Exacerbation Of Viral And AutoImmune Animal Models For Multiple Sclerosis By Bacterial DNA
Tsunoda I, Tolley ND, Theil DJ, Whitton JL, Kobayashi H, Fujinami RS
Brain Pathol 1999 Jul;9(3):481-93
Univ of Utah School of Medicine, Dept of Neurology, Salt Lake City 84132, USA
PMID# 10416988; UI# 99343431
Theiler's Murine EncephaloMyelitis Virus (TMEV) infection and Relapsing/Remitting Experimental Allergic EncephaloMyelitis (R-EAE) have been used to investigate the Viral and AutoImmune Etiology of Multiple Sclerosis (MS), a possible Th1-type mediated disease.
DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and OligodeoxyNucleotides, which contain CpG motifs, have been reported to enhance ImmunoStimulation.
Our objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert ImmunoStimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vivo.
We demonstrated that this Bacterially derived DNA could induce InterLeukin-12 (IL-12), Interferon (IFN), (Th1-promoting Cytokines), and IL-6 production as well as activate NK Cells.
Following pCMV injections, SJL/J mice were infected with TMEV or challenged with Encephalitogenic Myelin Proteolipid Protein (PLP) peptides.
pCMV injection exacerbated TMEV-induced DeMyelinating Disease in a dose-dependent manner. Exacerbation of the disease did not correlate with the number of TMEV-Antigen positive cells but did with an increase in anti-TMEV AntiBody.
pCMV injection also enhanced R-EAE with increased IFN and IL-6 responses.
These results caution the use of DNA vaccination in MS patients and other possible Th1-mediated diseases.
High Numbers Of Perforin mRNA Expressing CSF Cells In Multiple Sclerosis With Gadolinium-Enhancing Brain MRI Lesions
Kivisakk P, Stawiarz L, Matusevicius D, Fredrikson S, Soderstrom M, Hindmarsh T, Link H
Acta Neurol Scand 1999 Jul;100(1):18-24
Huddinge Univ Hospital, Karolinska Institutet, Division of Neurology, Sweden
PMID# 10416508; UI# 99342897
Enhanced expression of pro- and anti-inflammatory Cytokines is a common finding in MS, but attempts to correlate Cytokine expression with disease activity have produced conflicting results.
In this paper, Gadolinium-(Gd-)enhancing lesions on Brain MRI were used as markers for active inflammation in patients with MS not treated with any ImmunoModulatory drugs.
In parallel, in situ hybridization was used to detect blood and CerebroSpinal Fluid (CSF) MonoNuclear cells (MNC) expressing Cytokine mRNA.
An association was observed between numbers of Perforin mRNA expressing CSF MNC and numbers of Gd-enhancing Brain MRI lesions.
Perforin mRNA expressing CSF MNC were not detected in any of the patients lacking active lesions on Brain MRI.
The expression of Tumor Necrosis Factor-, InterLeukin-10 (IL-10) and IL-12 mRNA in CSF MNC did not differ between MS patients with and without active MRI lesions.
Based on the present finding, a role for Perforin in the disruption of the Blood-Brain Barrier in MS can be hypothesized.
The Multiple Sclerosis Collaborative Research Group
Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Simonian N, Lajaunie M, Miller DE, Wende K, Martens-Davidson A, Kinkel RP, Munschauer FE 3rd, Brownscheidle CM
Neurology 1999 Jul 13;53(1):139-48
Univ of Colorado Health Sciences Center, Dept of Radiology-MRI, Denver 80262, USA
PMID# 10408550; UI# 99335035
To determine if progressive Brain Atrophy could be detected over 1- and 2-year intervals in Relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of Interferon-beta-1a (Avonex).
All subjects had mild to moderate disability, with baseline Expanded Disability Status Scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry.
Atrophy measures included Third and Lateral Ventricle width, Brain width, and Corpus Callosum area.
Significant increases were detected in Third Ventricle Width at year 2 and Lateral Ventricle width at 1 and 2 years. Significant decreases in Corpus Callosum area and Brain width were also observed at 1 and 2 years.
Multiple regression analyzes suggested that the number of Gadolinium-enhancing lesions at baseline was the single significant contributor to change in Third Ventricle Width.
Atrophy over 1 and 2 years as indicated by enlargement of the Third and Lateral Ventricles and shrinkage of the Corpus Callosum was greater for patients entering the trial with enhancing lesions.
Greater disability increments over 1 and 2 years were associated with more severe Third Ventricle enlargement.
In patients with Relapsing MS and only mild to moderate disability, significant Cerebral Atrophy is already developing that can be measured over periods of only 1 to 2 years.
The course of Cerebral Atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions.
Brain Atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.
Leppert D, Hughes P, Huber S, Erne B, Grygar C, Said G, Miller KM, Steck AJ, Probst A, Fuhr P
Neurology 1999 Jul 13;53(1):62-70
Univ Hospitals, Dept of Research, Basel, Switzerland
PMID# 10408538; UI# 99335023
To determine the expression pattern and cellular source of Matrix MetalloProteinases (MMPs) in Chronic Inflammatory DeMyelinating PolyNeuropathy (CIDP) and NonSystemic Vasculitic Neuropathy (NSVN).
MMPs are EndoPeptidases involved in tissue destruction and infiltration by Immune Cells in Multiple Sclerosis and Guillain-Barre Syndrome.
Enzyme inhibitors of MMPs attenuate clinical symptoms in corresponding animal models of these diseases.
MMP inhibition may therefore be a novel approach for the treatment of CIDP and NSVN. However, the spectrum of MMPs expressed in chronic inflammatory NeuroPathies has not been established.
