Epigenetic programming underpins B cell dysfunction in human SLE

Scharer, Christopher D.; Blalock, Emily L.; Tian, Mi; Barwick, Benjamin G.; Jenks, Scott A.; Deguchi, Toshio; Cashman, Kevin S.; Neary, Bridget; Patterson, Dillon G.; Hicks, Sakeenah L.; Khosroshahi, Arezou; Lee, F. Eun-Hyung; Wei, Chungwen; Sanz, Iñaki; Boss, Jeremy M.

doi:10.1038/s41590-019-0419-9

Cited by 168 publications

(185 citation statements)

References 67 publications

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“…The emergence of CD11c + DN B cells is not unique to active SLE, and even healthy subjects display this B cell subset in the blood and tonsil albeit at a lower frequency . The differentiation mechanism by which resting naïve B cells become activated and differentiate into CD11c + DN B cells in humans is currently under extensive investigation.…”

Section: Introductionmentioning

confidence: 99%

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ueno

2019

Eur J Immunol

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Generation of autoantibodies is a hallmark of systemic lupus erythematosus (SLE). As demonstrated in a number of lupus mouse models, recent evidence suggests that both GC and extrafollicular pathways contribute to the generation of autoantibodies also in human SLE, and that CD11c+ IgD−CD27−(double negative:DN) B cells play a central role in the latter pathway. In this mini‐review, the author will first briefly summarize the features of CD11c+ DN B cells in human SLE, and discuss how the IL‐12‐STAT4 axis might contribute to the generation of autoantibodies in SLE. In addition, various types of CD4+ helper T cell subsets promoting the generation of autoantibodies in SLE will be described, and finally it will be discussed how these recent discoveries contribute to understanding of SLE pathogenesis and treatment of SLE patients.

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Section: Introductionmentioning

confidence: 99%

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Ueno

2019

Eur J Immunol

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“…162 This demonstrates how the epigenome serves as a record of developmental history. 162 Analysis of the epigenetic program in B-cell subsets representing a range of differentiation stages revealed that an SLE disease state existed in the naive B-cell subset, suggesting the SLE environment was establishing a heritable phenotype that could impact later differentiation trajectories. Enhancers are the primary regulatory elements that are different between cell types.…”

Section: Epigenetic Regulation Of Sle B-cells Implications For Undmentioning

confidence: 98%

“…Some of the strongest evidence for altered epigenetic programs comes from studies of twins discordant for SLE that have distinct DNA methylation patterns in CD4 + T-cells. 161,162 This indicates that B-cells may be under the control of epigenetic processes that are distinct from other immune lineages, even within the same autoimmune disease. 161,162 This indicates that B-cells may be under the control of epigenetic processes that are distinct from other immune lineages, even within the same autoimmune disease.…”

Section: Epigenetic Regulation Of Sle B-cells Implications For Undmentioning

confidence: 99%

“…162 In fact, the expression of these factors is enriched in the naive SLE B-cell compartment, indicating that SLE B-cells have received both BCR and TLR stimulation in their past, respectively. Identified transcription factors can provide clues to the cellular history, active signaling networks, and future phenotype potential.…”

Section: Epigenetic Regulation Of Sle B-cells Implications For Undmentioning

confidence: 99%

“…162 In fact, the expression of these factors is enriched in the naive SLE B-cell compartment, indicating that SLE B-cells have received both BCR and TLR stimulation in their past, respectively. 162 Interestingly, these transcription factors can be activated by both BCR and TLR stimulation but can also be enhanced by interferon signaling networks. 60 Perhaps early and chronic exposure to such receptor signaling events represents attacks on tolerance.…”

Section: Epigenetic Regulation Of Sle B-cells Implications For Undmentioning

confidence: 99%

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Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

Cashman

Jenks

Woodruff

et al. 2019

Immunological Reviews

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It is well established that normal immune systems are endowed with a significant degree of autoreactivity. Accordingly, effective tolerogenic mechanisms are required to censor autoreactive cells and to ultimately prevent their differentiation into pathogenic effector cells. In this review, we will discuss how immunological tolerance is enforced in the human B-cell compartment. We shall also discuss the breakdown of B-cell tolerance in human autoimmune diseases.Finally, we will review different experimental approaches to measure B-cell tolerance in human disease. | B-CELL TOLER AN CE . CHECK P OINTS AND MECHANIS MS . LE SSONS LE ARNED THROUG H MOUS E S TUD IE SMouse models have been instrumental in defining multiple checkpoints and distinct mechanisms underpinning the enforcement of B-cell tolerance. Tolerance checkpoints are classified into central and peripheral mechanisms based on anatomical location and stage AbstractThe maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B-cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess.Functional autoreactive, flow cytometric, and single-cell cloning assays have proven to be critical in deciphering breaks in B-cell tolerance within autoimmunity; however, newer approaches to assess human B-cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.

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Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus

Breitbach

Ramaker

Roberts

et al. 2019

Arthritis & Rheumatology

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Objective. To determine the stage of B cell development at which a systemic lupus erythematosus (SLE)associated DNA methylation signature originates in African American (AA) and European American (EA) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations.Methods. B cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence-activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE-associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls.Results. Regression analysis across all B cell stages resulted in identification of 60 CpGs that reached genomewide significance for SLE-associated methylation differences (P ≤ 1.07 × 10 −7 ). Interrogation of ethnicity-specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon (IFN)-regulated genes and binding of EBF1 in AA patients (each P < 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic [ROC] area under the curve [AUC] 0.98), and when applied to CD19+ pan-B cells (mean ROC AUC 0.95) and CD4+ pan-T cells (mean ROC AUC 0.97) from the independent validation cohort.Conclusion. These results indicate that SLE-specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN-regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE-associated epigenetic changes.

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Epigenetic programming underpins B cell dysfunction in human SLE

Cited by 168 publications

References 67 publications

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

The IL‐12‐STAT4 axis in the pathogenesis of human systemic lupus erythematosus

Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease

Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus

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