RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?

Vecellio, Matteo; Cohen, Corentin; Roberts, Amity R.; Wordsworth, P; Kenna, Tony J.

doi:10.3389/fimmu.2018.03132

Cited by 27 publications

(23 citation statements)

References 84 publications

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“…These findings might enlighten us on the importance of ILCs in the pathogenesis of SpA. Runx3 is a pivotal transcription factor that induces RORγt and AHR, which guides the differentiation of ILC3 precursors to IL-17A and IL-22 expressing mature ILC3 (159). The transcription factor Tbet has already been found to be crucial in the development and differentiation ILC1.…”

Section: Spondyloarthritismentioning

confidence: 85%

Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases

et al. 2020

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The emerging concept of microbiota contributing to local mucosal homeostasis has fueled investigation into its specific role in immunology. Gut microbiota is mostly responsible for maintaining the balance between host defense and immune tolerance. Dysbiosis of gut microbiota has been shown to be related to various alterations of the immune system. This review focuses on the reciprocal relationship between gut microbiota and innate immunity compartment, with emphasis on gut-associated lymphoid tissue, innate lymphoid cells, and phagocytes. From a clinical perspective, the review gives a possible explanation of how the "gut microbiota-innate immunity" axis might contribute to the pathogenesis of autoimmune diseases like rheumatoid arthritis, spondyloarthritis, and systemic lupus erythematosus.

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Section: Spondyloarthritismentioning

confidence: 85%

Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases

et al. 2020

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“…The common mechanisms from these networks revealed several lymphoid and myeloid cells and their expressing DAGs. The lymphoid cells such as CD4 + Th1, CD4 + Treg, and NK were predominant in all the statistically significant common-cell gene networks, showing that these diseases were indeed mainly driven by the aggressive T-cell response (36)(37)(38)55). Pathways such as interleukin (IL-4 and IL-13), TLR, TCR signaling, etc., was found to be enriched in the top DAGs of the common cell-gene networks of these IMIDs.…”

Section: Common Cell-gene Network Reveal Drug Repurposing Targetsmentioning

confidence: 97%

“…We find RUNX3 expression highest in the NK cells, followed by CD8 + Tcells and Th1 cells (Supplementary Figure S1A). The exact role of RUNX3 in AS is unclear and possibly involves regulation, differentiation, and activation of Th1 and T-bet cells (36). Further research is required to establish the exact role of RUNX3 in AS and the above-identified lymphoid cell subsets.…”

Section: The Disease-gene Network Of the 12 Imids Reveal Several Common Dagsmentioning

confidence: 99%

Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

Devaprasad

Pandit

2021

Front. Immunol.

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ObjectiveDevelopment and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism.MethodsUsing transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.ResultsWe found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn’s disease and other IMIDs.ConclusionsExisting methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.

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“…Finally, deletions in RUNX3 gene can also result in malignancies of T cells (217). Among the phenotypes associated with polymorphisms in the RUNX3 gene locus are ankylosing spondylitis (218)(219)(220), psoriatic arthritis (221), Crohn disease (222), asthma (223) and multiple sclerosis (224). In B cells, RUNX3 is upregulated by the Epstein-Barr virus-encoded TF EBNA2, leading to accelerated proliferation of infected cells (225).…”

Section: Runx3mentioning

confidence: 99%

Runx Transcription Factors in T Cells—What Is Beyond Thymic Development?

et al. 2021

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Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood cell development during different stages of cell lineage specification. However, recent studies show evidence of complex relationships between RUNX proteins, chromatin-modifying machinery, the cytoskeleton and different transcription factors in various non-embryonic contexts, including mature T cell homeostasis, inflammation and cancer. In this review, we discuss the diversity of Runx functions in mature T helper cells, such as production of cytokines and chemokines by different CD4 T cell populations; apoptosis; and immunologic memory acquisition. We then briefly cover recent findings about the contribution of RUNX1, RUNX2 and RUNX3 to various immunologic diseases. Finally, we discuss areas that require further study to better understand the role that Runx proteins play in inflammation and immunity.

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RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?

Cited by 27 publications

References 84 publications

Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases

Crosstalk Between Gut Microbiota and Innate Immunity and Its Implication in Autoimmune Diseases

Integration of Immunome With Disease-Gene Network Reveals Common Cellular Mechanisms Between IMIDs and Drug Repurposing Strategies

Runx Transcription Factors in T Cells—What Is Beyond Thymic Development?

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