Differential Effects Of IL-21 During Initiation And Progression Of AutoImmunity Against NeuroAntigen
Vollmer TL, Liu R, Price M, Rhodes S, La Cava A, Shi FD
J Immunol 2005 Mar 1;174(5):2696-2701
Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013
The Cytokine IL-21 is closely related to IL-2 and IL-15, a Cytokine family that uses the common gamma-chain for signaling. IL-21 is expressed by activated CD4+ T-Cells.
We examined the role of IL-21 in the AutoImmune Disease Experimental Autoimmune Encephalomyelitis (EAE), an animal model for human Multiple Sclerosis.
IL-21 administration before induction of EAE with a NeuroAntigen, Myelin Oligodendrocyte Glycoprotein Peptide 35-55, and adjuvant enhanced the inflammatory influx into the CNS.
As well as the severity of EAE, Autoreactive T-Cells purified from IL-21-treated mice transferred more severe EAE than did the control Encephalitogenic T Cells.
No such effects were observed when IL-21 was administered after EAE progressed. Additional studies demonstrated that IL-21 given before the induction of EAE boosted NK Cell function, including secretion of IFN-γ.
Depletion of NK Cells abrogated the effect of IL-21. Therefore, IL-21, by affecting NK Cells, has differential effects during the initiation and progression of AutoImmune responses against NeuroAntigens.
Andrews HE, Nichols PP, Bates D, Turnbull DM
Med Hypotheses 2005;64(4):669-77
University of Newcastle upon Tyne, The Medical School, Department of Neurology, Framlington Place, NE2 4HH, UK
Multiple Sclerosis is the most common Inflammatory DeMyelinating Disease of the Central Nervous System and is the leading cause of non traumatic Neurological disability in young adults.
In recent years it has become increasingly evident that Axonal degeneration is a key player in the pathogenesis of disability in MS but the mechanisms that lead to Axonal Damage are not fully understood.
It seems likely that the causes of Axonal Damage vary at different stages of the disease and several theories have evolved that address the mechanisms leading to Axonal Loss in the acute stages of DeMyelination.
There has been relatively little attention given to investigation of the mechanisms involved in chronic Axonal Loss in the Progressive stages of MS.
We propose a hypothesis that Mitochondria play a key role in this chronic Axonal Loss.
Following DeMyelination there is redistribution of Sodium Channels along the Axon and Mitochondria are recruited to the DeMyelinated regions, to meet the increased energy requirements necessary to maintain Conduction.
The Mitochondria present within the chronically DeMyelinated Axons will be functioning at full capacity. The Axon may well be able to function for many years due to these adaptive mechanisms
But, we propose that eventually, despite AntiOxidant defences, free radical damage will accumulate and Mitochondrial function will become compromised.
ATP concentration within the Axon will decrease and the effect on Axonal function will be profound.
The actual cause of cell death could be due to a number of mechanisms related to Mitochondrial dysfunction including failure of Ionic homeostasis, Calcium influx, Mitochondrial mediated cell death or impaired Axonal Transport.
Whatever the cause of Axonal Loss our hypothesis is that Mitochondria are central to this process.
We explore steps to test this hypothesis and discuss the possible therapeutic approaches which target the Mitochondrial mechanisms that may contribute to chronic Axonal loss.
Marrie RA, Fisher E, Miller DM, Lee JC, Rudick RA
J Neurol Sci 2005 Feb 15;228(2):161-6
The Cleveland Clinic Foundation, Department of Neurology (Mellen Center), 9500 Euclid Avenue, Cleveland, OH 44195, USA
Functional imaging studies have demonstrated a relationship between Fatigue and altered Cerebral activation patterns in Multiple Sclerosis patients, but no relationship between Fatigue and Brain Atrophy has been demonstrated.
We hypothesized that the subjective complaint of Fatigue would predict the severity of destructive Brain pathology.
We assessed the relationship between Fatigue and Brain Atrophy longitudinally.
In a cohort of 134 patients previously enrolled in a 2-year clinical trial of Interferon-beta-1a and re-evaluated 8 years after randomization into the trial.
Brain Atrophy was measured using the Brain Parenchymal Fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8.
Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8.
