B Cell-Intrinsic Role for IRF5 in TLR9/BCR-Induced Human B Cell Activation, Proliferation, and Plasmablast Differentiation

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.

Association of IRF5 rs2004640 polymorphism and systemic lupus erythematosus: A meta‐analysis

“…Therefore, there were 28 different comparisons in this meta‐analysis, including 11 228 SLE cases and 14 374 controls. This meta‐analysis consisted of two studies involving North American populations, nine studies involving Asian populations, four studies involving Latin American populations, nine studies involving European populations, and another four studies involving African American populations, African populations, mixed populations and Caucasian populations, respectively (Table ).…”

“…Therefore, the relationship between genetic polymorphisms and susceptibility to autoimmune diseases has become a hot topic. IRF5 is a transcription factor that plays a vital role in regulating IFN and immune system activation . The IRF5 gene contains several polymorphisms related to autoimmune diseases.…”

“…In addition, the process of differentiation of CD4 T cells into pro‐inflammatory subgroups Th1 and Th17 induced by macrophages is partially dependent on the activation of IRF5 . In SLE patients, IRF5 polymorphisms play significant roles in early skewness of B cell subgroup distribution and the destruction of self‐tolerance, resulting in the increase of circulating antibody secreting cells and autoantibodies . Therefore, it is important in autoimmunity, especially in SLE.…”

“…IRF5 is a transcription factor that plays a vital role in regulating IFN and immune system activation. 28 The IRF5 gene contains several polymorphisms related to autoimmune diseases. One of them called rs2004640, is located in the promoter or untranslated regions of IRF5.…”

IRF5 regulates unique subset of genes in dendritic cells during West Nile virus infection

“…28,29 Beyond cytokines, IRF5 regulates expression of genes essential for B cell differentiation, activation, and proliferation downstream of TLR9 and B cell receptor signaling. 30,31 These studies firmly established an important and versatile role of IRF5 in modulating both innate and adaptive immune responses through actions in various cell types. The precise function of IRF5 in regulating immune gene expression in response to virus infection remains to be elucidated.…”