B cell trafficking in multiple sclerosis

• Applicant: Privatdozent Dr. Markus Kowarik
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 215939592

Multiple lines of evidence indicate that B lymphocytes play an important role in the pathophysiology of multiple sclerosis (MS). B cells can be detected in MS lesions and cerebrospinal fluid (CSF) from MS patients, furthermore the CSF is characterised by the persistence of intrathecal oligoclonal immunoglobulin (IgG) bands. Recently, B cell follicle-like structures in the brain meninges have been identified and B cell depleting therapies have been shown to be highly effective in MS. However, the identity of the antigenic stimuli, the location of antigen presentation and mechanism of B cell influx into the inflamed CNS remain unclear. The purpose of this study is to determine the place of antigenic stimuli of B cells and to characterize B cell trafficking into the inflamed CNS.B cells in MS CSF demonstrate cardinal features of an antigen-driven T cell-mediated response. In MS CSF, clonally-expanded memory B cells, plasmablasts and mature plasma cells can be identified by virtue of their identical patterns of Ig gene rearrangements. These post-germinal center B cell populations show significant overlap between parenchymal, meningeal and CSF compartments. We would like to extend this preliminary work and perform deep sequencing analysis of CSF and peripheral blood B cells to establish the dynamic relationship between the immune cells in these two compartments. Using novel surface markers (CXCR5), lineage specific markers (BLIMP-1 and PAX-5) and cell survival genes (BMCA and MCl-1), we will be able to evaluate the location of antigenic stimuli of B cells in MS and establish the trafficking pattern of B cells and migratory plasmablasts into the CNS.New MS therapies, such as natalizumab and fingolimod, directly affect lymphocyte trafficking and exert differential effects on B cells. Using specialized cell sorting and deep sequencing, we will be able to examine B cell trafficking under these therapies and establish markers indicative of a salutatory treatment response.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jeffrey Bennett, Ph.D.