Link Between ExcitoToxic Oligodendroglial Death And DeMyelinating Diseases
Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A, Sanchez-Gomez MV
Trends NeuroSci 2001 Apr 1;24(4):224-230
Universidad del Pais Vasco, Departamento de Neurociencias, 48940, Leioa, Spain
Oligodendrocytes, the Myelinating cells of CNS Axons, are highly vulnerable to ExcitoToxic signals mediated by Glutamate receptors of the AMPA and Kainate classes.
Receptors in these cells are commonly activated by Glutamate that is released from Axons and Glial Cells.
In addition, Oligodendrocytes contribute to the control of ExtraCellular Glutamate levels by means of their own transporters.
However, acute and chronic alterations in Glutamate homeostasis can result in overactivation of AMPA and Kainate receptors and subsequent ExcitoToxic Oligodendroglial death.
Furthermore, DeMyelinating lesions caused by ExcitoToxins can be similar to those observed in Multiple Sclerosis.
This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the Neurological score of animals with Experimental AutoImmune EncephaloMyelitis, indicates that Oligodendrocyte ExcitoToxicity could be involved in the PathoGenesis of DeMyelinating Disorders.
Two Subsets Of Dendritic Cells Are Present In Human CerebroSpinal Fluid
Pashenkov M, Huang YM, Kostulas V V, Haglund M, Soderstrom M, Link H
Brain 2001 Mar;124(Pt 3):480-492
Karolinska Institutet, Huddinge Univ Hospital, Divisions of Neurology, Infectious Diseases and Ophthalmology, Stockholm, Sweden
Little is known about the presence of Dendritic Cells in the human CNS.
To investigate the occurrence of Dendritic Cells in the CSF, paired blood/CSF samples from patients with Multiple Sclerosis, Acute Optic Neuritis, Lyme NeuroBorreliosis, other inflammatory Neurological Diseases and non-inflammatory Neurological Diseases were examined using flow cytometry.
Almost all CSF samples contained Myeloid (lin- CD11c+ HLA-DR++ CD123(dim)) and plasmacytoid (lin-CD11c- HLA-DR+ CD123(high)) Dendritic Cells. In Non-Inflammatory Neurological Diseases, Dendritic Cells of either subset only constituted up to 1% of CSF MonoNuclear Cells.
Myeloid CSF Dendritic Cells were elevated in Optic Neuritis, NeuroBorreliosis and other inflammatory Neurological Disorders, while Plasmacytoid Dendritic Cells were elevated in all NeuroInflammatory conditions studied, with especially high numbers in NeuroBorreliosis.
Numbers of CSF Dendritic Cells correlated with the common parameters of CNS inflammation.
The Myeloid Dendritic Cells in CSF expressed higher levels of HLA-DR, CD86, CD80 and CD40 than those in blood, whereas expression of these molecules by Plasmacytoid Dendritic Cells was equal in blood and CSF.
Both CSF and blood Dendritic Cells expressed the Chemokine receptor CCR5. This is the first demonstration that Dendritic Cells are present in human CSF and that Plasmacytoid Dendritic Cells are present in a Non-Lymphoid compartment.
Myeloid and Plasmacytoid Dendritic Cells in CSF may contribute to orchestration of the local Immune Responses.
Mandler RN, Dencoff JD, Midani F, Ford CC, Ahmed W, Rosenberg GA
Brain 2001 Mar;124(Pt 3):493-498
Univ of New Mexico Health Sciences Center, Depts of Neurology, NeuroScience and Cell Biology and Physiology, Albuquerque, New Mexico, USA
Matrix MetalloProteinases (MMPs) are increased in the CSF of patients with Multiple Sclerosis. Devic's Neuromyelitis Optica (DNO) is a DeMyelinating syndrome that involves the Optic Nerve and Cervical Cord but differs pathologically from Multiple Sclerosis.
Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in Multiple Sclerosis would be absent in patients with DNO.
CSF was collected from 23 patients with Relapsing/Remitting or Secondary/Progressive Multiple Sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers.
Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of Multiple Sclerosis patients but not in that of DNO patients.
