An arrayed CRISPR screen of primary B cells reveals the essential elements of the antibody secretion pathway

BACKGROUND: Humoral immunity depends on the differentiation of B cells into antibody secreting cells (ASCs). Excess or inappropriate ASC differentiation can lead to antibody-mediated autoimmune diseases, while impaired differentiation results in immunodeficiency. METHODS: We have used CRISPR/Cas9 technology in primary B cells to screen for regulators of terminal differentiation and antibody production. RESULTS: We identified several new positive (Sec61a1, Hspa5) and negative (Arhgef18, Pold1, Pax5, Ets1) regulators that impacted on the differentiation process. Other genes limited the proliferative capacity of activated B cells (Sumo2, Vcp, Selk). The largest number of genes identified in this screen (35) were required for antibody secretion. These included genes involved in endoplasmic reticulum-associated degradation and the unfolded protein response, as well as post-translational protein modifications. DISCUSSION: The genes identified in this study represent weak links in the antibody-secretion pathway that are potential drug targets for antibody-mediated diseases, as well as candidates for genes whose mutation results in primary immune deficiency.