ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Yuan, Qian; Arellano, Gabriel; Ifergan, Igal; Lin, Jean Z.; Snowden, Caroline; Kim, Taehyeung; Thomas, Jane Joy; Law, Calvin; Guan, Tianxia; Balabanov, Roumen; Kaech, Susan M.; Miller, Stephen D.; Choi, Jaehyuk

doi:10.1016/j.celrep.2021.109602

Cited by 25 publications

(13 citation statements)

References 77 publications

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“…Similarly, transcription factors with more than 1.5-fold increase of binding motifs in ‘closing’ ChARs were termed as reg-TFs. According to the literature, many of these patho-TFs and reg-TFs were previously reported to involve in regulating the Th17 to Th1 switch, corroborating the accuracy of our analysis ( 25 – 29 , 37 , 44 , 56 – 76 ) ( Table S1 ).…”

Section: Resultssupporting

confidence: 89%

“…These transcription factors are predicted according to the appearance of their binding motifs in opening ChARs. Majority of them have been previously reported to participate in regulating the pathogenic Th17 ( 44 , 68 – 76 ). Thus, these known transcription factors, as well as the residual ones we identified in this study, are all worth further exploring.…”

Section: Discussionmentioning

confidence: 99%

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Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

Zhao

Zeng

et al. 2022

Front. Immunol.

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Pathogenic Th17, featured by their production of pro-inflammatory cytokines, are considered as a key player in most autoimmune diseases. The transcriptome of them is obviously distinct from that of conventional regulatory Th17. However, chromatin accessibility of the two Th17 groups have not been comprehensively compared yet. Here, we found that their chromatin-accessible regions(ChARs) significantly correlated with the expression of related genes, indicating that they might engage in the regulation of these genes. Indeed, pathogenic Th17 specific ChARs (patho-ChARs) exhibited a significant distribution preference in TSS-proximal region. We further filtered the patho-ChARs based on their conservation among mammalians or their concordance with the expression of their related genes. In either situation, the filtered patho-ChARs also showed a preference for TSS-proximal region. Enrichment of expression concordant patho-ChARs related genes suggested that they might involve in the pathogenicity of Th17. Thus, we also examined all ChARs of patho-ChARs related genes, and defined an opening ChAR set according to their changes in the Th17 to Th1 conversion. Interestingly, these opening ChARs displayed a sequential accessibility change from TSS-proximal region to TSS-distal region. Meanwhile, a group of patho-TFs (transcription factors) were identified based on the appearance of their binding motifs in the opening ChARs. Consistently, some of them also displayed a similar preference for binding the TSS-proximal region. Single-cell transcriptome analysis further confirmed that these patho-TFs were involved in the generation of pathogenic Th17. Therefore, our results shed light on a new regulatory mechanism underlying the generation of pathogenic Th17, which is worth to be considered for autoimmune disease therapy.

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Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

Zhao

Zeng

et al. 2022

Front. Immunol.

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“…We therefore hypothesize that activation of TLR 7 by mRNA vaccines may upregulate IL-17, a cytokine of critical importance in the immunopathogenesis of MS. Thus, the vaccine might have acted to amplify the inflammatory process during a relapse in these patients ( 12 , 16 ). This contrasts with TLR 9 signaling by adenovirus-based vaccines, and may account for the scarcity of severe relapses observed with this vaccine ( 12 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

“…This contrasts with TLR 9 signaling by adenovirus-based vaccines, and may account for the scarcity of severe relapses observed with this vaccine ( 12 , 17 ). Interestingly, the most clinically aggressive cases had also the highest levels of IL-6, suggesting a major differentiation toward Th1 and Th17 ( 16 , 18 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series

Quintanilla‐Bordás¹,

Gascón-Giménez

Alcalá³

et al. 2022

Front. Neurol.

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IntroductionmRNA coronavirus disease 2019 (COVID-19) vaccination has been widely used to arrest the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Rarely, autoimmune events such as relapses in patients with multiple sclerosis (MS) have been reported after vaccination. However, the possible effects of vaccination in a patient already experiencing the symptoms of a relapse represent an unusual scenario that has not been described.Patients and MethodsThis is a retrospective case series of four patients from three major tertiary referral centers that received mRNA COVID-19 vaccination after starting with symptoms of acute demyelination of the central nervous system due to non-recognized MS. A detailed description of each case, including MRI studies, serum light-neurofilament levels, and cerebrospinal fluid (CSF) cytokine profile, is provided.Case DescriptionAll patients presented exacerbation of ongoing symptoms after vaccination (range 14–112 days first dose). All patients presented MRI features suggestive of highly active MS and fulfilled McDonald 2017 criteria at the time of presentation. All patients presented high serum light-neurofilament levels and oligoclonal G bands restricted to the CSF. Higher levels of interleukin-6 in the CSF were present in the more severe cases.DiscussionWe describe exacerbation of relapses after mRNA COVID-19 vaccination. We hypothesize RNA sensors such as Toll-like receptor 7 may be activated and contribute to amplify the inflammatory response during a relapse.ConclusionPatients should seek medical attention if experiencing acute neurological symptoms, especially before vaccination. Fast diagnostic procedures and prompt treatment should be performed in these patients. Pharmacovigilance and further study are warranted to confirm causality.

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“…However, STAT5 activation mediated by IL-2 inhibits Th17 cell differentiation (70). In multiple sclerosis, Qian et al discovered that zinc-finger E homeobox-binding 1 (ZEB1), a transcription factor, enhances JAK-STAT4/3 signaling during Th1/Th17 differentiation by suppressing the production of a JAK2-targeting miRNA (71). TGF-b, retinoic acid, and IL-2 in the periphery promote Treg cell differentiation, and its master transcription factor is Foxp3 (72)(73)(74).…”

Section: Subsets and Functions Of Th Cellsmentioning

confidence: 99%

Emerging Roles of T Helper Cells in Non-Infectious Neuroinflammation: Savior or Sinner

Liu

Fan

et al. 2022

Front. Immunol.

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CD4+ T cells, also known as T helper (Th) cells, contribute to the adaptive immunity both in the periphery and in the central nervous system (CNS). At least seven subsets of Th cells along with their signature cytokines have been identified nowadays. Neuroinflammation denotes the brain’s immune response to inflammatory conditions. In recent years, various CNS disorders have been related to the dysregulation of adaptive immunity, especially the process concerning Th cells and their cytokines. However, as the functions of Th cells are being discovered, it’s also found that their roles in different neuroinflammatory conditions, or even the participation of a specific Th subset in one CNS disorder may differ, and sometimes contrast. Based on those recent and contradictory evidence, the conflicting roles of Th cells in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, epilepsy, traumatic brain injury as well as some typical mental disorders will be reviewed herein. Research progress, limitations and novel approaches concerning different neuroinflammatory conditions will also be mentioned and compared.

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ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Cited by 25 publications

References 77 publications

Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

Proximal and Distal Regions of Pathogenic Th17 Related Chromatin Loci Are Sequentially Accessible During Pathogenicity of Th17

Case Report: Exacerbation of Relapses Following mRNA COVID-19 Vaccination in Multiple Sclerosis: A Case Series

Emerging Roles of T Helper Cells in Non-Infectious Neuroinflammation: Savior or Sinner

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