Zymography, reverse zymography and ELISA (Enzyme-Linked ImmunoSorbent Assay) were used to measure Gelatinase A (MMP-2), Gelatinase B (MMP-9) and Tissue Inhibitors of MetalloProteinases (TIMPs).
Zymograms showed that Multiple Sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups.
We conclude that Multiple Sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.
Glatiramer Acetate Blocks InterLeukin-1-Dependent Nuclear Factor-kappaB Activation And RANTES Expression In Human U-251 MG Astroglial Cells
Li QQ, Bever CT
Brain Res Mol Brain Res 2001 Feb 19;87(1):48-60
Univ of Maryland School of Medicine, Depts of Neurology, Pharmacology, and Experimental Therapeutics, 21201, Baltimore, MD, USA
RANTES is a basic 8-kDa polypeptide of the C-C Chemokine subfamily with strong ChemoAttractant activity for T-Lymphocytes and Monocytes/Macrophages that are implicated in the PathoGenesis of Multiple Sclerosis (MS) lesions.
Glatiramer Acetate is a drug recently approved for the treatment of MS. We therefore investigated the effect of Glatiramer Acetate on RANTES expression in Glial Cells in vitro.
Treatment of human U-251 MG Astroglial cells with Glatiramer Acetate blocks IL-1ß-induced RANTES Chemokine production in a dose- and time-dependent manner.
Glatiramer Acetate also decreased steady-state levels of RANTES mRNA in these cells, which was attributable to reduced transcription, as assessed by nuclear run-on assays.
In addition, we showed that NF-kappaB may be the transcriptional activator responsible for the IL-1ß-mediated RANTES Gene expression in this system.
Our data indicated that the IL-1ß-induced increase in RANTES was associated with an increase in in vitro nuclear extract binding activity specific for the NF-kappaB site in the promoter region of the RANTES gene.
The increases in RANTES mRNA and protein expression were suppressed by the NF-kappaB inhibitors GlioToxin, IsoHelenin, and Pyrrolidine Dithiocarbamate (PDTC).
Furthermore, we demonstrated that the increase in NF-kappaB DNA-binding activity was prevented by pretreatment with Glatiramer Acetate or the NF-kappaB inhibitors.
Our results suggest that Glatiramer Acetate may inhibit IL-1ß-stimulated RANTES expression in human Glial Cells by blocking NF-kappaB activation, thus identifying part of the molecular basis for its anti-inflammatory and ImmunoSuppressive effects in DeMyelinating Diseases.
Induction Of sTNF-R1 And sTNF-R2 By Interferon beta-1b In Correlation With Clinical And MRI Activity
Laske C, Oschmann P, Tofighi J, Kuehne SB, Diehl H, Bregenzer T, Kraus J, Bauer R, Chatzimanolis N, Kern A, Traupe H, Kaps M
Acta Neurol Scand 2001 Feb;103(2):105-13
Justus-Liebig Univ, Dept of Neurology, Giessen, Germany
PMID# 11227128; UI# 21118711
To investigate the influence of Interferon-1b (IFN-ß-1b) on the Serum levels of sTNF -R1, sTNF-R2 and TNF-beta in patients with Multiple Sclerosis (MS) in correlation with clinical and MRI activity.
Materials And Methods
Serum samples were obtained every 3 months from 24 patients treated with 8 x 10(6) U of IFN-ß-lb every other day (treatment group).
And from 21 patients without any ImmunoModulatory therapy (control group) over a 15-month observation period.
The Cytokine levels were measured by ELISA. Cranial MRI was performed every 6 months to determine the burden of disease of every patient.
In the treatment group we found an obvious increase of sTNF-R1 and sTNF-R2 (P < 0.001) and relatively stable Serum levels of TNF-ß with no statistical significance (P = 0.56).
In the control group, sTNF-R1 showed a significant decrease (P < 0.001) during the same observation period of 15 months.
During the 15-month observation period, the MRI-responders group had significant larger mean AUC (area under the concentration-time curve) values of sTNF-R1 (P = 0.04) and sTNF-R2 (P = 0.01) when compared to the group of MRI nonresponders.
The present data suggest that IFN-ß-1b induces the expression and shedding of TNF-R1 and TNF-R2. The magnitude of an increase of sTNF-Rs may be a marker for the effectiveness of treatment with IFN-ß-1b.