Genes, expression or function?


Multiple sclerosis (MS) has a prevalence of 1:1000 and is the most common neurological disorder in early adulthood. The initial symptoms include vision impairement (double vision), loss of coordination (dizziness, unsteady gait) and paresthesia (tingling, numbness). In the “relapsing-remitting course” of the disease, patients recover from symptoms. But some years later the number of attacks may increase leading to a “secondary progressive course”. The “primary progressive course” appears with more severe symptoms from the beginning. The diagnosis MS is based on clinical (neurological status) and paraclinical findings (liquor diagnostic). To date no pathognomonic parameter exists.

Neuroimmunological findings suggest a dysregulation of the immune system with activation of auto-reactive lymphocytes and the formation of autoantibodies against components of myelin such as myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Relapses are triggered by exogenous (eg viral infections) as well as endogenous factors (stress). A hypothesis to explain autoimmunity in MS is the impairment of regulatory T-cells (Tregs) which allows activation and reactivation of autoreactive T-cells, which penetrate the blood-brain-barrier leading to lesions of the white matter.

Evidence from genetic epidemiology (concordance rates of monozygotic twins, probability of illness in 1st degree relatives, increased risk for children in conjugal or consanguineous MS couples) suggest that more than one predisposing gene contribute to onset or different courses of the disease. On the other hand, a concordance rate of only 30% in monozygotic twin points to reduced penetrance of the disease. Differences between monozygotic twins include epigenetic factors (differences in the T-and B-cell receptor repertoire, monoallelic gene expression, X-inactivation, methylation and acetylation differences in other genes) and environmental factors. Different courses of the disease within families, either relapsing remitting with low to moderate disability or primarily chronic progressive, point to different expressivity of the autoimmune disease. Expressivity may be due to a) modifying genes, b) gene heterogeneity, c) epigenetic factors, or d) environmental factors. From the genetic point of view most autoimmune conditions are regarded as complex diseases.

In examining neuroimmune and genetic aspects of MS, two experimental strategies can be distinguished 1) the genome-wide linkage analysis and 2) the candidate gene approach. In genome-wide linkage analysis the pathogenesis of the disease is initially ignored. Parameters included are frequencies of genetic markers, probable mendelian inheritance and penetrance of the genetic trait. This method has proven very successful in monogenetic diseases but for complex diseases, this approach is still far behind the general expectations. This is attributed mainly to genetic heterogeneity and low to moderate contribution of each single predisposing gene.

The therapy of MS is based on findings mentioned above and includes either immunosuppressive (corticosteroids, azathioprine) or immuno-modulatory (interferon-beta, glatiramer acetate, Mitoxantron, Natalizumab, intravenous immunoglobulins) drugs as well as symptomatic treatment. None of these therapies, alone or in combination will cure MS.

 

Projects:

  1. Immunogenetic and pharmacogenetic analysis of complex diseases (MS)
  2. Aberrant expression of cytokines, ligands, receptors …..in MS
  3. Dysregulation of the immunesystem in patients with MS

 

Tools:

  1. Sequence and Pyrosequencing analysis
  2. Quantitativ PCR
  3. Cell separation and cell-culture