Human MBP-Specific T-Cells Regulate IL-6 Gene Expression In Astrocytes Through Cell-Cell Contacts And Soluble Factors
Colombatti M, Moretto G, Tommasi M, Fiorini E, Poffe O, Colombara M, Tanel R, Tridente G, Ramarli D
Glia 2001 Sep;35(3):224-33
Univ of Verona, Section of Immunology, Dept of Pathology, Verona, Italy
PMID# 11494413; UI# 21385055
One of the distinctive features of Multiple Sclerosis (MS) attacks is homing to the CNS of activated T-Cells able to orchestrate Humoral and cell-based events, resulting in Immune-mediated injury to Myelin and Oligodendrocytes.
Of the complex interplay occurring between T-Cells and CNS constituents, we have examined some aspects of T-Cell interactions with Astrocytes, the major components of the Glial Cells.
Specifically, we focused on the ability of T-Cells to regulate the Gene expression of InterLeukin-6 (IL-6) in Astrocytes, based on previous evidence showing the involvement of this Cytokine in CNS disorders.
We found that T-Cell adhesion and T-Cell soluble factors induce IL-6 Gene expression in U251 Astrocytes through distinct signaling pathways, respectively, resulting in the activation of NF-kappaB and IRF-1 transcription factors.
In a search for effector molecules at the Astrocyte surface, we found that alpha3beta1 Integrins play a role in NF-kappaB activation induced by T-Cell contact.
Whereas Interferon-gamma (IFN-) receptors dominate in IRF-1 induction brought about by T-Cell-derived soluble factors. Similar phenomena were observed also in normal fetal Astrocyte cultures.
We therefore propose that through Astrocyte induction, T-Cells may indirectly regulate the availability of a Cytokine which is crucial in modulating fate and behavior of cell populations involved in the PathoGenesis of MS inflammatory lesions.
Copyright 2001 Wiley-Liss, Inc.
Sequence Variation In The Transforming Growth Factor-ß1 (TGFß1) Gene And Multiple Sclerosis Susceptibility
Green AJ, Barcellos LF, Rimmler JB, Garcia ME, Caillier S, Lincoln RR, Bucher P, Pericak-Vance MA, Haines JL, Hauser SL, Oksenberg JR
J NeuroImmunol 2001 May 1;116(1):116-124
Univ of California at San Francisco, School of Medicine, Dept of Neurology, 513 Parnassus Avenue, S-256, 94143-0435, San Francisco, CA, USA
Genome screenings in Multiple Sclerosis (MS) have identified multiple susceptibility regions supporting a polygenic model for this disease.
Evidence for linkage was consistently observed at ch.19q13 suggesting the presence of an MS gene(s) in this region.
Several interesting candidate Genes are encoded within this region, including Transforming Growth Factor-beta 1 (TGF-ß1) and InterLeukin-11 (IL-11).
Both are multifunctional Cytokines with significant and well-characterized ImmunoModulatory properties.
We performed a comprehensive evaluation of common polymorphisms within the TGF-ß1 and IL-11 loci and three closely flanking microsatellite markers (D19S421, CEA, D19S908).
In 161 stringently ascertained and clinically characterized MS multiplex families using tests of both linkage (lod score, sib-pair analysis) and association (pedigree disequilibrium test or PDT).
Patients and families were stratified by HLA-DR2 status to search for two-locus interactions.
Suggestive evidence for linkage and association to CEA (lod score=1.25, theta;=0.20, p=0.015, respectively), located 0.4 cM from TGF-ß1, was observed in DR2 positive families only.
Distinct clinical phenotypes were also examined and an association between a TGFß1 haplotype and a mild disease course was present (p=0.008).
Raising the possibility that TGF-ß1 or a nearby locus may influence disease expression.
NK Cell-Mediated Lysis Of Autologous Human Oligodendrocytes
Morse RH, Seguin R, McCrea EL, Antel JP
J NeuroImmunol 2001 May 1;116(1):107-115
McGill University, Dept of Neurology, and
Montreal Neurological Institute and Hospital, NeuroImmunology Unit, 3801 UnivStreet, H3A 2B4, Montreal, Quebec, Canada
Although considered an AutoImmune Disease, the mechanisms underlying Oligodendrocyte (OL)/Myelin injury in Multiple Sclerosis (MS) remain to be established.
