The Role of the Transcription Factor Ets1 in Lupus and Other Autoimmune Diseases

Garrett‐Sinha, Lee Ann; Kearly, Alyssa; Satterthwaite, Anne B.

doi:10.1615/critrevimmunol.2017020284

Cited by 38 publications

(41 citation statements)

References 208 publications

(282 reference statements)

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“…In addition, these two populations express the lowest levels of ETS1, which as stated above is a TF that inhibits PC differentiation 68 and whose hypomorphic alleles are associated with increased SLE risk. 69 As previously discussed, Ets1 deficiency induces lupus-like disease in mice through the extrafollicular accumulation of autoreactive plasma cells. Interestingly, in contrast to the GC fate induced by the association of IRF4 with Ets1 through the TF PU-1 and SpiB, high IRF4 levels in an Ets1-independent fashion shifts IRF4 genomic targeting to lower-affinity Interferon Sequence Responsive Elements (ISRE) motifs that are enriched in genes involved in plasma cell differentiation.…”

Section: Char Ac Teriz Ation Of Human E X Tr Afolli Cul Ar B-cell Rmentioning

confidence: 89%

“…81 Interestingly, Ets1, whose hypomorphic variants confer increased risk for human SLE, has been shown to downregulate hyperresponsiveness and plasma cell differentiation in response to TLR9 stimulations, and its deficiency leads to systemic autoimmunity in mice. [67][68][69] Mechanistically, Ets1 levels sufficient to prevent plasma cell differentiation in response to BCR or TLR stimulation are maintained through the Lyn-CD22 inhibitory pathway. 82 In keeping with its regulatory function, Ets1 activity has been shown to be required to maintain B-cell tolerance and its deficiency leads to autoimmune disease through the accumulation of autoreactive extrafollicular plasmablasts.…”

Section: Additional Insight Into the Participation Of The Ef Responsementioning

confidence: 99%

“…These mechanisms are used by MRL/lpr and NZM congenic AM14-transgenic mice to induce powerful immune complexmediated activation of B cells and anti-chromatin autoantibody production 54,58,65,66. Moreover, TLR7 overexpression leads to or accelerates lupus-like disease in multiple mouse strains, and TLR7 gene copy number or polymorphisms are associated with susceptibility to human SLE [67][68][69]. Importantly, overexpression of TLR7 on B cells leads to the extrafollicular expansion of autoreactive anti-RNA transitional B cells in an interferon (IFN)-independent fashion 70.…”

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confidence: 99%

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Extrafollicular responses in humans and SLE

Jenks

Cashman

Woodruff

et al. 2019

Immunological Reviews

222

197

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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.

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Section: Char Ac Teriz Ation Of Human E X Tr Afolli Cul Ar B-cell Rmentioning

confidence: 89%

Section: Additional Insight Into the Participation Of The Ef Responsementioning

confidence: 99%

mentioning

confidence: 99%

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Extrafollicular responses in humans and SLE

Jenks

Cashman

Woodruff

et al. 2019

Immunological Reviews

222

197

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“…It is highly expressed in lymphocytes, though it is present at reduced levels in PBMCs and regulatory T cells from individuals with SLE [32,33]. Indeed, this altered expression is postulated to contribute to the pathophysiology of SLE, in part because Ets1 plays an important genetic regulatory role in preventing plasma cell differentiation and maintaining B cell self-tolerance [34]. ETS1 knock-out mice develop an autoimmune syndrome similar to SLE, complete with serum autoantibodies against double-stranded DNA and histones (as seen in SLE in humans) as well as anti-cardiolipin (an antiphospholipid antibody) [35].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Weeding

Coit

Yalavarthi

et al. 2018

Clinical Immunology

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Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thromboembolic events and pregnancy loss. We sought to characterize the DNA methylation profile of primary APS in comparison to healthy controls and individuals with SLE. In primary APS neutrophils compared to controls, 17 hypomethylated and 25 hypermethylated CpG sites were identified. Notable hypomethylated genes included ETS1, a genetic risk locus for SLE, and PTPN2, a genetic risk locus for other autoimmune diseases. Gene ontology analysis of hypomethylated genes revealed enrichment of genes involved in pregnancy. None of the differentially methylated sites in primary APS were differentially methylated in SLE neutrophils, and there was no demethylation of interferon signature genes in primary APS as is seen in SLE. Hypomethylation within a single probe in the IFI44L promoter (cg06872964) was able to distinguish SLE from primary APS with a sensitivity of 93.3% and specificity of 80.0% at a methylation fraction of 0.329.