The expression of MMP-2, MMP-3, MMP-7, and MMP-9 in T-Cells, Macrophages, and Stromal Cells in CIDP, NSVN, and noninflammatory NeuroPathies (NIN) was quantitated by ImmunoHistoChemistry.
Results were correlated with clinical and ElectroPhysiologic findings.
The production of MMP-2 and MMP-9 is increased in nerve tissue in CIDP and NSVN compared with NIN.
T-Cells are the predominant source of MMP-2 and MMP-9 in CIDP and NSVN, whereas Macrophages contribute only to a minor extent.
Stromal cells of the Perineurium/Epineurium are an additional source of MMP-2 in NSVN, but not in CIDP. Expression of MMP-3 and MMP-7 was not detectable in CIDP or NSVN.
Expression of MMP-2 and MMP-9 did not correlate with clinical disease activity and ElectroPhysiologic measurements.
The upregulation of MMP-2 and MMP-9 is a specific feature of CIDP and NSVN, and selective inhibitors of these enzymes could be used to prevent inflammatory tissue damage.
The similar increase of MMP-2 and MMP-9 in both DeMyelinating (CIDP) and NonDeMyelinating (NSVN) NeuroPathies raises doubts about whether MMPs play a primary role in DeMyelination.
Reporting Delay And Corrected Incidence Of Multiple Sclerosis
Esbjerg S, Keiding N, Koch-Henriksen N
Stat Med 1999 Jul;18(13):1691-1706
DICE, Svanemollevej 25, DK-2100 Copenhagen O., Denmark
The incidence of Multiple Sclerosis can be adjusted for reporting delay in a way similar to that for AIDS incidence as described in this paper.
Two models are applied to data from the Danish Multiple Sclerosis Registry. The first simply describes the delay distribution, the second is a regression model.
For the latter it is shown how goodness-of-fit assessment for both time-dependent and time-independent covariates can be handled using ideas from the Cox proportional hazards model.
The goodness-of-fit analysis shows that people with onset age below 40 years and people with onset age from 40 years and above should be analyzed separately and this is done throughout the paper.
The incidences are adjusted with the two estimated delays and an estimate of the variance for the adjusted incidence is given.
Finally the crude incidences are compared with the adjusted ones. We find that the incidence has been increasing since 1965 but mostly for people with onset age below 40 years.
Copyright 1999 John Wiley & Sons, Ltd.
Molecular Cloning And Characterization of MSRV-Related Sequences Associated With RetroVirus-Like Particles
Komurian-Pradel F, Paranhos-Baccala G, Bedin F, Ounanian-Paraz A, Sodoyer M, Ott C, Rajoharison A, Garcia E, Mallet F, Mandrand B, Perron H
Virology 1999 Jul 20;260(1):1-9
UMR 103 CNRS-bioMerieux, Ecole Normale Superieure de Lyon, 46, Allee d'Italie, Lyon Cedex 07, 69364, France
New sequences have been obtained by successive overlapping RT-PCR extensions from the pol region of a retroviral RNA (Multiple Sclerosis-associated RetroViral element, MSRV) amplified in RetroVirus-like particles from patients with Multiple Sclerosis.
gag and pol sequences are related to type C on CoViruses, whereas the env sequence is closer to type D.
A Tryptophan-like (W) tRNA primer-binding site was identified downstream of the RU5 region in the 5'LTR, and the U3R region cloned in the 3'LTR exhibited potent promoter activity.
MSRV clones define a novel family of endogenous elements, HERV-W.
From our data, HERV-W RNAs are copackaged in ExtraCellular particles which might be produced by replication-competent or TransComplemented HERV-W copies or by an exogenous member of the HERV-W family.
Copyright 1999 Academic Press
Chlamydia Pneumoniae Infection Of The Central Nervous System In Multiple Sclerosis
Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, Mitchell WM
Ann Neurol 1999 Jul;46(1):6-14
Vanderbilt School of Medicine, Dept of Neurology, Nashville, TN, USA
PMID# 10401775; UI# 99328202
Our identification of Chlamydia Pneumoniae in the CerebroSpinal Fluid (CSF) of a patient with Multiple Sclerosis (MS) led us to examine the incidence of this organism in the CSF.
From 17 patients with Relapsing/Remitting MS, 20 patients with Progressive MS, and 27 patients with Other Neurological Diseases (OND).
CSF samples were examined for Chlamydia Pneumoniae by culture, polymerase chain reaction assays, and CSF ImmunoGlobulin (Ig) reactivity with Chlamydia Pneumoniae elementary body Antigens. Chlamydia Pneumoniae was isolated from CSF in 64% of MS patients versus 11% of OND controls.
Polymerase chain reaction assays demonstrated the presence of Chlamydia Pneumoniae MOMP Gene in the CSF of 97% of MS patients versus 18% of OND controls.
Finally, 86% of MS patients had increased CSF AntiBodies to Chlamydia Pneumoniae elementary body Antigens as shown by enzyme-linked Immunosorbent assay absorbance values that were 3 SD greater than those seen in OND controls.
The specificity of this AntiBody response was confirmed by western blot assays of the CSF, using elementary body Antigens.
Moreover, CSF isoelectric focusing followed by western blot assays revealed cationic AntiBodies against Chlamydia Pneumoniae.
Infection of the Central Nervous System with Chlamydia Pneumoniae is a frequent occurrence in MS patients.
Although the organism could represent the PathoGenetic agent of MS, it may simply represent a secondary infection of damaged Central Nervous System tissue.
A therapeutic trial directed at eliminating Chlamydia Pneumoniae from the Central Nervous System may provide additional information on its role in MS.