Linear regression analyses were used to assess the relationship between changes in Fatigue and Atrophy progression.
Worsening Fatigue on the SIPSR during the initial 2 years was significantly associated with progressive Brain Atrophy over the subsequent 6 years.
The relationships between Fatigue and Brain Atrophy were independent of changes in disability, mood, or other MRI characteristics.
This suggests that the subjective complaint of Fatigue is linked to destructive pathologic processes in RRMS patients.
Ersoy E, Kus CN, Sener U, Coker I, Zorlu Y
Eur J Neurol 2005 Mar;12(3):208-11
SSK Hospital, Manisa, Turkey
The incidence of the NeuroPathological lesions and the severity of the clinical symptoms in Multiple Sclerosis (MS) are correlated with the amount of the transferred AutoTeactive T-Cells.
The balance between the T-helper 1 (Th1) and T-helper 2 (Th2) Cytokine phenotypes may affect the activity of the disease in MS patients. InterLeukin-10 (IL-10) is a Cytokine secreted by Th2 cells.
Thus, it has been thought that inducing IL-10 may have therapeutic effects in the treatment of MS patients. In this study, in order to determine whether different types of prophylaxis change the secretion of IL-10.
We measured the levels of IL-10 in Relapsing/Remitting Multiple Sclerosis (RRMS) patients receiving Interferon-beta-1b (IFN-ß-1b ) or Azathioprine (AZA).
Our study consisted of RRMS patients (n = 45) and healthy subjects (n = 15) as control group.
Patients were categorized into three groups as those receiving either IFN-ß-1b or AZA and those not receiving prophylaxis. Each group was compared with the control group.
Serum IL-10 levels were determined using ELISA method. IL-10 levels of those receiving IFN-ß-1b were found to be significantly higher than that of other groups.
These results support that the ability of inducing AntiInflammatory Cytokine IL-10 plays a role in the clinical advantage of IFN-ß-1b in MS treatment.
Regional Brain Atrophy Evolves Differently In Patients With Multiple Sclerosis According To Clinical Phenotype
Pagani E, Rocca MA, Gallo A, Rovaris M, Martinelli V, Comi G, Filippi M
AJNR Am J NeuroRadiol 2005 Feb;26(2):341-6
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Milan, Italy
Background And Purpose
Progressive Brain Atrophy is a well-known feature of Multiple Sclerosis (MS). We characterized the spatial evolution of Atrophy in different MS phenotypes.
Dual-echo and T1-weighted MR images were obtained in 70 patients with MS and 10 healthy control subjects at entry and after 15 months.
Within-group changes in regional Atrophy were assessed by applying Structural Image Evaluation Using Normalization of Atrophy software and statistical parametric mapping analysis. Reported differences are for P < .001>.
During follow-up, patients with Relapsing/Remitting MS (RRMS) differences significant Atrophy around the Ventricular System; PeriCerebellar Spaces; Cerebellar Tentorium; Putamen; Corpus Callosum; Cingulate Sulcus; Hippocampus; Parieto-Occipital Fissure; Lateral Fissure; and Frontal, Parietal, Temporal, and Occipital Cortex.
Patients with Secondary/Progressive MS developed significant Atrophy of the Cingulate Sulcus; Pulvinar; Caudate Nucleus; Anterior Orbital Gyrus; Mammillary Body; Fourth Ventricle; and regions of Frontal, Parietal, Temporal, and Occipital Cortex.
Patients with Primary/Progressive MS developed significant Atrophy of the BiLateral Central Sulcus; Caudate Nucleus; PrePontine and Quadrigeminal Cisterns; Lateral Ventricles; and regions of Frontal, Parietal, Temporal, and Occipital Cortex.
In all phenotypes, the development of Atrophy in some regions was significantly correlated with the accumulation of T2- and T1-visible lesions and clinical disability (r = -0.57 to -0.86).
In MS, Brain Atrophy develops involving different structures in the different phenotypes.
While Ventricular Enlargement is predominant in RRMS, Cortical Atrophy seems to be more important in the Progressive forms.
Measures of Regional Brain Atrophy were significantly correlated with disability, suggesting that this approach is promising for bridging the gap between clinical and MR imaging findings in MS.