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“…ETS1, controls lymphocyte differentiation, modulates cytokine and chemokine expression. Low expression levels of ETS1, leading to aberrant lymphocyte differentiation, have been found in systemic lupus erythematosus [37]. ETS1 also has a potential role in the regulation of angiogenesis [38].…”

Section: Discussionmentioning

confidence: 99%

Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent Giant Cell Arteritis

Smit

Lukowski

Anderson

et al. 2018

Preprint

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BackgroundGiant cell arteritis (GCA) is the most common form of vasculitis affecting elderly people. It is one of the few true ophthalmic emergencies. GCA is a heterogenous disease, symptoms and signs are variable thereby making it challenging to diagnose and often delaying diagnosis. A temporal artery biopsy is the gold standard to test for GCA, and there are currently no specific biochemical markers to categorize or aid diagnosis of the disease. We aimed to identify a less invasive method to confirm the diagnosis of GCA, as well as to ascertain clinically relevant predictive biomarkers by studying the transcriptome of purified peripheral CD4+ and CD8+ T lymphocytes in patients with GCA.Methods and FindingsWe recruited 16 patients with histological evidence of GCA at the Royal Victorian Eye and Ear Hospital (RVEEH), Melbourne, Australia, and aimed to collect blood samples at six time points: acute phase, 2–3 weeks, 6–8 weeks, 3 months, 6 months and 12 months after clinical diagnosis. CD4+ and CD8+ T-cells were positively selected at each time point through magnetic-assisted cell sorting (MACS). RNA was extracted from all 195 collected samples for subsequent RNA sequencing. The expression profiles of patients were compared to those of 16 age-matched controls. Over the 12-month study period, polynomial modelling analyses identified 179 and 4 statistically significant transcripts with altered expression profiles (FDR < 0.05) between cases and controls in CD4+ and CD8+ populations, respectively. In CD8+ cells, we identified two transcripts that remained differentially expressed after 12 months, namely SGTB, associated with neuronal apoptosis, and FCGR3A, which has been found in association with Takayasu arteritis (TA), another large vessel vasculitis. We detected genes that correlate with both symptoms and biochemical markers used in the acute setting for predicting long-term prognosis. 15 genes were shared across 3 phenotypes in CD4 and 16 across CD8 cells. In CD8, IL32 was common to 5 phenotypes: a history of Polymyalgia Rheumatica, both visual disturbance and raised neutrophils at the time of presentation, bilateral blindness and death within 12 months. Altered IL32 gene expression could provide risk evaluation of GCA diagnosis at the time of presentation and give an indication of prognosis, which may influence management.ConclusionsThis is the first longitudinal gene expression study undertaken to identify robust transcriptomic biomarkers of GCA. Our results show cell type-specific transcript expression profiles, novel gene-phenotype associations, and uncover important biological pathways for this disease. These data significantly enhance the current knowledge of relevant biomarkers, their association with clinical prognostic markers, as well as potential candidates for detecting disease activity in whole blood samples. In the acute phase, the gene-phenotype relationships we have identified could provide insight to potential disease severity and as such guide us in initiating appropriate patient management.

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The Role of the Transcription Factor Ets1 in Lupus and Other Autoimmune Diseases

Cited by 38 publications

References 208 publications

Extrafollicular responses in humans and SLE

Extrafollicular responses in humans and SLE

Genome-wide DNA methylation analysis in primary antiphospholipid syndrome neutrophils

Longitudinal expression profiling of CD4+ and CD8+ cells in patients with active to quiescent Giant Cell Arteritis

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