Toll-like receptor signalling in B cells during systemic lupus erythematosus

Abstract

B lymphocytes have a central role in autoimmune diseases, which are often defined by specific autoantibody patterns and feature a loss of B cell tolerance. A prototypic disease associated with B cell hyperactivity is systemic lupus erythematosus (SLE). In patients with SLE, the loss of B cell tolerance to autoantigens is controlled in a cell-intrinsic manner by Toll-like receptors (TLRs), which sense nucleic acids in endosomes. TLR7 drives the extrafollicular B cell response and the germinal centre reaction that are involved in autoantibody production and disease pathogenesis. Surprisingly, TLR9 seems to protect against SLE, even though it is required for the production of autoantibodies recognizing double-stranded DNA-associated antigens, which are abundant in SLE and are a hallmark of this disease. The protective function of TLR9 is at least partly mediated by its capacity to limit the stimulatory activity of TLR7. The roles of TLR7 and TLR9 in the effector function of B cells in lupus-like disease and in patients with SLE, and the unique features of TLR signalling in B cells, suggest that targeting TLR signalling in SLE might be therapeutically beneficial.

Fig. 1. Opposing roles of TLR7 and TLR9 in SLE.

Systemic lupus erythematosus (SLE) is characterized by the presence of autoreactive B cells that recognize DNA-associated antigens (such as unmethylated cytosine-phosphate-guanosine (CpG) motifs) and RNA-associated antigens (such as the single-stranded RNA (ssRNA) small nuclear RNA, U11). These self-antigens are thought to be released owing to dysregulated processes that increase the abundance of neutrophil extracellular traps (NETs), necrotic cells or apoptotic cells. These autoantigens can be recognized at the surface of B cells by the B cell receptor (BCR), which initiates their cellular internalization. Once in endosomes, self-antigens can trigger Toll-like receptor 7 (TLR7) and/or TLR9 in B cells. Genetic or environmental signals leading to the overexpression of TLR7 (such as gender, diet and the cytokine environment, including the level of type I interferons) increase the susceptibility of individuals to SLE. Under physiological conditions, TLR7 signalling is restrained by TLR9, which protects individuals from the development of SLE. By contrast, the disruption of TLR9 function can favour TLR7 signalling and facilitate the development of SLE. Such disruption can involve the intracellular protein UNC93B1, which drives TLR7 and TLR9 trafficking to endosomal compartments (a). D34A mutation in transmembrane UNC93B1 favours its interaction with TLR7 (b), which can raise the abundance of TLR7 in endosomes, intensify TLR7 signalling and initiate a fatal systemic inflammatory syndrome in an experimental model. ER, endoplasmic reticulum.

Fig. 2. TLRs drive plasma cell differentiation in SLE via different pathways.

Two distinct pathways generate pathogenic antibody-secreting cells in patients with systemic lupus erythematosus (SLE): germinal centre reactions and the extrafollicular pathway, both of which engage resting naive B cells. The germinal centre pathway generates the DN1 subset of double negative B cells (DN1 B cells; that is, IgD⁻ CD27⁻ cells that are CXCR5⁺) and the memory B cells produced in germinal centres can re-enter the germinal centre reaction or differentiate into antibody-secreting cells that produce isotype switched anti-Smith and anti-RNP. The spontaneous generation of the germinal centre is dependent on TLR7. TLR7 also drives the extrafollicular pathway, in which resting naive B cells become activated naive B cells (CD11c⁺IgD⁺CD27⁻CD21⁻MTG⁺CD23⁻) and, subsequently, the DN2 subset of IgD⁻ CD27⁻ double-negative B cells (DN2 B cells; IgD⁻ CD27⁻ CD11c⁺ Tbet⁺ CD69⁺CD21⁻CD24⁻CD38⁻CXCR5⁻FCRL4⁻FCRL5⁺). DN2 B cells are precursors of pathogenic antibody-secreting cells in patients with SLE, the differentiation into which is promoted by TLR7, IL-21 and IFNγ. Of note, resting naive B cells can also generate, in a manner dependent on the B cell receptor (BCR), regulatory plasma cells that are characterized by the cell surface expression of lymphocyte activation gene 3 protein (LAG-3). These regulatory plasma cells produce a uniquely high level of IL-10 in response to TLR signalling. At steady state, they also secrete IgM with reactivity against antigens expressed by damaged cells, suggesting that they might be involved in the clearance of damaged cells.