Astrocyte-Associated Axonal Damage In Pre-Onset Stages Of Experimental Autoimmune Encephalomyelitis
Wang D, Ayers MM, Catmull DV, Hazelwood LJ, Bernard CC, Orian JM
Glia 2005 Aug 15;51(3):235-40
La Trobe University, NeuroImmunology Laboratory, Department of BioChemistry, Bundoora, Victoria, Australia
Recent studies of Axon-Glia and Glia-Glia communication have emphasized interactivity and interdependence between Central Nervous System (CNS) components.
Concurrently, data from Imaging, BioChemical, and Morphological studies have changed the view of Multiple Sclerosis (MS) from a NeuroInflammatory condition with primary DeMyelination to one in which cumulative Axonal Damage drives progression.
We therefore studied Axonal Damage in the context of inflammation and Glial responses, from the pre-clinical to onset stage of murine Experimental Autoimmune Encephalomyelitis (EAE), an established MS model.
We report three major findings:
- The first evidence of Axonal injury before significant T-Cell entry into the Parenchyma
- Coincidence of the earliest manifestation of Axonal Damage and Astrocytic responses
- An association between accumulation of Axonal and Astrocytic changes and specific forms of MS
These data demonstrate the relationship between the initiation of Axonal injury and early inflammation.
Significantly, we show that, in common with a growing number of NeuroDegenerative conditions, the pathology of murine EAE is characterized by early active contribution from Astrocytes.
This marks a change in the understanding of the role of Astrocytes in MS pathogenesis and has important implications for the development of NeuroProtective strategies.
(c) 2005 Wiley-Liss, Inc.
The Activation Of Memory CD4+ T-Cells And CD8+ T-Cells In Patients With Multiple Sclerosis
Okuda Y, Okuda M, Apatoff BR, Posnett DN
J Neurol Sci 2005 Aug 15;235(1-2):11-17
Weill Medical College of Cornell University, Division of Hematology-Oncology, Department of Medicine, 1300 York Avenue, New York, NY 10021, USA; Osaka University Graduate School of Medicine, Department of Neurology, D-4, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
To reevaluate whether an association exists between the clinical course of Multiple Sclerosis (MS) and the activation of Memory T-Cells, we investigated the phenotype of T-Cells in peripheral blood and CerebroSpinal Fluid (CSF) of patients with MS using five-color flow cytometry.
A cross-sectional study with 39 Relapsing/Remitting MS patients demonstrated that the percentage of CD25+CD45RO+CD4+CD3+ cells was significantly increased in peripheral blood as well as in CSF of active MS patients compared with inactive MS patients.
A longitudinal study with 11 Relapsing/Remitting MS patients also showed a higher percentage of CD25+CD45RO+CD4+CD3+ cells in peripheral blood at the phase of exacerbation than during remission.
On the other hand, regardless of the disease activity, the percentage of CD25+CD45RO+CD8+CD3+ cells in peripheral blood was significantly higher in patients with MS than in healthy control subjects.
A lower percentage of CD25+CD45RO+CD8+CD3+ cells in CSF was observed in active MS patients compared with inactive MS patients.
These results suggest that the activation of Memory CD4+ T-Cells is associated with the exacerbation of MS and activation of Memory CD8+ T-Cells reflects systemic Immunological dysregulation in MS patients.
Transient as well as continuous activation of T-Cells by recall Antigens may be involved in the disease course of MS.
Relevance Of Immunological Variables In NeuroBorreliosis And Multiple Sclerosis
Bednarova J, Stourac P, Adam P
Acta Neurol Scand 2005 Aug;112(2):97-102
Masaryk University, Faculty Hospital, Department of Clinical MicroBiology, Brno, Czech Republic
The aims were to investigate the frequency of Intrathecal synthesis of specific AntiBodies against Measles (M), Rubella (R) and Varicella Zoster (Z) Viruses (MRZ reaction) as a diagnostic marker between Multiple Sclerosis (MS) and NeuroBorreliosis (NB) groups and to postulate the most typical CerebroSpinal Fluid (CSF) variables profile of these entities.
Three cohorts of patients were investigated: MS (n = 42), NB (n = 27) and Other Neurological Diseases (OND) (n = 15).
Measles, Rubella, Varicella Zoster and Borrelia-specific IgG AntiBodies were measured by ELISA, Q(alb) (CSF/Serum Albumin ratio) as a marker of Blood-CSF Barrier function and specific AntiBody Indices (AI) were calculated according to relevant formulae.
IgG OligoClonal Bands (OB) were detected by isoelectric focusing and immunoenzymatic staining.
Eighty-eight percent of MS patients had positive MRZ reaction and 26.2% had positive Anti-Borrelia AI.
Eighty-nine percent of NB patients had positive Anti-Borrelia AI and two patients had individually Anti-Measles and Rubella positive AI.
MS-CSF variables profile included the presence of IgG OB in 81%, elevated Q(alb) in 31% and normal cell count in 66.7%, Of NB patients IgG OB were positive in 74%, elevated Q(alb) in 81.5% and normal cell count in 7.4%.
MRZ reaction was proved as statistically significant marker in differential diagnosis between MS and NB.
Typical CSF variables profile of these two entities is highly supportive, especially when MRZ is included.
