Differential roles of type 1 and type 2 interferons in the regulation of spontaneous germinal centers and autoimmune responses
Open Access
- Author:
- Domeier, Phillip Patrick
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 20, 2018
- Committee Members:
- Ziaur Rahman, Dissertation Advisor/Co-Advisor
Ziaur Rahman, Committee Chair/Co-Chair
Aron Eliot Lukacher, Committee Member
Christopher Charles Norbury, Committee Member
Sarah Bronson, Outside Member - Keywords:
- Systemic Lupus Erythematosus
Germinal Center
B cell
Autoimmunity
Interferon
Type 1 interferon
Type 2 interferon
immune system - Abstract:
- Germinal centers (GCs) are required for high-affinity and class-switched antibody responses to pathogens. In patients with autoimmune disease, GCs develop in the absence of overt infection (called spontaneous germinal centers, Spt-GCs). Altered selection of B cells within Spt-GCs promote the development of high-affinity and class-switched antibodies to self-antigens (autoAbs). Systemic Lupus Erythematosus (SLE) is a polygenic autoimmune disease that is characterized by the excessive production of autoAbs that target nuclear self-antigens, causing systemic inflammation and organ failure. Current SLE therapies reduce pathogenic autoAb titers and associated disease pathology by immunosuppression, leaving patients susceptible to lethal infections. A characteristic signature of interferon-associated genes is a known biomarker of SLE initiation and progression. Interferon (IFN) blocking therapies have been proposed for the treatment of SLE, but immunosuppression complications remain a continuing challenge. The objective of this study is to understand how Type 1 and 2 IFNs differentially regulate Spt-GCs to identify novel targets for therapeutic intervention with limited immunosuppression complications. Primary investigation into IFN-blocking therapies suggests that the GC pathway could be altered during IFN-blockade, necessitating detailed analysis of the mechanisms that control GC to improve SLE treatments. To study Spt-GCs in SLE, we use a preclinical model, B6.Sle1b mice, that carry the lupus-associated SLAM (signaling lymphocytic activation molecule) family genes derived from NZM2410 mice. B6.Sle1b mice have an increased frequency of Spt-GCs, elevated numbers of self-reactive B cells and higher anti-nuclear autoantibody (ANA) titers as a result of altered GC selection. Using the B6.Sle1b model of SLE, we discovered that GC-derived serum IgG AutoAb titers are altered by modulation of both type 1 IFN (T1IFN) and type 2 IFN (T2IFN, IFNγ). B6.Sle1b mice that lack the receptor for type 1 IFN, (Sle1b.IFNaR1-/-) form smaller Spt-GCs with reduced titers of ANAs, whereas Sle1b.IFNgR1-/- mice fail to form Spt-GCs and also have reduced titers of ANAs. To determine how B cell intrinsic T1IFN and T2IFN signaling affects Spt-GC formation and activity, we used transgenic B cell transfer, bone marrow chimeras and conditional gene expression based approaches. We found that B cell intrinsic IFNgR1 expression and the associated downstream signaling pathways (STAT1 and Tbet) maintain a positive feedback signaling network that is required for the formation and regulation of Spt-GCs and elevated titers of ANAs. We also found that B cell intrinsic IFNaR1 signaling maintains Spt-GC structures by enhancing B cell receptor signaling to disrupt GC B cell selection. Collectively, these findings show that type 1 and type 2 IFNs differentially regulate Spt-GCs in SLE-prone mice, and these pathways can be further studied for the development of targeted therapeutics with limited immunosuppression complications.