS). Background Destruction of oligodendrocytes is a fundamental hallmark of MS. Although CD4 T cells are considered important contributors to this immunopathology, the mechanisms involved are not completely resolved. In recent years, CD4 T cells that acquire NK-associated markers have been implicated in tissue destruction in other immunopathologies such as Crohns Disease. We investigated whether cytotoxic NKG2+ CD4 T cells were detected in MS patients and whether human adult oligodendrocytes express the recognized ligands. We studied whether these receptors were involved in the immune-mediated injury of oligodendrocytes. Design/Methods: Proportions of NKG2D/C+ CD4 T cells in the blood of MS patients versus healthy donors were analyzed using flow cytometry (FACS). Peripheral blood mononuclear cells (PBMCs) from human donors are activated with the lectin phytohemagglutinin (PHA) and stained for NKG2C, NKG2D, CD4. CD4 T cells isolated from these cultures are incubated with primary cultures of human adult oligodendrocytes, and then analyzed by FACS for effector functions. Immunohistochemistry was done on post-mortem CNS sections of MS patients. Results: Our studies show an increased proportion of cytotoxic NKG2D/C+ CD4 T cells in the blood of MS patients. These CD4 T cells expressed elevated levels of lytic enzymes. We have previously shown that inflamed human oligodendrocytes upregulate NKG2D ligands; we now show that they can also express NKG2C ligand (HLA-E) upon inflammatory conditions mimicking MS lesions. Our functional results show that blocking NKG2C and NKG2D on PHA-activated CD4 T cells decreases their cytotoxicity towards the oligodendrocytes. Our in situ studies show that these cells are detected in post-mortem CNS sections of MS patients. Conclusions: Our results demonstrate that activated human CD4 T cells can mediate injury to oligodendrocytes through acquired cytotoxic NK-associated receptors. Supported by: Multiple Sclerosis Society of Canada (MSSOC). Disclosure: Dr. Zaguia has nothing to disclose. Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Saikali has nothing to disclose. Dr. Arbour has nothing to disclose.

Progressive multifocal leukoencephalopathy in transplant recipients

Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), a rare demyelinating disorder caused by oligodendrocyte destruction by JC virus. Reports of PML following transplantation were found using PubMed Entrez (1958-July 2010). A multicenter, retrospective cohort study also identified all cases of PML among transplant recipients diagnosed at Mayo Clinic, Johns Hopkins University, Washington University, and Amsterdam Academic Medical Center. At 1 institution, the incidence of posttransplantation PML was calculated. A total of 69 cases (44 solid organ, 25 bone marrow) of posttransplantation PML were found including 15 from the 4 medical centers and another 54 from the literature. The median time to development of first symptoms of PML following transplantation was longer in solid organ vs bone marrow recipients (27 vs 11 months, p = 0.0005, range of <1 to >240). Median survival following symptom onset was 6.4 months in solid organ vs 19.5 months in bone marrow recipients (p = 0.068). Case fatality was 84% (95% confidence interval [CI], 70.3-92.4%) and survival beyond 1 year was 55.7% (95% CI, 41.2-67.2%). The incidence of PML among heart and/or lung transplant recipients at 1 institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25-3.61). No clear association was found with any 1 immunosuppressant agent. No treatment provided demonstrable therapeutic benefit. The risk of PML exists throughout the posttransplantation period. Bone marrow recipients survive longer than solid organ recipients but may have a lower median time to first symptoms of PML. Posttransplantation PML has a higher case fatality and may have a higher incidence than reported in human immunodeficiency virus (HIV) patients on highly-active antiretroviral therapy (HAART) or multiple sclerosis patients treated with natalizumab.

