Intrinsic and Extrinsic Regulation of Autoreactive B cell Responses in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the sustained production of autoantibodies with a range of specificities that contribute to immune complex deposition and systemic inflammation. Autoantibody production signifies the breakdown of tolerance by autoreactive B cells. The positive selection of autoreactive B cell clones is succeeded by the differentiation of autoantibody-secreting cells (ASCs) through the extrafollicular (EF) and germinal center (GC) pathways. In this dissertation, we explore the complex mechanisms underlying B cell breaks of tolerance and autoantibody production using various SLE mouse models designed to interrogate distinct B cell differentiation pathways. In Chapter 2, we utilize a TLR7-driven B cell adoptive transfer lupus model to characterize the kinetics and regulators of extrafollicular pathogenic B cell differentiation. We additionally address the molecular mechanisms of complement receptor 2 (CR2/CD21) downregulation and CD21lo B cell accrual in SLE. Finally, we delineate the rapid, extrafollicular evolution of the follicular B cell repertoire in an autoreactive environment and outline the selective expansion of autoreactive clones. In Chapter 3, we investigate the complex roles of the integrin and complement receptor CD11c in regulating B cell tolerance. Through adoptive transfer and mixed bone marrow chimera approaches, we provide evidence for tissue-specific CD11c modulation of central and peripheral B cell tolerance, potentially supporting location-directed functions. In parallel, we demonstrate early evidence that exogenous C3 sensitization restricts the autoreactive B cell repertoire, implying a possible role for C3 ligand-receptor interactions in regulating autoreactivity. In Chapter 4, we demonstrate that the germline human IGHV1-69 allelic leucine (L54) and phenylalanine (F54) variants exhibit distinct functional autoreactivity in vivo. Using the 564Igi-based adoptive transfer lupus model, we show that L54-expressing murine B cells have a selective advantage in 564Igi recipients over the F54-expressing B cells, indicating that an intrinsically autoreactive germline B cell pool can be triggered to expand and differentiate in an autoimmune environment. Collectively, this work highlights multifaceted dysregulation of B cell development and responses in SLE and refines the mechanistic understanding of B cell tolerance.