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Grant for Multiple Sclerosis Innovation

Dr Lennart Mars

lennart_mars

 

4BL cells: novel mediators of tissue damage in relapsing and progressive MS?

 

Lennart Mars is based at the National Institute for Health and Medical Research, University of Lille, and will be working in conjunction with Dr Jan Bauer from the Center for Brain Research, University of Vienna, Austria. The subject of their winning research proposal is ‘4BL cells: novel mediators of tissue damage in relapsing and progressive MS?’

 

4BL B cells, which express inducible costimulatory molecule 4-1BBL, have a type I inflammatory phenotype characterized by the expression of the nuclear factor T-bet, the production of inflammatory cytokines interferon (IFN) gamma and tumor necrosis factor (TNF) alpha, and the induction of CD86, CXCR3, and the IFN gamma receptor. Preliminary data indicate that in the peripheral blood, 4BL cells make up around 23% of MS B cells in peripheral blood and 70% in the cerebrospinal fluid, implying that 4BL cells accumulate within the inflamed central nervous system.

 

Dr Lennart Mars and his team will further this explore and define the frequency, phenotype, and localization of 4BL cells in MS. Moreover, the function of 4BL cells in the orchestration of MS inflammation will be examined. This is expected to be mediated via cytokines, antigen-presentation, and cognate interactions with myeloid and adaptive T-cell subsets. We will focus on two potential cellular partners. First, CD8 T cells that co-localize with B cells within the ectopic follicles and that have been implied to interact with 4BL cells in the elderly. Second, the thymus-derived FoxP3- positive regulatory T cells, which are essential for immune homeostasis by inhibiting autoreactive T cells. The constitutive expression of 4-1BB by 4BL B cells implies the potential of the 4BL cells to infringe regulatory T cell function. Lastly, the pathogenic contribution will be assessed in animal models and their lesional localization and cell interactions will be examined using postmortem paraffin sections from MS brain samples.

 

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