Expression of leukemia inhibitory factor in the cerebrospinal fluid of patients with multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, characterized by infiltration of immune cells in the central nervous system, localized myelin destruction and loss of oligodendrocytes. Early detection of MS may be possible via blood and cerebrospinal fluid (CSF) tests based on disease pathology. Leukemia inhibitory factor (LIF), a neurotrophic cytokine, has previously been shown to limit autoimmune demyelination and oligodendrocyte loss in a murine model of MS. Given its potential role in neural cell death and survival, in the present study we measured expression of LIF in serum and CSF from patients with relapsing-remitting MS ( n = 46) and control subjects ( n = 42). We used western blot analysis and enzyme-linked immunosorbent assays (ELISA), to study LIF expression. Western blot analysis revealed that LIF was present in all CSF samples, and densitometric analysis showed that relative expression was significantly higher in CSF from patients with MS than in controls ( p < 0.001). ELISA analysis showed that the concentrations of LIF in both the serum (87.5 ± 11.46 ng/mL) and CSF (56 ± 10.72 ng/mL) of MS patients were significantly higher than those in control subjects (52 ± 8.23 ng/mL, 7.8 ± 3.76 ng/mL, respectively; p < 0.0001 for both serum and CSF), despite there being no significant difference in total protein concentration between the two groups ( p = 0.52 for serum, p = 0.2 for CSF). Our data suggest that serum and CSF concentrations of LIF may provide additional useful information during the differential diagnosis of MS. Our findings also indicate that LIF could be significantly involved in the pathophysiology of MS.

Functional expression of HLA-E by human oligodendrocytes (101.40)

Abstract Immune cells infiltrating the central nervous system (CNS) of Multiple Sclerosis (MS) patients contribute to the destruction of oligodendrocytes. We aim at characterizing mechanisms implicated in such CNS damage. HLA-E, a non-classical MHC class I molecule, is recognized by either the NKG2C or NKG2A receptors expressed on subsets of T cells and NK cells. While NKG2C is an activating receptor, NKG2A is described as an inhibitory receptor. Activated human immune effectors including NK and T cells can kill human oligodendrocytes in vitro, yet whether HLA-E could modulate such cytotoxicity is unresolved. We observed that human adult oligodendrocytes express basal HLA-E levels, which are upregulated upon pro-inflammatory cytokine treatments, mimicking the inflamed CNS observed in MS lesions. We performed in vitro functional assays using activated immune cells bearing either the NKG2A (NK cells) or NKG2C (CD4 T cells) receptor co-cultured with human oligodendrocytes. We observed that addition of blocking antibodies specific for NKG2A on NK cells increased the killing of oligodendrocytes compared to an isotype control. In contrast, we detected a decreased cytotoxicity against oligodendrocytes when we block the activating receptor NKG2C on a subset of CD56-positive CD4 T cells, which we previously identified as carrying cytotoxic properties. Our results support that human oligodendrocytes modulate via the expression of HLA-E, cytotoxic attacks mediated by several immune effectors.

Myelin damage of hippocampus and cerebral cortex in rat pentylenetetrazol model

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures, which also occur in demyelinating diseases of the central nervous system (CNS) with a higher prevalence. Meanwhile, demyelination occurrings have been occasionally observed in CNS of epilepsy patients, indicating an association between demyelination and epileptic seizures by an unknown mechanism. However, no confirmative experimental evidence has yet been given. Thus, by using a rat pentylenetetrazol model, electroencephalogram (EEG), Western blotting, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, the present study provided direct evidence that myelin sheath damage in rat hippocampus and cerebral cortex started in the early stage of epileptic seizures induction and lasted with no further increase in severity in the development of epileptic seizures. It was illustrated that myelin sheath damage was not the result of oligodendrocyte destruction, but the autoantibodies against myelin basic protein (MBP) produced in peripheral circulation accompanied by increased permeability of blood–brain barrier (BBB) formed in the development of epileptic seizures. This study firstly provided experimental evidence for myelin sheath damage in PTZ-induced rat's epileptic seizures and further demonstrated that its possible cause was autoimmunoreaction.