Effects Of Sex Hormones On CoStimulatory Molecule Expression In Multiple Sclerosis
Pelfrey CM, Moldovan IR, Cotleur AC, Zamor N, Rudick RA
J NeuroImmunol 2005 Jul 18
Lerner Research Institute, Cleveland Clinic Foundation, Department of NeuroSciences, NC30, 9500 Euclid Ave., Cleveland, OH 44195, United States; Institute of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH, 44106, United States
Sex Hormones play a central role as modulators of Immune responses and AutoImmune Diseases.
We hypothesized that suppression of MS disease during pregnancy may be mediated by Sex Steroid Hormones via regulation of CoStimulatory molecules such as CD40L or CD80/CD86 (B7-1/B7-2).
We tested two sex Hormones that are implicated in Immune suppression during pregnancy: Estriol and Progesterone. We also examined whether this regulation is gender-specific or disease-related.
PBMC from untreated Relapsing/Remitting Multiple Sclerosis (RR MS) patients and controls were examined for expression of T-Cell and Monocyte CoStimulatory molecules following Mitogen stimulation in the presence or absence of Sex Hormones.
In the absence of Hormones, we confirmed that mitogen stimulation induced significantly more CD40L on the surface of CD4+ T-Cells in MS patients compared to controls, and we extend these findings by showing there were no gender differences in induction of CD40L.
Although supra-physiologic doses of Hormones mildly suppressed CD40L expression on activated T-Cells, in vitro exposure to typical pregnancy-related physiologic doses of Estriol or Progesterone showed very little or no suppression of CD40L.
On Monocytes, neither Estriol nor Progesterone significantly altered the expression of CD80/CD86.
These results suggest that physiologic doses of Estriol or Progesterone cannot alter CD40L on T-Cells or CD80/CD86 on Monocytes sufficiently to explain the improvement observed in MS during pregnancy.
Thus, although amelioration of MS and other AutoImmune Diseases during pregnancy is thought to be due to increased sex Hormones, the present results do not support a role for suppression of CoStimulation via Estriol or Progesterone.
The Potential Role For Statins In The Treatment Of Multiple Sclerosis
Curr Opin Investig Drugs 2005 Jul;6(7):667-71
University of Otago Medical School, Department of Pharmacology and Toxicology, Dunedin, New Zealand
In 1995, it was observed that the administration of Statins to Heart transplant patients resulted in fewer episodes of rejection, thus a role for Statins in the treatment of Inflammatory Disease was suggested.
To date, the results of a single, open-label trial in Multiple Sclerosis patients have demonstrated that treatment with one of the Statins, Simvastatin, reduced the number and volume of lesions, as observed using Gadolinium-enhancing Magnetic Resonance Imaging.
While the results of this first study seem promising, the rationale for using a Cholesterol-lowering drug in a DeMyelinating Disease must be addressed, in addition to the potential problems that the side effects of Statins may produce in Multiple Sclerosis patients.
The Window Of Therapeutic Opportunity In Multiple Sclerosis Evidence From MonoClonal AntiBody Therapy
Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, Waldmann H, Compston DA
J Neurol 2005 Jul 27
Addenbrooke's Hospital, Department of Clinical NeuroSciences, Box 165, Cambridge CB2 2QQ, UK
From 1991-2002, we treated 58 patients with Multiple Sclerosis (MS) using the humanized MonoClonal AntiBody, Campath- 1H, which causes prolonged T-Lymphocyte depletion.
Clinical and surrogate markers of inflammation were suppressed. In both the Relapsing/Remitting (RR) and Secondary/Progressive (SP) stages of the illness, Campath-1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both
p < 0.001).
Remarkably, MRI scans of patients with SP disease, treated with Campath-1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease.
Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting Cerebral Atrophy, attributable to ongoing Axonal loss.
The rate of Cerebral Atrophy was greatest in patients with established Cerebral Atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04).
In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath-1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these patients with unusually active disease.
In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.
We speculate that this represents the beneficial effects of early rescue of Neurons and Axons from a toxic inflammatory environment, and that prevention of DeMyelination will prevent long-term Axonal Degeneration.
These concepts are currently being tested in a controlled trial comparing Campath-1H and IFN-ß in the treatment of drug-naive patients with early, active RR MS.
Brain Atrophy And Lesion Load In A Large Population Of Patients With Multiple Sclerosis
Tedeschi G, Lavorgna L, Russo P, Prinster A, Dinacci D, Savettieri G, Quattrone A, Livrea P, Messina C, Reggio A, Bresciamorra V, Orefice G, Paciello M, Brunetti A, Coniglio G, Bonavita S, Di Costanzo A, Bellacosa A, Valentino P, Quarantelli M, Patti F, Salemi G, Cammarata E, Simone IL, Salvatore M, Bonavita V, Alfano B
Neurology 2005 Jul 26;65(2):280-5
Second University of Naples, Department of Neurological Sciences, Piazza Miraglia
2, 80138 Naples, Italy
To measure White Matter (WM) and Gray Matter (GM) Atrophy and lesion load in a large population of patients with Multiple Sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method.
The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were Abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f).
Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f.
MRI data showed significant differences between patients with Relapsing/Remitting and Secondary/Progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found.
Patients with Multiple Sclerosis have significant Atrophy of both White Matter (WM) and Gray Matter (GM);
Secondary/Progressive patients have significantly more Atrophy of both WM and GM than do Relapsing/Remitting patients and a significantly higher lesion load (abnormal WM fraction);
Lesion load is related to both WM and even more to GM Atrophy;
Lesion load and WM and GM Atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and Brain Atrophy); and
GM Atrophy is the most significant MRI variable in determining the final disability.