Lymphocyte Subset Differences In Patients With Chronic Fatigue Syndrome, Multiple Sclerosis And Major Depression
Robertson MJ, Schacterle RS, Mackin GA, Wilson SN, Bloomingdale KL, Ritz J, Komaroff AL
Clin Exp Immunol 2005 Aug;141(2):326-32
Dana-Farber Cancer Institute, Harvard Medical School, Division of Hematologic Malignancies, Boston, MA, USA
Chronic Fatigue Syndrome (CFS) is a heterogeneous disorder of unknown Etiology characterized by debilitating fatigue, along with other symptoms, for at least 6 months.
Many studies demonstrate probable involvement of the Central and Autonomic Nervous System, as well as a state of generalized Immune activation and selective Immune dysfunction in patients with CFS.
The aim of this study was to compare the Lymphocyte subsets of patients with Chronic Fatigue Syndrome to those of patients with Major Depression and Multiple Sclerosis as well as those of healthy control subjects.
No differences were found in total numbers of T-Cells, B-Cells or Natural Killer (NK) Cells.
However, differences were found in T, B and NK cell subsets. Patients with Major Depression had significantly fewer resting T (CD3+/CD25-) Cells than the other groups.
Patients with Major Depression also had significantly more CD20+/CD5+ B-Cells, a subset associated with the production of AutoAntiBodies. Compared to patients with Multiple Sclerosis, patients with CFS had greater numbers of CD16+/CD3- NK Cells.
Further study will be required to determine whether these alterations in Lymphocyte subsets are directly involved in the pathophysiology of these disorders, or are secondary effects of the causal agent(s).
Kynurenine Metabolism In Multiple Sclerosis
Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L
Acta Neurol Scand 2005 Aug;112(2):93-6
University of Szeged, Department of Neurology, Szeged, Hungary
Excitatory Amino Acid Receptors are involved in the normal physiology of the Brain, and may play a role in the pathogenesis of Neurological Disorders such as Huntington's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, etc.
It has been demonstrated that the blockade of one of these Receptors ameliorates the symptoms of Experimental Allergic Encephalomyelitis, an animal model of Multiple Sclerosis (MS).
In a recent study, a decreased level of Kynurenic Acid was found in the CerebroSpinal Fluid of patients with MS. The only known endogenous excitotoxin Receptor antagonist is the Tryptophan metabolite Kynurenic Acid.
Another metabolite is Quinolinic Acid, which exerts different action: it is an ExcitoToxin Receptor Agonist. The ratio of these two metabolites is determined by the activities of Kynurenine AminoTransferase I and II (KAT I and KAT II).
In this study, we measured the activities of these Enzymes and the concentration of Kynurenic Acid in the Red Blood Cells (RBC) and in the plasma of patients with MS. KAT activities were detected both in the RBC and in the plasma.
As compared with the control subjects, the KAT I and KAT II activities were significantly higher in the RBC of the patients. The concentration of Kynurenic Acid is elevated in the plasma of MS patients, and there is a tendency to an elevation in the RBC.
These changes may indicate a compensatory protective mechanism against Excitatory NeuroToxic effects. Our data demonstrate the involvement of the Kynurenine System in the pathogenesis of MS, which may predict a novel therapeutic intervention.
E-Selectin A561C And G98T Polymorphisms Influence Susceptibility And Course Of Multiple Sclerosis
Galimberti D, Fenoglio C, Clerici R, Comi C, De Riz M, Rottoli M, Piccio L, Ronzoni M, Venturelli E, Monaco F, Poloni M, Bresolin N, Scarpini E
J NeuroImmunol 2005 Aug;165(1-2):201-5
University of Milan, IRCCS Ospedale Maggiore Policlinico, Department of Neurological Sciences, "Dino Ferrari" Center, Via F. Sforza, 35, 20122, Milan, Italy
Three hundred seven patients with MS and 300 controls were genotyped for G98T and A561C SNPs in the E-Selectin gene, and genetic data were correlated with the course of the disease.
The frequency of the T/T genotype of the G98T SNP was significantly increased in RR-MS patients compared with controls, while was absent in PP-MS. The frequency of the A561C SNP was significantly decreased in SP-MS compared with Benign RR-MS.
The T/T genotype of the G98T SNP is likely to confer an increased risk to develop MS. The A561C polymorphism seems to act as protective factor towards the progression to SP-MS.
Francis GS, Rice GP, Alsop JC; PRISMS Study Group
Neurology 2005 Jul 12;65(1):48-55
Serono International, Geneva, Switzerland
Debate continues concerning the relevance of Neutralizing AntiBody (NAB) development on the efficacy of Interferon (IFN) therapy in patients with Multiple Sclerosis (MS).
The PRISMS (Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis) Study of subcutaneous IFN-ß-1a showed significant benefit on all efficacy outcomes.
With no significant impact from NAB development on relapses at 2 years. The 2-year extension permitted longer observation following NAB development.
Exploratory post-hoc analyses of pharmacodynamic response and clinical and MRI outcomes were performed on data from 368 patients with Relapsing MS treated with IFN from study start, based on NAB status.
Persistent Nabs, above 20 NU/mL, were present in 14% of the 44-microg three times weekly (TIW) and 24% of the 22-microg TIW group over 4 years. NAB development was associated with reduced pharmacodynamic marker induction at 1 year.
