Multiple sclerosis (MS) is a neuro-inflammatory disease of the central nervous system (CNS) that causes demyelination and axonal damage. Current therapies available to MS patients are sub-optimal, and there is no cure for this chronic, debilitating disease. B cell depletion therapies have shown promise in several treatment trials, yet B cells can also play protective and anti-inflammatory roles that are important during health and disease. Determining the mechanisms by which B cell antigen presentation mediates neuroinflammation and tolerance in MS is crucial for developing immunomodulatory therapies targeted to encephalitogenic B cell functions. Using an in vivo conditional MHCII expression system and experimental autoimmune encephalomyelitis (EAE), our lab has demonstrated that B cells are not sufficient antigen presenting cells (APCs) for passive EAE induced by adoptive transfer of encephalitogenic CD4 T cells unless enough B cells recognize the cognate antigen, myelin oligodendrocyte glycoprotein (MOG). Further experiments have supported our hypothesis that MOG-specific, membrane bound B cell receptor, rather than MOG-specific secreted immunoglobulin, is critical to the propagation of CD4 T cell auto-reactivity, likely for efficient capture of target antigen. These findings highlight the importance of soluble antibody independent B cell functions to MS pathogenesis.
In Aim 1 I will determine restrictions on the location of B cell antigen presentation by quantifying B cell localization and MHCII expression in the CNS compartment. I will also assay murine cerebrospinal fluid for the presence of intrathecal immunoglobulin indicative of B:T cell cognate interactions within the CNS. Lastly, the capacities of non-specific and antigen-specific B cells from passive EAE mice to traverse an in vitro blood brain barrier model will be tested.
In Aim 2 I will define the effect of antigen-specifc B cells on CD4 T cell lineage fate during EAE. T cell cytokine production will be determined in antigen recall assays using nave and in vitro- primed splenocytes from WT mice and mice with conditional expression in various APC subsets. Additionally, I will define the cytokine expression profile of B cells from different B-cell dependent EAE models and quantify B cell expression of IL-1?. The hypothesis that B cells shape T cell lineage plasticity will be tested by modulating th timing of B cell antigen presentation in passive EAE in conjunction with dendritic cell MHCII expression. Successful completion of the research proposed in these aims will increase our understanding of cellular mechanisms of inflammatory demyelinating diseases of the CNS. We will identify where important pathogenic functions of B cells occur in EAE and distinguish mechanisms of pathogenic cytokine generation as potential targets for immunotherapy in MS.
Amelioration of multiple sclerosis disease activity after B cell depletion therapy has motivated renewed interest in the pathogenic functions of B lymphocytes in neuro-inflammatory disease. In the proposed project, I will use a murine model of multiple sclerosis to determine the compartmental requirements for B cell antigen presentation and define the ability of B cells to shape encephalitogenic CD4 T cell lineage fates. Understanding the mechanisms employed by antigen- specific B cells to drive experimental autoimmune encephalomyelitis will inform the development of more effective treatments for human disease.
