B cells in SLE

Introduction

B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE), including the unique capacity of plasma cells as ultimately differentiated autoreactive B cells to produce autoantibodies. These antibodies reacting against self-antigens participate in the induction and maintenance of tissue damage and represent hallmarks of SLE, which is characterized by the largest variety of specificities, with 180 autoantibodies so far described. The central role of B cells in SLE is further highlighted by the fact that the only successful new therapy for SLE in more than 50 years is an agent that blocks BAFF/BLyS (B-cell activating factor or B lymphocyte stimulator)—belimumab and interferes with B cells and plasma cell survival.

Independent of the production of autoantibodies by plasma cells, B cells contribute to the pathogenesis of SLE through the presentation of antigens to T cells, the production of pro- and antiinflammatory cytokines and regulatory mechanisms, such as costimulation. Notably, B cells can also regulate autoimmunity through production of antiinflammatory cytokines, such as interleukin (IL)-10—a cytokine that has been extensively study in mouse models of lupus, with data available indicating that IL-10 produce by B cells suppresses the disease. A subset of B cells with supressing capacity, partially mediated by IL-10, was found to be functional defective in SLE patients. Recently, it was found that, in vivo, IL-10 is produced by a subset of murine plasma cells that distinctively express at their surface the inhibitory receptor LAG-3. This finding may represent the possibility to modulate these cells in the context of human SLE, but further studies are needed to employ the potential of such regulatory plasma cells. As for regulatory T cells, there is increasing interest in the therapeutic potential of certain regulatory B cell subsets, including IL-10, Il-27, and IL-35 producing B cells as reviewed for human and murine autoimmunity in more detail elsewhere.

Even though SLE is considered as a B cell disease or dominated by humoral autoimmunity, our understanding of the roles of B cell in the course of the disease is far from complete. The various and complex functions of B cells in SLE are emphasized by certain therapeutic developments co-targeting different aspects of B cells in this complex disease.

In this chapter, we address the characteristic of B cells in SLE, with a focus on human lupus. We describe abnormalities in B cell subset distribution as well as surface and intracellular signaling defects owned by post-activated B cells, characteristically present in SLE patients. While current data indicate the involvement of B cells in SLE, their role in induction and maintenance remain to be further delineated. Despite the role of autoreactive plasma cells, a key question followed over the last decades is how and where the break of immune tolerance occurs subsequently resulting in SLE. Intimately connected with this topic, various studies using a number of different technologies sought to identify defects of central as well as peripheral selection checkpoints. In this regard, a main focus addressed abnormalities of B cell differentiation including subset distribution and functional disturbances that will be a covered in the subsequent chapters.