We utilized in vitro assays to demonstrate that human OLs, as well as other Glial elements (Astrocytes, Microglia), were susceptible to injury mediated by peripheral blood-derived MonoNuclear Cell preparations (MNCs).
Enriched for Natural Killer (NK Cells) by depleting CD3+/-CD19+ cells through use of either magnetic beads or cell sorting.
Cytotoxic effects of the NK cell-enriched effectors were dependent on pre-exposure of these cells to IL-2. Furthermore, we found that autologous OLs were as susceptible to injury mediated by IL-2 activated NK Cells as were heterologous OLs.
In context of the tissue injury that occurs in MS, our results suggest that the inflammatory milieu in MS lesions could provide conditions required for NK cell activation.
And that such effector cells can bypass the putative protective effects of self-MHC Class I molecules that may be expressed on OLs.
A Study Of InterLeukin-1 Cluster Genes In Susceptibility To And Severity Of Multiple Sclerosis
Luomala M, Lehtimaki T, Elovaara I, Wang X, Ukkonen M, Mattila K, Laippala P, Koivula T, Hurme M
J Neurol Sci 2001 Apr 1;185(2):123-127
Tampere Univ Hospital, Centre for Laboratory Medicine, Laboratory of AtheroSclerosis Genetics, Dept of Clinical Chemistry, FinnMedi 2/3 Floor, P.O. Box 2000 33521, Tampere, Finland
In this explorative study, InterLeukin-1 (IL-1) Receptor Antagonist (IL-1RA; polymorphism of variable number of tandem repeats: VNTR), IL-1alpha (-889), IL-1ß (-511) and IL-1ß (+3953) polymorphisms were studied in relation to susceptibility to and severity of Multiple Sclerosis (MS), in 93 MS patients and 400 normal controls.
No associations were found for any polymorphisms, alone or in combination. However, in our MS cohort, females were found to be IL-1RA allele 2 carriers more frequently than males (33/49 vs. 16/44, p=0.0028).
Using a cohort of 109 controls, IL-1RA allele 2 carriers were more frequently women with MS than control women (33/49 vs. 23/43, odds ratio (OR)=2.19, 95% confidence interval (CI) 1.02-4.72, p=0.043, P(C)=ns).
The data suggest that the IL-1 cluster Genes make no major contribution to MS, but the tentative association between IL-1RA allele 2 and susceptibility of MS in women warrants further studies.
Limitations Of The Paced Auditory Serial Addition Test As A Measure Of Working Memory In Multiple Sclerosis
Fisk JD, Archibald CJ
J Int Neuropsychol Soc 2001 Mar;7(3):363-72
Dalhousie University, Halifax, Nova Scotia, Canada
PMID# 11311037; UI# 21204977
The Paced Auditory Serial Addition Test (PASAT) is a commonly used procedure that combines elements of both a working memory task and a test of information processing speed.
Patients with Multiple Sclerosis (MS) have consistently been found to be impaired on this test and it has been recommended as a core outcome measure in clinical trials.
The standard score for this task is the number of correct responses at each stimulus presentation rate but a concern has been raised that subjects may ignore some test items.
In order to chunk the information into manageable portions and avoid performing several Cognitive tasks simultaneously.
To account for this strategy, one can examine the proportion of correct responses that are consecutive (termed Dyads), since such responses require that the task be performed according to the instructions.
We compared a group of 35 mildly to moderately disabled MS patients and matched healthy controls on the PASAT.
The MS patients made significantly fewer correct responses at the 2 slowest presentation rates (2.4, 2.0 s/digit) while their scores at faster rates (1.6, 1.2 s/digit) did not discriminate them from controls as well.
Nevertheless, the MS patients' percentage of Dyads was significantly lower than that of the control sample across all stimulus presentation rates.
While our study supports the use of the PASAT as a test that distinguishes MS patients from healthy individuals, our results also illustrate problems that lie in the interpretation of this difference in performance.
