Kurtzke JF, Heltberg A
J Clin Epidemiol 2001 Jan;54(1):1-22
Veterans Affairs Medical Center, NeuroEpidemiology Section, 50 Irving Street, NW, Washington, DC 20422, and
Georgetown Univ, School of Medicine, Dept of Neurology, Washington, DC, USA
The Faroe Islands are a semi-independent unit of the Kingdom of Denmark and are located in the North Atlantic Ocean between Norway and Iceland. Efforts to identify all cases of Multiple Sclerosis (MS) since 1900 among Faroese have been continuing for over a quarter century.
As of 1998 prevalence was 66 per 100,000, age adjusted to 1960 US population, with a rate of 100 for women and 34 for men. Median survival was at 29 to 34 years with no significant difference by sex.
Faroese with overseas residence indicated that at least 2 years of exposure from age 11 on in a high-risk area are required for acquisition of MS. Among native resident Faroese the first instance of symptom onset was in 1943, heralding a type 1 epidemic of 21 cases.
This was followed by three successive epidemics of 10, 10, 13 cases, with membership in each epidemic defined by calendar time and age of exposure.
Age at exposure for epidemic I was 11 to 45 years; for later epidemics age 11 was the minimum. We believe the source of MS on the Faroes was their occupation by British troops for 5 years in World War II.
We think they introduced a widespread, specific, persistent (but unknown) infection, probably asymptomatic, which we call the Primary Multiple Sclerosis affection (PMSA).
Only a small proportion of those affected with PMSA will years later show any clinical signs of MS. Models of transmission of PMSA through successive cohorts of Faroese fit the data for epidemics II and III, and predicted the occurrence of epidemic IV.
The Faroese provide an ideal location to determine the nature of PMSA, since the disease has remained geographically stable for 50 years without further spread throughout the islands.
OverExpression Of The Apoptosis Inhibitor FLIP In T-Cells Correlates With Disease Activity In Multiple Sclerosis
Semra YK, Seidi OA, Sharief MK
J NeuroImmunol 2001 Feb 15;113(2):268-274
Guy's Hospital, Guy's, King's and St Thomas' School of Medicine, Dept of NeuroImmunology, SE1 9RT, London, UK
The cellular caspase-inhibitory protein FLIP has been recently identified as a potent regulator of T-Lymphocyte susceptibility to Fas-mediated programmed cell death (Apoptosis).
Since impairment of Apoptosis may be involved in Multiple Sclerosis (MS), we investigated the dynamics of cellular FLIP in unstimulated and activated T-Lymphocytes from MS patients, Inflammatory and Non-Inflammatory Neurological Disorders, and healthy subjects.
Cellular expression of the long and short forms of FLIP protein was similar in unstimulated T-Cells from MS patients and controls, but was significantly higher in activated T-Cells from patients with clinically active MS.
This high FLIP expression in active MS correlated with cellular resistance to Fas-mediated Apoptosis.
In contrast, cellular expression of the Anti-Apoptotic Protein Bcl-2 did not differ between active and stable disease, and was relatively similar between the MS group and controls.
These findings suggest that cellular overexpression of the Anti-Apoptotic protein FLIP is a feature of clinically active Multiple Sclerosis.
Analysis Of InterLeukin-4 Receptor alpha Chain Variants In Multiple Sclerosis
Hackstein H, Bitsch A, Bohnert A, Hofmann H, Weber F, Ohly A, Linington C, Maurer M, Poser S, Rieckmann P, Bein G
J NeuroImmunol 2001 Feb 15;113(2):240-248
Justus-Liebig University, Institute of Clinical Immunology and Transfusion Medicine, LanghansstraBe 7, D-35392, Giessen, Germany
A recent candidate Gene study employing microsatellite markers suggested a possible linkage of Multiple Sclerosis (MS) with the InterLeukin-4 receptor (IL-4R) gene.
Consequently, we investigated the association of different IL-4R variants with MS in 341 German MS patients and 305 healthy controls.
Analysis of the first 100 MS patients for six IL-4R variants showed an increased frequency of the R551 variant in MS patients.
Versus healthy controls and carriage of the same IL-4R variant was weakly associated with Myelin Oligodendrocyte Glycoprotein (MOG) AutoAntiBody production.
