TRANSCRIPTIONAL REGULATION OF B CELL RESPONSES IN PROTECTION AND AUTOIMMUNITY. PDF Download

Author: Adam James Fike
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Languages : en
Pages : 0

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Book Description
Humoral immunity plays a pivotal role in both protective and autoimmune responses. Following a vaccination or pathogenic challenge, B lymphocytes respond by differentiating through germinal center (GC) or extrafollicular (EF) pathways to ultimately become antibody forming cells, which produce antibodies to protect the host. In autoimmune diseases, like systemic lupus erythematosus (SLE), these pathways become dysregulated which allows autoreactive B cells to produce antibodies against self-antigen. Thus, deciphering the transcriptional networks that regulate protective and aberrant responses in autoimmune diseases is paramount to guiding insights for new vaccines or therapeutics for autoimmune conditions. The GC is a site of B cell evolution and is the dominant source of high-affinity long lived plasma cells (LLPCs). GCs are canonically organized into two distinct niches, the dark (DZ) and light (LZ) zone. A bottle neck for the selection of high-affinity B cells within the GC is at the T cell-mediated selection stage in the light zone (LZ) of the GC. STAT3 is a transcription factor activated by several cytokines and signals critical to B cell biology and has a known role in plasma cell maturation. How STAT3 influences the GC reaction remains incompletely understood. Using numerous stage-specific and inducible B cell intrinsic systems, we determined that STAT3 is not required for the initiation or maintenance of a GC reaction, but rather is required for the zonal organization of the GC. STAT3-deficient GCs have an expansion of the LZ and reduction of the DZ. STAT3 exerts its functions independent of any effects on proliferation, cell cycle progression, DNA damage, or apoptosis. Further, we identified that STAT3 is not required for memory B cell (MBC) formation or the initial progression towards a plasma cell but is required for post-GC PC maturation. We discovered that STAT3 is activated in the LZ of the GC in a T-dependent manner, which permits STAT3 to orchestrate the transcriptional program required for LZ GC B cells to progress into DZ GC B cells. We next sought to delineate the functions of another STAT transcription factor, STAT4, in regulating SLE and Th1-mediated B cell responses. STAT4 has been suggested to be involved in autoimmune and protective B cell responses, but its exact contribution remains undefined. Further, numerous GWAS identified polymorphisms in or near the Stat4 locus in SLE patients. To examine the role of STAT4 in the regulation of B cell responses in SLE-like autoimmunity, we investigated the effects of STAT4 deficiency in three autoimmune- or lupus-prone mouse models: Fc[gamma]RIIB-/-, B6.Sle1b, and imiquimod treated B6.Sle1b.We found no significant effects of STAT4 on autoimmune B and T cell responses, and SLE-like autoimmunity. We next investigated if STAT4 deficiency impacted B cell responses to immunization or influenza viral infection. Again, we identified no significant impact on B or T cell responses in the absence of STAT4. From these results, we conclude that STAT4 is not required for autoimmune or protective B cell responses. Finally, B cell responses in SLE are heavily dependent upon Toll-like receptor 7 (TLR7) signaling. TLR7 activation results in the activation of several transcription factors, including interferon regulatory factor 7 (IRF7). IRF7 has been generally suspected to be involved in promoting autoimmunity, but its functions in various immune cells remain unexplored. We utilized mouse models of SLE autoimmunity and scRNAseq to delineate the mechanisms by which IRF7 in B cells drives autoimmune B cell differentiation into GC B cells and autoantibody producing antibody forming cells (AFC). Specifically, IRF7 regulates activated B cell differentiation into GC and antibody forming cell (AFC) pathways during an autoimmune response by controlling the metabolic and transcriptional program required for differentiation. These findings highlight the critical involvement of IRF7 as a primary driver of dysregulated B cell responses in systemic autoimmunity. Collectively, the findings presented in this body of work advance in our understanding of the transcriptional control of protective and autoimmune B cell responses.