Ion channels regulating plasma cell differentiation and humoral immunity - PROJECT SUMMARY B cells are critical for immune responses to infection and in many forms of autoimmune disease. They develop in the bone marrow and migrate to lymph nodes and spleen, where they further mature. At the end of this process, B cells express a high affinity B cell receptor with which they recognize antigen and which allows them to develop further into either memory B cells or long-lived plasma cells. Both types of cells migrate to the bone marrow and provide long-term protection from reinfection with the same pathogen. Plasma cells are a B cell type that produces large quantities of antibodies that are critical for neutralizing pathogens such as influenza virus, or more recently, SARS-CoV2. Several forms of primary immunodeficiency are caused by defects in B cell development or maturation including agammaglobulinemia and common variable immunodeficiency (CVID), which are characterized by a complete or partial lack of antibody production. Underlying these forms of immunodeficiency are mutations in a plethora of genes that encode transcription factors, cell surface receptors and signal transduction molecules. Some of these mutations occur in genes encoding ion channels. Ion channels are located in the cell membrane or membranes of intracellular organelles. They function as gateways to mediate the transport of charged ions such as calcium, zinc or chloride. Inherited mutations in two ion channels were shown to prevent the development of B cells resulting in agammaglobulinemia. Studies in mice have identified additional ion channels that are required for B cell function. Overall however, the role of ion channels in B cells is poorly understood with only a handful of the more than 600 known ion channel genes implicated in B cell function to date. This is even more extreme for plasma cells because no ion channel has yet been reported that specifically regulates plasma cell development or function. This lack of information is in strong contrast to the well established role of ion channels in cells of the brain, nerves, heart, muscle or kidney. It also represents a missed opportunity from a basic science perspective and our ability to understand how immune responses to infection are regulated, and from a therapeutic perspective because ion channels are excellent drug targets. Drugs modulating ion channel function are a mainstay in the treatment of cardiovascular diseases, neurological and psychiatric disorders and type 2 diabetes. We have therefore conducted genetic screens to identify novel ion channels that regulate the development of B cells into plasma cells and identified around 10 such channels. We investigated several of these further and confirmed that inhibiting their expression in B cells interferes with plasma cell development. In this proposal, we will focus on two of these channels and determine the molecular and cellular mechanisms by which they control the development of B cells into plasma cells and their ability to mount an antibody response to infection with viral pathogens such as influenza.