However, further analysis of all 341 MS patients did not confirm the finding that this IL-4R variant represents a general Genetic risk factor for MS but revealed an increased frequency of the R551 variant in MS patients with Primary/Progressive MS (PPMS, n=48).
As compared to patients with Relapsing/Remitting MS or Secondary/Progressive MS (RR/MS, SP/MS n=284; P=0.005 for genotype differences) and to 305 healthy controls (P=0.001 for genotype differences).
This association was statistically independent of the presence of the well-known MS susceptibility allele HLA-DRB1*15. After correction for multiple comparisons only the genotype differences between PPMS patients and healthy controls remained statistically significant.
These results indicate, that the IL-4R variant R551 may influence the Genetic predisposition for PPMS but does not represent a general Genetic risk factor for MS.
Multiple Sclerosis: Genomic Rewards
Oksenberg JR, Baranzini SE, Barcellos LF, Hauser SL
J NeuroImmunol 2001 Feb 15;113(2):171-184
Univ of California, School of Medicine, Dept of Neurology, 94143-0435, San Francisco, CA, USA
A large body of Immunologic, Epidemiologic, and Genetic data indicate that tissue inury in Multiple Sclerosis (MS) results from an abnormal Immune Response to one or more Myelin Antigens.
That develops in Genetically susceptible individuals after exposure to an as-yet undefined causal agent.
The Genetic component of MS etiology is believed to result from the action of several Genes of moderate effect.
The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other Genes, post transcriptional regulatory mechanisms, and significant nutritional and environmental influences.
Equally significant, it is also likely that Genetic heterogeneity exists, meaning that specific Genes influence susceptibility and PathoGenesis in some affects but not in others.
Results in multiplex MS families confirm the Genetic importance of the MHC region in conferring susceptibility of MS.
Susceptibility may be mediated by the Class II Genes themselves (DR, DQ or both), related to the known function of these molecules in the normal Immune Response, e.g. Antigen binding and presentation and T-Cell repertoire determination.
The possibility that other Genes in the MHC or the Telomeric region of the MHC are responsible for the observed Genetic effect cannot be excluded.
The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the Genetic effect in MS remains to be explained.
Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease.
The past few years have seen real progress in the development of laboratory and analytical approaches to study Non-Mendelian complex Genetic disorders and in defining the pathological basis of DeMyelination.
Setting the stage for the final characterization of the Genes involved in MS susceptibility and PathoGenesis.
Their identification and characterization is likely to define the basic Etiology of the disease, improve risk assessment and influence therapeutics.
Bakshi R, Dmochowski J, Shaikh ZA, Jacobs L
J Neurol Sci 2001 Mar 15;185(1):19-26
Univat Buffalo, State Univ of New York, Dept of Neurology, Buffalo, NY, USA
Cortical and SubCortical Gray Matter HypoIntensities on T2-weighted MR images (T2) occur commonly in MS Brains and have been related to disease duration, clinical course, and the level of Neurologic disability.
These HypoIntensities have been reported to occur in the Thalamus, Basal Ganglia, and Rolandic Cortex. We assessed whether T2 HypoIntensity is associated with the severity of White Matter plaques and Atrophy of MS Brains.
In 114 MS patients, HypoIntensity of the Thalamus, Putamen, Caudate, and SensoriMotor Cortex was ordinally rated against age- and gender-matched normal controls on 1.5-T MRI fast Spin-Echo axial T2.
Regional and global T2 HyperIntense and T1 HypoIntense Parenchymal lesion loads were ordinally rated.
Enlargement of SubArachnoid and Ventricular spaces (Atrophy) was ordinally rated vs. age- and gender-matched normal controls. T2 HypoIntensity was highly, positively correlated with many other MRI variables.
Regression modeling showed that T2 HypoIntensity was related to total Atrophy, total T2 lesion load, Third Ventricular Enlargement, Parietal Atrophy, and to a lesser extent, Frontal T1 lesions and Cerebellar T2 lesions, but not related to Gadolinium enhancement.
Ordinal ratings of T2 Lesions and Central Atrophy showed high correlations with quantitative computerized assessments.
We conclude that Gray Matter HypoIntensity on T2 may reflect pathologic Iron deposition and Brain degeneration in MS.
This T2 HypoIntensity is associated with Brain Atrophy and other MR markers of tissue damage.
Further study is warranted to determine if T2 HypoIntensity is predictive of disease course in MS and is a useful surrogate outcome measure in therapeutic trials.