Quantification Of Magnetization Transfer Rate And Native T1 Relaxation Time Of The Brain: Correlation With Magnetization Transfer Ratio Measurements In Patients With Multiple Sclerosis
Karampekios S, Papanikolaou N, Papadaki E, Maris T, Uffman K, Spilioti M, Plaitakis A, Gourtsoyiannis N
NeuroRadiology 2005 Mar;47(3):189-96
University Hospital of Heraklion, University of Crete, Department of Radiology, P.O. Box 1352, Heraklion, Crete, 71110, Greece
The purpose of this paper is to perform quantitative measurements of the Magnetization Transfer Rate (k-for) and native T1 relaxation time (T1free) in the Brain Tissue of normal individuals and patients with Multiple Sclerosis (MS).
By means of multiple gradient echo acquisitions, and to correlate these measurements with the Magnetization Transfer Ratio (MTR).
Quantitative Magnetization Transfer imaging was performed in five normal volunteers and 12 patients with Relapsing/Remitting MS on a 1.5 T Magnetic Resonance (MR) scanner.
The T1 relaxation time under Magnetization Transfer irradiation (T1sat) was calculated by means of fitting the signal intensity over the flip angle in several 3D spoiled gradient echo acquisitions (3 degrees, 15 degrees, 30 degrees, and 60 degrees ).
While a single acquisition without MT irradiation (flip angle of 3 degrees ) was utilized to calculate the MTR. The k-for and T1free constants were quantified on a pixel-by-pixel basis and parametric maps were reconstructed.
We performed 226 measurements of k-for, T1free, and the MTR on Normal White Matter (NWM) of healthy volunteers (n=50), and Normal-Appearing White Matter (NAWM) and pathological Brain areas of MS patients (n=120 and 56, respectively).
Correlation coefficients between k-for-MTR, T1free-MTR, and T1free-k-for were calculated.
Lesions were classified, according to their characteristics on T1-weighted images, into:
- IsoIntense (compared to White Matter)
- Mildly HypoIntense, showing signal intensity
- Lower than White Matter and higher than Gray Matter
- Severely HypoIntense, revealing signal intensity
"Dirty" White Matter (DWM) corresponded to areas with diffused high signal, as identified on T2-weighted images.
Strong correlation coefficients were obtained between MTR and k-for for all lesions studied (r(2)=0.9, p < 0.0001), for mildly HypoIntense plaques (r(2)=0.82, p < 0.0001), and for DWM (r(2)=0.78, p=0.0007).
In contrast, comparison between MTR and T1free values yielded rather low correlation coefficients for all groups assessed.
In severely HypoIntense lesions, an excellent correlation was found between k-for and T1free measurements (r(2)=0.98, p < 0.0001).
Strong correlations between k-for and T1free were found for the rest of the subgroups, except for the NAWM, in which a moderate correlation was obtained (r(2)=0.5, p < 0.0001).
We conclude that k-for and T1free measurements are feasible and may improve our understanding of the pathological Brain changes that occur in MS patients.
Rio J, Tintore M, Tellez N, Nos C, Galan I, Montalban X
Med Clin (Barc) 2005 Feb 5;124(4):140-1
Unitat de NeuroImmunologia Clinica, Hospital Universitari Vall d'Hebron, Barcelona, Espana
Background And Objective
Our goal was to evaluate the relation between the presence of Neutralizing AntiBodies (NABs) to Interferon-ß-1b in Multiple Sclerosis (MS) patients and the clinical evolution in the following years.
Patients And Method
As we previously reported, we tested NABs in 68 patients treated with Interferon-ß-1b after 2 years of treatment.
We prospectively followed this cohort every three months for a minimum period of 6 years collecting data about relapses, disability, secondary effects and dropouts.
During the 6 year follow-up period, the annualized relapse rate did not differ between patients with and patients without NABs.
A sustained progression was observed in 33% of positive patients and in 38% of patients without NABs. No differences were found in the proportion of patients who reached an EDSS score of 6. Secondary effects were similar in both groups.
Although our results do not vouch for a negative effect of the presence of NABs on the clinical evolution of MS patients treated with Interferon-ß.
Further longitudinal studies to clarify the real effect of the presence of NABs in these patients are still much needed.