Multiple sclerosis (MS) disease, a progressive disorder of the white matter
of the central nervous system, continuous to challenge investigators trying
to understand the pathogenesis of the disease and to prevent its progression.
MS is generally believed to be an immune mediated disorder that occurs in genetically
susceptible people. Although the sequence of event that initiates the disease
remains largely unknown. MS typically begins in early adulthood and has variable
prognosis. Fifty per cent of patients will need help walking within fifteen
year after the onset of disease. The prevalence of MS varies considerable around
the world. Kurtzke classified regions of the world according to prevalence:
a low prevalence was considered less than 5 cases per 100.000 persons an intermediate
prevalence was 5 to 30 per 100.000 persons and a high prevalence was more than
30 per 100.000 persons. The prevalence is highest in North Europe, Shoutern
Australia and the middle part of North America. There has been a trend towards
an increasing prevalence and incidence in Southern Europe. The reasons for the
variation in the prevalence and the incidence of MS worldwide are not understood.
Environmental and genetically explanation have been offered and both factors
probably have a role. Studies that show that the incidence of MS among the adopted
children of patient with MS is not higher than expected seem to argue against
the possibility that a transmissible factor is primarily responsible for the
increased risk of the disease among relatives and instead suggest that genetic
factors may be responsible. The disease typically manifests between the ages
of 20 and 40 and affects women twice as often as man. MS is generally categorised
has been either relapsing-remitting (RR) or primary-progressive (PP) in onset.
The RR form of disease is characterised by series of attacks that risolves in
varying degrees of disability from which the patient recover partly or completely
usually followed by remission period of variable duration before another attack.
The PP forms lack that acute attacks and instead typically involved a gradual
clinical decline.
The primary goal of this WP is focused to generate T cells, both ab and gd TCR+, obtained from the blood of MS patients and from healthy individuals, specific for lipid antigens isolated from human myelin. We will generate appropriate antigen presenting cells expressing CD1 molecules to enable presentation of lipid antigens. We will establish lipid-specific primary T cell lines during the first 6 months of the project, and from those T cell clones will be generated and used for further studies in collaboration with the other Units. In addition we will perform immunophenotyping of the cells present in the CSF of MS patients. The complexity of the immune system is such that identification of phenotypically (and functionally) homogeneous subsets requires the simultaneous measurement of several cell surface antigens. Unless subsets are uniquely identified by appropriate multiple markers, comparative functional studies between individuals will be artefactually affected by a differential (and unknown) representation of unresolved, functionally distinct subsets. Furthermore, we will establish cells lines and clones from cells present in the CSF in order to study their functional attributes. Subsets of interest will be sorted and expanded according to standard procedures. All lines and clones will then be tested for their reactivity towards relevant CNS antigens. Antigen responsiveness will be evaluated by proliferation assays and by measurement of cytokines produced following antigen-specific challenge.
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