Progressive multifocal leukoencephalopathy (PML) after transplantation

Progressive multifocal leukoencephalopathy (PML) after transplantation

Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice

Glia maturation factor (GMF), a primarily CNS localized protein was discovered and characterized in our laboratory. We previously demonstrated that GMF is the upstream regulator for excessive production and release of proinflammatory cytokines/chemokines in brain cells leading to the destruction of oligodendrocytes, the myelin forming cells, and neurons. We also reported that mice lacking endogenous GMF (GMF-deficient, GMF-KO) were resistant to myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) induced EAE, since immunization induced only delayed EAE with diminished severity. In the present study we show that a replication-defective adenovirus-GMF construct caused expression of GMF in CNS of GMF-KO mice and reinstated MOG35–55 induced early and severe EAE. Our results show that MOG35–55 immunization caused only a muted EAE and inflammation/demyelination in mice lacking endogenous GMF. The diminished incidence of EAE in GMF-KO mice was consistent with the significantly reduced expressions of cytokines/chemokines. The muted severity of EAE in GMF-KO mice was restored to full blown levels upon reintroduction of GMF using an adeno-GMF-virus (Adv-GMF) vector. Consistent with the clinical findings, histological examination of the CNS of mice with EAE revealed profound differences between wild type (Wt), GMF-KO, and GMF-KO mice with re-introduced GMF (GMF-KO+Adv-GMF). Spinal cord sections from mice with EAE were analyzed for the infiltration of mononuclear cells (inflammation) and myelin loss (demyelination). In Wt mice, 40% of spinal cord quadrants were positive for demyelination and 45% of spinal cord quadrants were positive for inflammation at the peak of EAE. Drastically reduced infiltrates (15%) and demyelination (10%) were found in GMF-KO mice that developed reduced severity of EAE. Upon GMF reintroduction in GMF-KO mice, MOG35–55 immunization caused extensive monocytes infiltration (48%) and demyelination (46%), similar to that observed in the immunized Wt mice. The levels of cytokine/chemokine in the spinal cords of mice at three time points, corresponding to the onset, peak severity and recovery period of EAE, show a distinct pattern of very large increases in IFN-γ, TNF-α, GM-CSF and MCP-1 in Wt and GMF-KO+Adv-GMF mice compared to GMF-KO and GMF-KO+Adv-LacZ mice.

Cleavage of transaldolase by granzyme B causes the loss of enzymatic activity with retention of antigenicity for multiple sclerosis patients.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS resulting from a progressive loss of oligodendrocytes. Transaldolase (TAL) is expressed at selectively high levels in oligodendrocytes of the brain, and postmortem sections show concurrent loss of myelin basic protein and TAL from sites of demyelination. Infiltrating CD8(+) CTLs are thought to play a key role in oligodendrocyte cell death. Cleavage by granzyme B (GrB) is predictive for autoantigenicity of self-proteins, thereby further implicating CTL-induced death in the initiation and propagation of autoimmunity. The precursor frequency and CTL activity of HLA-A2-restricted TAL 168-176-specific CD8(+) T cells is increased in MS patients. In this paper, we show that TAL, but not myelin basic protein, is specifically cleaved by human GrB. The recognition site of GrB that resulted in the cleavage of a dominant TAL fragment was mapped to a VVAD motif at aa residue 27 by N-terminal sequencing and confirmed by site-directed mutagenesis. The major C-terminal GrB cleavage product, residues 28-337, had no enzymatic activity but retained the antigenicity of full-length TAL, effectively stimulating the proliferation and CTL activity of PBMCs and of CD8(+) T cell lines from patients with MS. Sera of MS patients exhibited similar binding affinity to wild-type and GrB-cleaved TAL. Because GrB mediates the killing of target cells and cleavage by GrB is predictive of autoantigen status of self proteins, GrB-cleaved TAL-specific T cell-mediated cytotoxicity may contribute to the progressive destruction of oligodendrocytes in patients with MS.

