Autoreactive B cells in SLE, villains or innocent bystanders?

Abstract

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.

Putative role of marginal zone B cells in pathophysiological processes

“…64 Transitional T1 B cell stage is considered to be the main checkpoint for the establishment of the B cell autotolerance. 65 As mentioned above, the strength of tonic BCR signalling regulates weather the cells survive and continue to the next stage. 27,65,66 However, additional control by IFN and BAFF signal, interaction with MZM, and expression of S1P1 receptor determine the fate of potentially autoreactive B cells.…”

“…65 As mentioned above, the strength of tonic BCR signalling regulates weather the cells survive and continue to the next stage. 27,65,66 However, additional control by IFN and BAFF signal, interaction with MZM, and expression of S1P1 receptor determine the fate of potentially autoreactive B cells. 33,65,67 The particularly important event during establishment of B cell tolerance is interaction with marginal zone macrophages.…”

“…27,65,66 However, additional control by IFN and BAFF signal, interaction with MZM, and expression of S1P1 receptor determine the fate of potentially autoreactive B cells. 33,65,67 The particularly important event during establishment of B cell tolerance is interaction with marginal zone macrophages. MZM are responsible for capturing and presentation of apoptotic cells that flow by blood to the spleen, thus suppressing innate and adaptive immunity to apoptotic cells in the spleen.…”

Transitional B cells involved in autoimmunity and their impact on neuroimmunological diseases

“…The immature B cells transit to the marginal sinuses and red pulp of the spleen through the bone marrow sinusoids and bloodstream, after which the immature transitional 1 (T1) B cells migrate into the periarteriolar lymphoid sheath (PALS) of the white pulp in response to positive selection [24,25]. BCR-mediated negative selection occurs at the T1 B cell stage, which serves to remove the self-reactive B cells; the remaining T1 B cells give rise to the late transitional B cells (T2/T3 B cells) [26,27]. These gradually develop into naïve follicular mature (FM) or marginal zone (MZ) B cells and eventually into mature naïve B cells ( Fig.…”

Systemic lupus erythematosus: new horizons for diagnosis and therapy

“…[44][45][46] и служит ярким примером практической реализации концепции трансляционной медицины [47]. Напомним, что расширение представлений о роли В-клеток в иммунопатогенезе СКВ [48,49] привлекло внимание к изучению В-клеточных цитокиновых лигандов в качестве возможных «мишеней» для терапевтических воздействий. Особый интерес привлек BAFF (В cell-activating factor), известный также как BLyS (В lymphocyte stimulator), который относится к числу важных медиаторов «цитокиновой» регуляции функции, пролиферации и дифференцировки В-клеток [50,51].…”