Target Discovery for Autoimmune Disease: Fibrinogen-like Protein 1 as a Novel B Cell Inhibitory Ligand
Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Chen, Lieping
Abstract
Cell surface receptor/ligand interactions are critical for governing immune cell activity. B cells are important components of the immune system that generate protective antibodies and activate immunity. Two B cell receptors, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and B cell activating factor belonging to the tumor necrosis factor family receptor (BAFFR), help mediate B cell survival, proliferation, activation, and antibody production. The ligands for TACI are B cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation inducing ligand (APRIL). BAFFR has only one known ligand, BAFF. These ligands and their receptors have clinical relevance as targets in autoimmune disease, particularly systemic lupus erythematosus (SLE), a disease that involves hyperactivated B cells. Despite its importance, no negative regulator has been identified for this pathway until now. Here, we identify fibrinogen-like protein 1 (FGL1) as a novel inhibitory ligand of TACI and BAFFR, but not of a closely related family member, B cell maturation antigen (BCMA). First cloned as a gene upregulated in liver carcinoma, FGL1 is a secreted protein normally produced by hepatocytes. It is upregulated upon conditions of liver injury and also plays a role in metabolism. Our group was the first to identify a direct inhibitory role of FGL1 on T cells, the killer or helper cells of the immune system, via lymphocyte-activation gene 3 (LAG3). However, FGL1-knockout (KO) mice developed autoimmune symptoms such as autoantibodies and dermatitis upon aging. This phenomenon was not observed in LAG3-KO mice, implicating the presence of additional receptor(s). Thus, we set out to find other receptor(s) with autoimmune relevance for FGL1. Chapter 1 provides an introductory framework to understanding this new interaction. Within it, I outline central roles of co-signaling cell surface molecules in immune regulation, with LAG3 given as an example on T cells. A general overview of therapeutically relevant B cell pathways in autoimmune disease is provided. Next, I introduce TACI and BAFFR, discussing their biochemistry, biology, and role in autoimmune disease. Lastly, I conclude with a review regarding FGL1, from the biochemical to cellular, organismal, and human disease applications. Chapter 2 describes the discovery, validation, and biochemical characterization of the FGL1/TACI and FGL1/BAFFR interactions. We identify a distinct N-terminal binding site for FGL1, which differs from the binding sites of the known ligands BAFF and APRIL. Chapter 3 presents the functional effects of this interaction. We uncover an anti-proliferative role for FGL1 via BAFFR in vitro and an inhibitory role for T-independent antibody production via TACI in vivo. FGL1-mediated TACI downregulation is discussed as one mechanism by which FGL1 may exert its inhibition. In Chapter 4, we propose that FGL1 impedes lymphadenopathy in a mouse model of autoimmune disease, inducing specific downregulation of a TACI+ B cell subpopulation in pathologic lymph nodes. Chapter 5 concludes with a summary and future directions of this original research, including potential human disease applications. In summary, this dissertation uncovers an entirely new set of B cell targetable interactions and their biochemistry, biology, mechanism, and autoimmune relevance.
Recommended Citation
Su, Tianjiao Tina, "Target Discovery for Autoimmune Disease: Fibrinogen-like Protein 1 as a Novel B Cell Inhibitory Ligand" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1104.
https://elischolar.library.yale.edu/gsas_dissertations/1104