Enhanced Microglial Clearance of Myelin Debris in T Cell-Infiltrated Central Nervous System

Acute multiple sclerosis lesions are characterized by accumulation of T cells and macrophages, destruction of myelin and oligodendrocytes, and axonal damage. There is, however, limited information on neuroimmune interactions distal to sites of axonal damage in the T cell-infiltrated central nervous system. We investigated T-cell infiltration, myelin clearance, microglial activation, and phagocytic activity distal to sites of axonal transection through analysis of the perforant pathway deafferented dentate gyrus in SJL mice that had received T cells specific for myelin basic protein (TMBP) or ovalbumin (TOVA). The axonal lesion of TMBP-recipient mice resulted in lesion-specific recruitment of large numbers of T cells in contrast to very limited T-cell infiltration in TOVA-recipient and -naïve perforant pathway-deafferented mice. By double immunofluorescence and confocal microscopy, infiltration with TMBP but not TOVA enhanced the microglial response to axonal transection and microglial phagocytosis of myelin debris associated with the degenerating axons. Because myelin antigen-specific immune responses may provoke protective immunity, increased phagocytosis of myelin debris might enhance regeneration after a neural antigen-specific T cell-mediated immune response in multiple sclerosis.

Altered proteolytic events in experimental autoimmune encephalomyelitis discovered by iTRAQ shotgun proteomics analysis of spinal cord

BackgroundAbnormal activation of protease activities during experimental autoimmune encephalomyelitis (EAE) in rats, a rodent model of multiple sclerosis, have been implicated in either the direct destruction of myelin components or the intracellular signal transduction pathways that lead to lymphocyte infiltration, oligodendrocyte destruction, neuronal dysfunctions and axonal degeneration. The identification of changes in regulated proteolytic events during EAE is crucial for uncovering activated proteases that may underline the pathological features such as inflammation and demyelination. We searched for either non-tryptic or semi-tryptic peptides from a previous shotgun proteomics study using isobaric tags for relative and absolute quantification (iTRAQ) to compare the proteomes of normal and EAE rat lumbar spinal cords.ResultsWe discovered that several proteins, such as α1-macroglobulin, a protease inhibitor, α1B-glycoprotein, β2-microglobulin, neurofilament light polypeptide and sulfated glycoprotein 1 had non-tryptic peptide iTRAQ ratios that were substantially different from the overall protein iTRAQ ratios, suggesting that such peptides may be markers for the proteolytic products generated by the protease(s) altered during EAE. Indeed, subsequent Western blotting confirmed the dysregulation of specific protein cleavages in EAE tissues. Additional proteolytic changes in α2-macroglobulin, another protease inhibitor similar to α1-macroglobulin was also observed.ConclusionThe results from this study revealed changes among both neuronal protein processing and endogenous proteolysis modulators in EAE animals. This information may provide a rationale for protease inhibitor-based therapeutic interventions for multiple sclerosis.

Microvascular aberrations in the white matter in Alzheimer's disease

Alzheimer's disease (AD) has been associated with abnormalities in the cerebral white matter (WM) such as myelin degeneration, axonal loss, and oligodendrocyte destruction. The cerebrocortical microvessels display basement membrane pathology, collagen deposition in the vessel wall, pericyte end endothel cell degeneration.

Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s).

Potential mechanisms of the human polyomavirus JC in neural oncogenesis.

The human polyomavirus JC (JCV) is a small DNA tumor virus and the etiologic agent of the progressive multifocal leukoencephalopathy. In progressive multifocal leukoencephalopathy, active JCV replication causes the lytic destruction of oligodendrocytes. The normal immune system prevents JCV replication and suppresses the virus into a state of latency so that expression of viral proteins cannot be detected. In a cellular context that is nonpermissive for viral replication, JCV can affect oncogenic transformation. For example, JCV is highly tumorigenic when inoculated into experimental animals, including rodents and monkeys. In these animal tumors, there is expression of early T-antigen but not of late capsid proteins, nor is there viral replication. Moreover, mice transgenic for JCV T-antigen alone develop tumors of neural tube origin. Detection of JCV genomic sequences and expression of viral T-antigen and agnoprotein suggest a possible association of this virus with a variety of human brain and non-CNS tumors. Here, we discuss the mechanisms involved in JCV oncogenesis, briefly review studies that do and do not support a causative role for this virus in human CNS tumors, and identify key issues for future research.

