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"Characterization Of The Role of IRF5 in B Cell Activation and Plasma Cell Differentiation"

by
Saurav De
Molecular Biology, Genetics and Cancer Track
B.S. 2006, The Ohio State University, Columbus, OH
M.A. 2010, Hunter College, NY



Thesis Advisor: Dr. Betsy Barnes, Ph.D.
Associate Professor
Department of Microbiology, Biochemistry and Molecular Genetics

Thursday, July 28, 2016
11:30 A.M., Rutgers NJMS Cancer Center, room G1196


Abstract

Recognition of foreign antigen by B cells triggers rapid proliferation and differentiation to specialized antibody secreting cells (ASCs) known as plasma cells. A large gene-regulatory network of transcription factors is tasked with regulating this multi-step process, however, the full repertoire of transcription factors required have not been fully defined. This study shows that the transcription factor interferon regulatory factor 5 (IRF5) is critical for the generation of human plasma cells. IRF5 knockdown performed in primary human na´ve B cells resulted in a retention of IgD na´ve B cells and a complementary reduction in plasma cell differentiation following stimulation with anti-IgM and CpG-B. Additionally IRF5 knockdown also resulted in reduced expression of AID and IgG1, IgG2 and IgG3 secretion. IRF5 was found to regulate the earliest stages of ASC differentiation, with IRF5 knockdown resulting in reduced B cell proliferation and activation. Transcriptome profiling following IRF5 knockdown showed decreases in the expression of B cell response genes, proliferation-associated genes and cytokines. Furthermore, ChIP-Seq analysis identified IRF5 bound to presumptive promoter regions of several genes involved in B cell activation and ASC differentiation, including IRF4, ERK1 and MYC. As IRF5 has been previously implicated in various autoimmune diseases, we further detail a unique strategy to utilize small peptide inhibitors to inhibit IRF5 activity in B cells. IRF5 nuclear translocation was reduced following treatment with our inhibitor, as well as expression of IRF5 dependent genes. Results presented in this study, demonstrate IRF5 as a critical transcriptional regulator of human plasma cell generation through its control of a specific gene repertoire responsible for B cell activation, proliferation and differentiation.


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