Distinct Effector B Cells Induced by Unregulated Toll-like Receptor 7 Contribute to Pathogenic Responses in Systemic Lupus Erythematosus

Autoreactive B-cell development in SLE (systemic lupus erythematosus) is often considered in terms of the extrinsic stimuli and factors that drive B cells into autoantibody production. This review focuses on the novel concept that autoreactive B cells are initially programmed at the transitional stage for heightened susceptibility for development into autoantibody secreting plasmablasts (Figure 1). During peripheral B-cell development in the spleen, transitional B-cells expressing elevated levels of endogenous intracellular interferon-β (IFNβ) exhibit enhanced survival and activation through the B-cell receptor (BCR), a feature associated with more active SLE, particularly in African American (AA) patients. 1 Following passage through the transitional stage, a second major defect is the failure of B cells to maintain the integrity of tolerogenic splenic marginal zone macrophages (MZM), which normally function to remove apoptotic cell debris in a non-inflammatory fashion through upregulation of indoleamine-pyrrole 2,3-dioxygenase (IDO). 2 This failure is amplified by the type I IFN-driven migratory properties of marginal zone-precursor (MZ-P) B cells as they lose their tethering to sphingosine-1-phosphate (S1P) and drift across the follicular exclusion barrier. 3-8 Here they act as potent antigen-carrying, co-stimulatory cells expressing inflammatory cytokine IL-6 and low levels of the antiinflammatory cytokine IL-10. 9 In addition, Ag transporting MZ-P B-cells Abstract The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B-cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B-cells encounter T-follicular helper cells (Tfh) that produce interleukin (IL)-21, IL-4 and pathogenic cytokines, IL-17 and IFN gamma (IFNɣ). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B-cell stage as a major juncture where transient autocrine IFNβ expression by developing B-cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody-producing plasmablasts. Recent studies highlight transitional B-cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B-cell responsiveness to cytokines and other environment factors.

Section: Type II Ifn and Autoreactive B Cells In Slesupporting

confidence: 87%

Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

“…93 We conclude that the impaired selection of developing autoreactive B cells in patients with autoimmune diseases likely favors the production of circulating CD19 hi CD27 − CD21 −/lo B cells that express autoreactive antibodies, produce pro-inflammatory cytokines, and thereby foster severe disease manifestation. Usage is shown as a frequency of the total unique IGHV sequences (y-axis) for each subject (symbols).…”

Section: Toler An Ce Check P Oint Defec Ts Alter the Naive B-cell Rmentioning

confidence: 84%

Impaired B‐cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies

Meffre

O’Connor

2019

108

100

A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered Bcell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27 − CD21 −/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens. K E Y W O R D Sautoantibodies, autoimmune disease, B-cell development, immune tolerance checkpoint

“…96 GC responses (right, red) result in the highest levels of affinity maturation, memory formation, and LLPC development, but are slower to develop The source of receptor diversity of the GC reaction comes both from a diverse naive repertoire as well as the accumulation of receptor mutations by cells dividing in the dark zone due to the high expression of activation-induced cytidine deaminase (AID) and the error-prone DNA polymerase "eta". In the GC environment B cells compete for limited survival resources, and through rapid rounds of division, mutation, and selection, those with the highest fitness (ie, BCR affinity) emerges as the foundation of the ensuing humoral immune F I G U R E 1 Pathways of B-cell activation.…”

Section: G Erminal Center Re S P On S Ementioning

confidence: 99%

“…Whether GC are formed by the same activated naive B cells that contribute to the EF response, possibly through asymmetric division, 84 remains unknown. Indeed, blood studies in SLE have proven highly informative for this purpose and have provided critical information for our understanding of the human EF activation pathway and its participation in SLE.Experimentally, these goals were accomplished by taking advantage of a comprehensive B-cell Immunomics approach to: (a) identify Bcell subsets abnormally expanded during acute SLE flares; and (b) to establish a developmental link between B-cell subsets of interest through deep sequencing of the BCR repertoire and integrated transcriptional and epigenetic analysis [94][95][96]. In turn, this limitation stems at least in part from lack of access to lymphoid tissue in the study of SLE or more in general in subjects experiencing an acute immune response, in the setting which extrafollicular responses would be expected to occur.…”

mentioning

confidence: 99%

Extrafollicular responses in humans and SLE

Jenks

Cashman

Woodruff

et al. 2019

Self Cite

222

197

Summary Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.