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Investigation of immunological preconditions in MS patients "MS immunopathic trait"

Doctoral thesis
Authors Sara Haghighi
Date of public defense 2004-11-26
ISBN 91-628-6333-9
Publication year 2004
Published at Institute of Clinical Neurosciences
Language en
Keywords multiple sclerosis, siblings, CSF, oligoclonal, cytokine, sulfatide, genetics, trait
Subject categories Medical and Health Sciences


We examined 47 MS patients, 47 healthy siblings and 50 healthy unrelated individuals with blood and CSF analysis and found that 19 % (9/47) of healthy siblings of clinically definite multiple sclerosis patients had an intrathecal immunological reaction to ¡Ý 2 CSF-enriched OCB, in contrast to 4% (2/50) of the unrelated healthy controls. We termed this condition ¡°MS immunopathic trait¡±. We challenged whether this subgroup with the MS immunopathic trait was really asymptomatic, using a more stringent method, high-pass resolution perimetry (HRP). With this method, siblings as a group did not differ from the healthy controls. We measured CSF neurofilament light protein (NFL), and glial fibrillary acidic protein (GFAp), in MS patients and their healthy siblings. There was no increase in CSF GFAp and NFL in the healthy siblings of MS patients, nor in the subgroup of the healthy siblings with the MS immunopathic trait. The verification of the MS immunopathic trait was the precondition for the subsequent aims. The next aim was to clarify whether MS immunopathic trait as a phenotype segregates with any particular pattern, and to examine whether there is any candidate gene or genes. We studied two extended families in which MS not only segregates but also approximately 18% of the CSF investigated blood relatives have the MS immunopathic trait, but with no neurological symptoms. Both families fit a genetic model for autosomal dominant inheritance for the MS immunopathic trait. We performed a genome scan using 285 successful markers, to test the hypothesis that a single gene is causing the MS immunopathic trait in these families. Using a parametric method, we identified regions with suggestive linkage at chromosome 6q12 with a LOD-score of 2.4, and suggestive linkage at chromosome 19q13.2 with a LOD-score of 2.2 when family A was analysed alone. In family B, all MS patients, one individual with the MS immunopathic and all blood relatives had the rare HLA type DRB1*0103, which is associated with other autoimmune diseases. However, the suggestive linkage to chromosome 6q21 raises the question whether this suggestive linkage is a protective gene for MS immunopathic trait or a new susceptibility gene for MS disease. A further aim was to examine whether this phenotype had further neurochemical and immunological characteristics, which could be identical or different from MS. In the healthy siblings group, we found significantly increased CSF levels of sulfatide, CSF galactosylceramide (GalCer), TNF-alpha, and CSF IgG antibodies to measles, and serum IgM antibodies to sulfatide and GalCer, as compared to the controls. It was recently shown that GalCer increases and sulfatide reduces the level of the proinflammatory cytokines IL-1beta, IL-6 and TNF-alpha. The occurrence of this differential effect in MS was supported by a significant correlation between CSF GalCer and IL-6 levels in the MS immunopathic trait group. This finding may indicate a greater likelihood for individuals with the higher levels of GalCer to have increased level of IL-6. The absence of axonal damage markers as CSF GFAp and NFL in the healthy siblings, in combination with increased CSF levels of sulfatide, allowed for the tentative conclusion that myelin damage is an earlier event than axonal damage. The present material should give us an opportunity to study whether antiviral or antimyelin antibodies are the earlier event and to further redefine the MS immunopathic trait phenotype.

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