AUTHOR=Trezise Stephanie , Kong Isabella Y. , Hawkins Edwin D. , Herold Marco J. , Willis Simon N. , Nutt Stephen L. 

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1089243

DOI=10.3389/fimmu.2023.1089243

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>We have used CRISPR/Cas9 technology in primary B cells to screen for regulators of terminal differentiation and antibody production.</p></sec><sec><title>Results</title><p>We identified several new positive (<italic>Sec61a1</italic>, <italic>Hspa5</italic>) and negative (<italic>Arhgef18</italic>, <italic>Pold1</italic>, <italic>Pax5</italic>, <italic>Ets1</italic>) regulators that impacted on the differentiation process. Other genes limited the proliferative capacity of activated B cells (<italic>Sumo2</italic>, <italic>Vcp</italic>, <italic>Selk</italic>). 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.</p></sec><sec><title>Discussion</title><p>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.</p></sec>