Multifactorial Regulation of Germinal Center Responses and Autoimmunity
Open Access
- Author:
- Schell, Stephanie
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 18, 2019
- Committee Members:
- Dr. Ziaur Rahman, Dissertation Advisor/Co-Advisor
Dr. Ziaur Rahman, Committee Chair/Co-Chair
Dr. Todd Schell, Committee Member
Dr. Neil Christensen, Committee Member
Dr. Lisa Shantz, Outside Member - Keywords:
- Autoimmunity
Germinal Center
B Cells
Systemic Lupus Erythematosus
Apoptotic Cells
TLR7
miRNA
MAVS - Abstract:
- Germinal center (GC) responses are central to protective antibody production and memory B cell responses following infection and vaccination. GCs can also form spontaneously in the absence of overt infection (spontaneous GCs). When dysregulated, spontaneous GCs generate autoreactive B cells found in diseases such as systemic lupus erythematosus (SLE). Therefore, studying GC responses provides crucial insight for both the development of effective vaccines and novel therapeutic strategies for autoimmunity. RNA sensing and miRNA activity have emerged as crucial events in GC responses and autoimmunity development. TLR7 is perhaps the most crucial factor in spontaneous GC formation and autoimmunity but the source of TLR7 ligands has been unclear. We determined herein that self-RNA released from dead cells stimulates TLR7 in GC B cells to promote enhanced GC responses, establishing self-RNA as an important stimulus. Autoimmune-prone mice that accumulated dead cells in GCs showed enhanced autoimmunity, which was directly linked to aberrant GC B cell selection. While TLR7 has been established in these responses, we also assessed the requirement for cytosolic RNA sensing in spontaneous GC responses. Importantly, different requirements for MAVS during B cell development and GC responses were observed depending on genetic background. On a typical B6 background, the MDA5-MAVS pathway was not overtly required for GC responses but regulated antibody production. In vitro studies further indicated that MAVS can regulate B cell activation. Additional studies are required to determine the cell-intrinsic contributions of this RNA sensing pathway in vivo and specifically during autoimmunity. The final project focused on the contribution of miR-21 to foreign antigen induced GC responses and autoimmunity. Study revealed that miR-21 has a multifaceted role in the GC response to foreign antigen. Specifically, miR-21 was required for the development of ICOSL-expressing moDCs that can contribute to Tfh priming and in a B cell-intrinsic manner to promote GC B cell activation and proliferation. Additionally, autoimmune-prone mice lacking miR-21 had ablated autoantibody titers, suggesting the promise of further mechanistic study in the autoimmune model. Altogether, these studies clarify several gaps in knowledge about RNA sensing and miRNA function in the GC response and autoimmunity.