Pathogenic and therapeutic aspects of intrathecal immune responses in multiple sclerosis
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AbstractMultiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The target antigen of the intrathecal immune response has not been identified, and the immune response in MS may also hold neuroprotective potential.
MS patients display an increased frequency of T cells that recognize CSF IgG. Work in this thesis shows that these T cells recognize idiotopes, which are mutated fragments on the IgG variable regions. We show that idiotope specific T cells from the blood and CSF of MS patients recognize several epitopes on self-IgG, that autologous B cells may present their own idiotope to T cells, and that idiotope specific T cells are able to induce apoptosis of oligodendrocytes. Idiotope-driven T-B cell collaboration has been shown to cause severe autoimmunity in animal models, and we postulate that a similar mechanism may contribute to the immune mediated tissue destruction in MS brains.
As a model for neuroprotective immune responses in MS, we have investigated the mechanism of action of glatiramer acetate (GA), a widely used MS treatment. GA was shown to shift the phenotype of GA reactive T cells from the CSF from pro-inflammatory to anti-inflammatory.
List of papers
Paper I Hestvik AL, Skorstad G, Price DA, Vartdal F and Holmoy T. Multiple sclerosis: glatiramer acetate induces anti-inflammatory T cells in the cerebrospinal fluid. Mult Scler. 2008; 14: 749-58.
Paper II Holmøy T, Fredriksen AB, Thompson KM, Hestvik AL, Bogen B and Vartdal F. Cerebrospinal fluid T cell clones from patients with multiple sclerosis: recognition of idiotopes on monoclonal IgG secreted by autologous cerebrospinal fluid B cells. Eur J Immunol. 2005; 35: 1786-94.
Paper III Hestvik AL, Vartdal F, Fredriksen AB, Thompson KM, Kvale EO, Skorstad G, Bogen B and Holmoy T. T cells from multiple sclerosis patients recognize multiple epitopes on self-IgG. Scand J Immunol. 2007; 66: 393-401.
Paper IV Hestvik AL, Skorstad G, Vartdal F and Holmoy T. Idiotope-specific CD4+ T cells induce apoptosis of human oligodendrocytes. J Autoimmun. 2009; 32: 125-32.