Early growth response-1 protein is induced by JC virus infection and binds and regulates the JC virus promoter

JC virus (JCV) is a human polyomavirus that can emerge from a latent state to cause the cytolytic destruction of oligodendrocytes in the brain resulting in the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Previous studies described a cis-acting transcriptional regulatory element in the JCV non-coding control region (NCCR) that is involved in the response of JCV to cytokines. This consists of a 23 base pair GGA/C rich sequence (GRS) near the replication origin (5112 to +4) that contains potential binding sites for Sp1 and Egr-1. Gel shift analysis showed that Egr-1, but not Sp1, bound to GRS. Evidence is presented that the GRS gel shift seen on cellular stimulation is due to Egr-1. Thus, TPA-induced GRS gel shift could be blocked by antibody to Egr-1. Further, the TPA-induced GRS DNA/protein complex was isolated and found to contain Egr-1 by Western blot. No other Egr-1 sites were found in the JCV NCCR. Functionally, Egr-1 was found to stimulate transcription of JCV late promoter but not early promoter reporter constructs. Mutation of the Egr-1 site abrogated Egr-1 binding and virus with the mutated Egr-1 site showed markedly reduced VP1 expression and DNA replication. Infection of primary astrocytes by wild-type JCV induced Egr-1 nuclear expression that was maximal at 5–10 days post-infection. Finally, upregulation of Egr-1 was detected in PML by immunohistochemistry. These data suggest that Egr-1 induction may be important in the life cycle of JCV and PML pathogenesis.

The Effects of Natural Products on Multiple Sclerosis Disease

Multiple sclerosis (MS) is an inflammatory disease of the Central Nervous System (CNS) that is characterized by intermittent damage to myelin caused by the destruction of oligodendrocytes. It is the major cause of non-traumatic disability in young adults with considerable social impact and economic consequences. Worldwide, MS may affect 2.5 million individuals. Approximately 400,000 Americans acknowledge having MS and every week about 200 new cases of MS are diagnosed. Naturopaths use both a broad range and multiple complementary and alternative medicine (CAM) therapies for treating MS and report treatment effectiveness on the following outcomes: quality of life; symptom severity; relapse rates; and disease progression. The Human body is part of nature and keeping it in rhythm with nature by taking natural products (NP) ensures a strong system. There are some putative NP in MS treatment like Asperlicin, fungal metabolites Lovastatin and Ciclosporin, Botulinum toxin type A, Sativex, herbal medicine such as St. John's wort, valerian, cranberry, ginkgo biloba, cannabis [1], curcuma and ginger [2]. Echinacea, Astragalus, Asian ginseng, Siberian ginseng, and Garlic are used as immune stimulating herbs. Bee venom therapy [3], traditional Chinese medicine, Ayurveda and Homeopathy [4] are alternative therapies for MS [5]. The treatments of MS are expensive and associate with uncomfortable side effects that place a burden on patients [6]. One of the important role of the National Health Service is providing health services including an appropriate treatment (less expensive with slight side effects) and NP can be suitable choice.

Leucoencefalopatía multifocal progresiva en la provincia de Cádiz, España

Progressive multifocal leukoencephalopathy (PML), which is caused by the reactivation of an infection due to the JC human polyoma virus, affects immunocompromised patients and more especially those infected by the human immunodeficiency virus. It produces a multifocal neurological clinical picture due to the destruction of oligodendrocytes and the subsequent demyelination.To analyse the epidemiological, semiological and radiological characteristics of a sample of patients diagnosed with PML in the province of Cadiz, and to study their rates of survival.Our sample consisted of 23 patients with PML who presented an unfavourable immunological situation and deficient therapeutic compliance. Factors studied included time to progression of the symptoms, clinical features, neuroimaging and survival.The mean time elapsed between the appearance of symptoms and diagnosis was 30 days. There was a wide range of manifestations: motor symptoms were the most prevalent and cognitive compromise was far less common. All the patients submitted to magnetic resonance imaging of the head and only eight of those who underwent computerised axial tomography displayed multiple insults. The mean survival time was 60 days in the case of the seven deaths and over two years in those who survived.The symptoms of the patients were similar to those reported in the literature, except for the absence of dementia. Magnetic resonance imaging was better than tomography at detecting multiple, dispersed insults and is more cost-effective for diagnosing PML. The survival time of most of the patients was higher than that reported in previous studies.

