Defining the Role of B Cells in CNS Demyelination
Abstract
Multiple sclerosis is characterized by localized lesions in the brain and spinal cord where myelin, the fatty insulation around axons, is lost. Myelin is produced by cells called oligodendrocytes and when it is lost or damaged axons fail to transmit information, which results in compromised function. The causes of MS are not well-defined; however, in many cases early in the disease, while there is robust remyelination and functional recovery this ultimately fails as the disease progresses. The reasons for remyelination failure are not well understood, although the presence of oligodendrocyte precursors in chronic lesions suggests that it is not a lack of new cells but rather changes in the environment of the lesion that limit the ability of these cells to mature into myelinating oligodendrocytes. In this proposal we will test the hypothesis that a major obstacle to myelin repair are changes in the environment that result from the presence of B cells in the brain and spinal cord. For many years, MS was considered a T cell-mediated disease, however, more recent studies showing that systemic B cell depletion is highly effective in early relapsing remitting MS has demonstrated a critical role for B cells in the disease. Unfortunately, systemic B cell depletion studies do not allow recovery later in the disease and B cells remain present in the brain and spinal cord. One likely explanation is that these central nervous system (CNS) B cells continue to inhibit repair. Consistent with this idea in exciting new studies we have found that in a model of chronic MS, selective depletion of CNS B cells in the brain and spinal cord results in functional benefit. In order to better understand how the removal of CNS B cells may improve functional recovery, we outline two sets of studies in this proposal. In the first set of studies, we will use an animal model we have developed that allows us to selectively deplete B cell in the brain and spinal cord while leaving the peripheral immune system intact. We will induce B cell-dependent Experimental Allergic Encephalitis (EAE) in these animals and, once they have developed disease, we will deplete CNS B cells and measure functional recovery and remyelination. Our preliminary data suggests there is functional recovery following CNS B cell depletion, and in the current proposal we will measure the functional effects of CNS B cell depletion and assess the extent of myelin repair in the lesions through quantification of the number of oligodendrocyte precursors and mature oligodendrocytes as well as the level of remyelinated axons using a combination of light and electron microscopy. We anticipate that following B cell depletion there will be increases in both the number of oligodendrocytes and remyelinated axons that correlates with the level of functional recovery. In the second set of studies, we will define changes in CNS glial cell responses following CNS B cell depletion to identify the cell-cell interactions by which B cells inhibit myelin repair. Our hypothesis is that B cells stimulate the CNS innate immune system (astrocytes and microglia) resulting in an environment that inhibits myelin repair. To test this hypothesis, we will characterize the changes in astrocyte and microglia cytokine expression in EAE animals following B cell depletion using RNA analyses. These studies will identify potential inhibitory pathways to myelin repair and identify novel targets for therapeutic intervention. While we predict that B cell signal through the innate immune system, it is also possible that there is a direct cell-cell signaling between CNS B cells and OPCs that inhibits OPC differentiation and/or oligodendrocyte survival. We will address this issue through RNA analysis, as described above, and will follow up as needed with co-culture studies in vitro. Together these studies will provide important new insights into the role of CNS B cells in myelin repair and identify novel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210382
Entities
People
- Robert Miller
Organizations
- George Washington University
- United States Army