AUTHOR=De Saurav , Zhang Baohong , Shih Tiffany , Singh Sukhwinder , Winkler Aaron , Donnelly Robert , Barnes Betsy J. TITLE=B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01938 DOI=10.3389/fimmu.2017.01938 ISSN=1664-3224 ABSTRACT=

Upon recognition of antigen, B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs). During this transition, B cells are reliant upon a multilayer transcription factor network to achieve a dramatic remodeling of the B cell transcriptional landscape. Increased levels of ASCs are often seen in autoimmune diseases and it is believed that altered expression of regulatory transcription factors play a role in this imbalance. The transcription factor interferon regulatory factor 5 (IRF5) is one such candidate as polymorphisms in IRF5 associate with risk of numerous autoimmune diseases and correlate with elevated IRF5 expression. IRF5 genetic risk has been widely replicated in systemic lupus erythematosus (SLE), and loss of Irf5 ameliorates disease in murine lupus models, in part, through the lack of pathogenic autoantibody secretion. It remains unclear, however, whether IRF5 is contributing to autoantibody production through a B cell-intrinsic function. To date, IRF5 function in healthy human B cells has not been characterized. Using human primary naive B cells, we define a critical intrinsic role for IRF5 in B cell activation, proliferation, and plasmablast differentiation. Targeted IRF5 knockdown resulted in significant immunoglobulin (Ig) D retention, reduced proliferation, plasmablast differentiation, and IgG secretion. The observed decreases were due to impaired B cell activation and clonal expansion. Distinct from murine studies, we identify and confirm new IRF5 target genes, IRF4, ERK1, and MYC, and pathways that mediate IRF5 B cell-intrinsic function. Together, these results identify IRF5 as an early regulator of human B cell activation and provide the first dataset in human primary B cells to map IRF5 dysfunction in SLE.