Over the entire 4 years of study, relapse and disability measures were similar between NAB+ and NAB- patients.
However, once NABs developed, significant differences were noted between NAB+ and NAB- groups, particularly on MRI and relapse measures. The presence of binding AntiBodies alone did not affect outcome.
Neutralizing AntiBody development in Interferon-treated patients is correlated with reduced efficacy and is a potential cause for renewed disease activity.
Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K; Danish Multiple Sclerosis Study Group
Neurology 2005 Jul 12;65(1):33-9
Copenhagen University Hospital, Rigshospitalet, Copenhagen MS Center, Department of Neurology, DK-2100 Copenhagen, Denmark
Neutralizing AntiBodies (NABs) occur frequently in patients receiving Interferon-beta (IFN-ß) for Multiple Sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-ß therapy.
The authors used an antiviral neutralization bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-ß.
Patients were classified into three groups:
- Persistently NAB-negative patients, defined as patients without any positive samples at any time
- Definitely NAB-positive patients, defined as patients who had at least two consecutive positive samples; and
- Patients with fluctuating NAB-positive and NAB-negative samples
A total of 455 patients were included in the study. Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating.
More patients treated with IFN-ß-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-ß-1b (Betaferon) and IFN-ß-1a (Rebif).
Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive.
NABs should be measured in all patients treated with IFN-ß. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued.
Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.
Diffusion Tensor Imaging In Multiple Sclerosis: A Tool For Monitoring Changes In Normal-Appearing White Matter
Cassol E, Ranjeva JP, Ibarrola D, Mekies C, Manelfe C, Clanet M, Berry I
Mult Scler 2004 Apr;10(2):188-96
University Paul Sabatier, Department of BioPhysics and Multimodality Imaging, Toulouse-Rangueil, France
Our objectives were to determine the reproducibility of Diffusion Tensor Imaging (DTI) in volunteers.
And, to evaluate the ability of the method to monitor longitudinal changes occurring in the Normal-Appearing White Matter (NAWM) of patients with Multiple Sclerosis (MS).
DTI was performed three-monthly for one year in seven MS patients: three Relapsing/Remitting (RRMS), three Secondary/Progressive (SPMS) and one Relapsing SP.
They were selected with a limited Cerebral lesion load. Seven age- and sex-matched controls also underwent monthly examinations for three months.
Diffusivity and Anisotropy were quantified over the segmented whole SupraTentorial White Matter, with the indices of Diffusion Trace (Tr) and Fractional Anisotropy (FA).
Results obtained in volunteers show the reproducibility of the method. Patients had higher Trace and lower Anisotropy than matched controls (P < 0.0001).
Over the follow-up, both Tr and FA indicated a recovery after the acute phase in RRMS and a progressive shift towards abnormal values in SPMS.
Although this result is not statistically significant, it suggests that DTI is sensitive to microscopic changes occurring in tissue of normal appearance in conventional images.
And could be useful for monitoring the course of the disease, even though it was unable to clearly distinguish between the various PhysioPathological processes involved.
Molecular Mechanisms Of Cytokine-Induced NeuroProtection: NFkappaB And NeuroPlasticity
Barger SW, Moerman AM, Mao X
Curr Pharm Des 2005;11(8):985-98
University of Arkansas for Medical Sciences, Department of Geriatrics, Little Rock, AR 72205, USA
Since the first attempts to understand the mechanisms of learning, memory, development, and other instances of NeuroPlasticity, Gene expression has been an attractive explanation for the persistence of such processes.
It has been hypothesized that changes in the levels of expression of a Gene, or a coordinated set of Genes, would be necessary for dramatic structural changes like the growth of new Neurites.
And more subtle BioChemical changes at existing Synapses might also result from an alteration in the array of Gene products being manufactured in the relevant cells.
However, a great deal of what is classified as NeuroPlasticity is dependent on primary changes in ElectroPhysiological activity or other conditions at Synapses.
Therefore, a seminal question to those interested in the molecular underpinnings of NeuroPlasticity is that of signal transduction:
How do changes in Synaptic activity get communicated to the Nucleus?
To many who learn about the regulation of the transcription factor NFkappaB with this question in mind, its utility seems clear.
Furthermore, NFkappaB is an important signaling factor for Cytokines that appear to participate in several pathological conditions (e.g., Parkinson's Disease, Multiple Sclerosis, and Depression).
So, understanding its mechanisms of action and its relationship to other elements of Cytokine signaling may be fundamental to determining the role of the Inflammatory System in Psychiatric and NeuroDegenerative conditions.
For these reasons, NFkappaB has garnered considerable attention in various aspects of NeuroPlasticity, from long-term potentiation to the most dramatic forms of Plasticity: cell birth and death.
In a few cases, elegant experimental design has resulted in convincing evidence for the involvement of NFkappaB in specific phenomena.
However, the complexity of this transcription factor-including confusion over what exactly is meant by "NFkappaB"-has led to some misleading conclusions, as well.
This chapter highlights some of the potential red herrings to be encountered in the study of NFkappaB and will summarize the data and interpretations in which some degree of confidence can be placed.
The final answers will depend on the application of models and tools only now in development.