Progressive multifocal leukoencephalopathy in rheumatic diseases: Evolving clinical and pathologic patterns of disease

Progressive multifocal leukoencephalopathy (PML) is a rare, serious, and usually fatal demyelinating disease that occurs predominantly in severely immunosuppressed patient populations. The etiologic agent is the JC virus (JCV), a polyomavirus that is widely distributed as a latent infection in the general population but becomes activated, leading to destruction of myelin-producing oligodendrocytes. Patients who survive this complication are left with devastating neurologic sequelae. PML has been described mainly in patients infected with the human immunodeficiency virus (HIV). However, other immunosuppressed patient populations, including those with malignancies, organ transplants, and systemic lupus erythematosus (SLE) (1–20) and other rheumatic diseases (22–32), are at risk of developing this complication. The appearance of PML in 0.1% of patients treated in clinical trials with the biologic therapeutic agent natalizumab (33,34), an antagonist of 4 integrin, greatly hindered the development of this promising new agent for the treatment of multiple sclerosis (MS), as well as plans for expanded indications for this agent in Crohn’s disease and rheumatoid arthritis (RA), for which it was already in clinical trials. In addition, on December 18, 2006, the US Food and Drug Administration (FDA) in conjunction with Genentech and Biogen Idec, the makers of rituximab, a recently approved biologic agent for the treatment of RA, issued a warning to health care providers, informing them that 2 patients receiving rituximab for the treatment of SLE (an unapproved indication) had developed PML (35). Recent years have witnessed advances in better understanding of the pathologic response to JCV and the pathogenesis of PML (36). An evolving clinical picture is emerging: PML is a protean disease that is difficult to distinguish clinically from immune-mediated diseases of the central nervous system (CNS), such as MS, neuropsychiatric SLE, and vasculitis of the CNS (37,38). Thus, it is timely to review PML. We describe herein the microbiology, epidemiology, immunology, and pathology of PML, its changing clinical and pathologic spectrum, recent advances in our understanding of the pathogenesis of PML, and its relevance to physicians treating patients with rheumatic disorders. We report the results of a systematic literature review of all 36 patients with rheumatic diseases who have developed PML, including a previously unreported case in a patient treated at Cleveland Clinic. Nearly two-thirds of the cases of PML occurred in patients with SLE, and many cases of PML in SLE occurred in patients who had had minimal immunosuppression, which raises the possibility that SLE itself may predispose to PML.

Activation of the subventricular zone in multiple sclerosis: Evidence for early glial progenitors

In multiple sclerosis (MS), oligodendrocyte and myelin destruction lead to demyelination with subsequent axonal loss. Experimental demyelination in rodents has highlighted the activation of the subventricular zone (SVZ) and the involvement of progenitor cells expressing the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the repair process. In this article, we studied the distribution of early PSA-NCAM(+) progenitors in the SVZ and MS lesions in human postmortem brains. Compared with controls, MS SVZ showed a 2- to 3-fold increase in cell density and proliferation, which correlated with enhanced numbers of PSA-NCAM(+) and glial fibrillary acidic protein-positive (GFAP(+)) cells. PSA-NCAM(+) progenitors mainly were Sox9(+), and a few expressed Sox10 and Olig2, markers of oligodendroglial specification. PSA-NCAM(+) progenitors expressing Sox10 and Olig2 also were detected in demyelinated MS lesions. In active and chronic active lesions, the number of PSA-NCAM(+) progenitors was 8-fold higher compared with chronic silent lesions, shadow plaques, and normal-appearing white matter. In active and chronic active lesions, PSA-NCAM(+) progenitors were more frequent in periventricular lesions (30-50%) than in lesions remote from the ventricular wall. These data indicate that, as in rodents, activation of gliogenesis in the SVZ occurs in MS and suggest the mobilization of SVZ-derived early glial progenitors to periventricular lesions, where they could give rise to oligodendrocyte precursors. These early glial progenitors could be a potential target for therapeutic strategies designed to promote myelin repair in MS.