Dysregulation of T Follicular Helper Cells in Lupus

Mountz, John D.; Hsu, Hui‐Chen; Ballesteros-Tato, André

doi:10.4049/jimmunol.1801150

Cited by 38 publications

(48 citation statements)

References 153 publications

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“…The canonical Tfh is one in which STAT3 signaling, either through IL-6 or IL-21, can upregulate Bcl6, the canonical transcription factor for Tfhs ( Figure 6). 11,15,171,194,203 The underlying mechanism for the production of such autoantibodies is by definition due to a loss of tolerance at some step before or at this GC stage of development. Bcl6 turns on a program of Tfh genes that can promote B-cell development and at the same time, turns off the Tfh's ability to develop into other Tfhs.…”

Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

“…Whether this GC reaction is normal or pathogenic is determined by the cytokines produced by the Tfh and the cytokine receptors expressed by the GC B cell. [194][195][196] After successful interaction with T cells, the B cell has the potential to encounter a spectrum of Tfhs each of which possess a different transcription factor that drives a different program and different cytokines that can promote B-cell development. The canonical Tfh is one in which STAT3 signaling, either through IL-6 or IL-21, can upregulate Bcl6, the canonical transcription factor for Tfhs ( Figure 6).…”

Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

“…Weinstein and coworkers have shown that Tfhs exhibit synchronous development from Bcl6-IL21 producing Tfh to a IL-4 producing Tfh. 196 11,15,171,194,203 The underlying mechanism for the production of such autoantibodies is by definition due to a loss of tolerance at some step before or at this GC stage of development.…”

Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

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Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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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.

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Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

Section: Stimulation Of Autoreactive B Cells By Tfhmentioning

confidence: 99%

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Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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“…A key cytokine produced by Tfh cells is IL-21, a factor that potently promotes B cell activation and Ab secretion (1,2). Although Tfh cells are critical for the proper production of Abs, the overproduction of Tfh cells can lead to autoimmunity as Tfh cells can help B cells to produce self-reactive Abs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Thus, the proper regulation of Tfh cell differentiation is essential for normal immune function as well as preventing autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2–Deficient Mice

et al. 2019

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Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell–specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell–deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.

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“…There are potential protective autoantibodies in SLE patients, such as anti-oxLDL-IgM, anti-ApoB100 antibodies, anti-choline phosphate (PC) antibodies and anti-malondialdehyde (MDA) antibodies. The first three have a synergistic effect: they reduce the level of oxLDL, the uptake of oxLDL, and the formation of foam cells (105)(106)(107). And Anti-PC-IgM increases Tregs in SLE and atherosclerosis, reduces IL-17 and TNF-a, and makes dendritic cells (DCs) immature (33).…”

mentioning

confidence: 99%

IFN-I Mediates Dysfunction of Endothelial Progenitor Cells in Atherosclerosis of Systemic Lupus Erythematosus

Ding

Xiang

2020

Front. Immunol.

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Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.

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Dysregulation of T Follicular Helper Cells in Lupus

Cited by 38 publications

References 153 publications

Autoreactive B cells in SLE, villains or innocent bystanders?

Autoreactive B cells in SLE, villains or innocent bystanders?

Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2–Deficient Mice

IFN-I Mediates Dysfunction of Endothelial Progenitor Cells in Atherosclerosis of Systemic Lupus Erythematosus

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