It appears that a chunking strategy may be common in the PASAT, particularly as task demands increase, and that this may mask actual performance differences.
If so, the total correct response score alone is limited as a measure of Working Memory and Information Processing Speed.
More detailed analyzes of PASAT performance, coupled with other measures of information processing, may help clarify the underlying Cognitive Deficits of MS patients.
Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z, Riven-Kreitman R, Tarcik N, Teitelbaum D
J NeuroImmunol 2001 Apr 2;115(1-2):152-60
Hadassah Univ Hospital, Dept of Neurology, Jerusalem, Israel
PMID# 11282165; UI# 21179333
Humoral and Cellular Immune Responses were followed in Multiple Sclerosis patients treated with Copolymer-1 (Cop-1, Glatiramer Acetate, Copaxone®) who participated in three different clinical trials.
All patients (130) developed Cop-1 reactive AntiBodies, which peaked at 3 months after initiation of treatment, decreasing at 6 months and remaining low.
IgG1 AntiBody levels were 2-3-fold higher than those of IgG2. The proliferative response of Peripheral Blood MonoNuclear Cells (PBMC) to Cop-1 was initially high and gradually decreased during treatment.
AntiBodies and T-Cell responses to MBP were low and did not change significantly during the treatment.
The Humoral and Cellular Immunological Responses to Cop-1 do not correlate with the side effects and do not affect its therapeutic activity.
The preferential production of IgG1 over IgG2 AntiBodies may indicate that Th2 responses are involved in mediating the clinical effect of Cop-1.
Smith KJ, Kapoor R, Hall SM, Davies M
Ann Neurol 2001 Apr;49(4):470-6
Guy's, King's and St Thomas' School of Medicine, Dept of NeuroImmunology, London, United Kingdom
PMID# 11310624; UI# 21204542
Axonal Degeneration is a major cause of permanent deficit in Inflammatory Neurological Diseases such as Multiple Sclerosis.
Axons undergo degeneration specifically at the site of the inflammatory Lesions, suggesting that locally produced inflammatory factors mediate the phenomenon.
One such factor is Nitric Oxide (NO), which we have previously reported can cause reversible Conduction Block in Axons.
Here we confirm these observations and extend them to show that Axons exhibit the early stages of Wallerian Degeneration.
If, they are conducting Impulses at physiological frequencies, while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of Inflammation.
Rat Dorsal Roots were concurrently exposed in vivo to both NO and sustained Impulse activity at 1, 50, or 100 Hz.
Although our in vivo observations necessarily focused on the more acute responses, Morphological examination of exposed roots at the end of the recording period revealed:
Nodal and ParaNodal changes consistent with acute Wallerian Degeneration in roots stimulated at 50 or 100 Hz.
This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop.
In these experiments the formation of Myelin ovoids and frank AxonoLysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal.
We propose that the combination of normal Impulse traffic and NO at sites of inflammation may cause Axonal Degeneration.
And, that electrical activity may therefore be an important factor in causing permanent Disability in patients with NeuroInflammatory Disorders.
Multiple Sclerosis Etiology
Rev Neurol 2001 Feb 1-15;32(3):285-8
Baylor College of Medicine, Dept of Neurology, 6560 Fannin, Suite 1224, Houston, Texas 77030, USA
PMID# 11310288; UI# 21205435
Multiple Sclerosis (MS) is probably caused by many pathological factors, both intrinsic and extrinsic.
When we consider the Etiology of MS, we have to take three basic factors into account:
- Immunological factors: evidence of involvement of the Immune System has been found in Plasma, tissues and CSF;
- Viral factors: Epidemiological studies suggest that MS may be a result of contact with environmental factors during childhood or adolescence, and
- Genetic factors although there is no evidence that MS is inherited directly, there is between 12 and 15 times more involvement of persons from affected families than from the general population.
Regarding treatment, since this is a polysymptomatic disorder, the specialist should choose the most suitable drug or intervention in each case, according to the alterations which affect quality of life or the severity of the presenting symptom.
Three pharmacological treatments are emphasized: Steroids, ImmunoModulation and ImmunoSuppression.
In this article we review the Etiology of MS and its pharmacological treatment.