Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

Kidani, Yoko; Bensinger, Steven J.

doi:10.1172/jci74141

Cited by 19 publications

(9 citation statements)

References 28 publications

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“…LXR/RXR pathway found to be affected in anti-dsDNA + patients is involved in lipid metabolism and inflammation. Recently, a study reported that perturbation in lipid homeostasis in SLE patients affects the functioning of T cells [27]. Other affected pathways are Nur77 signaling in T lymphocytes and Role of NFAT in regulation of immune response .…”

Section: Discussionmentioning

confidence: 99%

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

et al. 2016

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Systemic lupus erythematosus (SLE) patients exhibit immense heterogeneity which is challenging from the diagnostic perspective. Emerging high throughput sequencing technologies have been proved to be a useful platform to understand the complex and dynamic disease processes. SLE patients categorised based on autoantibody specificities are reported to have differential immuno-regulatory mechanisms. Therefore, we performed RNA-seq analysis to identify transcriptomics of SLE patients with distinguished autoantibody specificities. The SLE patients were segregated into three subsets based on the type of autoantibodies present in their sera (anti-dsDNA+ group with anti-dsDNA autoantibody alone; anti-ENA+ group having autoantibodies against extractable nuclear antigens (ENA) only, and anti-dsDNA+ENA+ group having autoantibodies to both dsDNA and ENA). Global transcriptome profiling for each SLE patients subsets was performed using Illumina® Hiseq-2000 platform. The biological relevance of dysregulated transcripts in each SLE subsets was assessed by ingenuity pathway analysis (IPA) software. We observed that dysregulation in the transcriptome expression pattern was clearly distinct in each SLE patients subsets. IPA analysis of transcripts uniquely expressed in different SLE groups revealed specific biological pathways to be affected in each SLE subsets. Multiple cytokine signaling pathways were specifically dysregulated in anti-dsDNA+ patients whereas Interferon signaling was predominantly dysregulated in anti-ENA+ patients. In anti-dsDNA+ENA+ patients regulation of actin based motility by Rho pathway was significantly affected. The granulocyte gene signature was a common feature to all SLE subsets; however, anti-dsDNA+ group showed relatively predominant expression of these genes. Dysregulation of Plasma cell related transcripts were higher in anti-dsDNA+ and anti-ENA+ patients as compared to anti-dsDNA+ ENA+. Association of specific canonical pathways with the uniquely expressed transcripts in each SLE subgroup indicates that specific immunological disease mechanisms are operative in distinct SLE patients’ subsets. This ‘sub-grouping’ approach could further be useful for clinical evaluation of SLE patients and devising targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

et al. 2016

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“…The levels of expression of cellular GSLs are systematically controlled by de novo synthesis, turnover, and recycling . The biosynthesis of GSLs and their trafficking to and from plasma membranes are increased in SLE T cells, leading to the aberrant accumulation of gangliosides in lipid rafts .…”

Section: Gangliosides In Adaptive Immunitymentioning

confidence: 99%

The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

et al. 2018

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Lipid rafts formed by glycosphingolipids (GSLs) on cellular membranes play important roles in innate and adaptive immunity. Lactosylceramide (LacCer) forms lipid rafts on plasma and granular membranes of human neutrophils. These LacCer‐enriched lipid rafts bind directly to pathogenic components, such as pathogenic fungi‐derived β‐glucan and Mycobacteria‐derived lipoarabinomannan via carbohydrate‐carbohydrate interactions, and mediate innate immune responses to these pathogens. In contrast, a‐series and o‐series gangliosides form distinct rafts on CD4+ and CD8+ T cell subsets, respectively, contributing to the respective functions of these cells and stimulating adaptive immune responses through T cell receptors. These findings suggest that gangliosides play indispensable roles in T cell selection and activation. This Review introduces the involvement of GSL‐enriched lipid rafts in innate and adaptive immunity.

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“…Noteworthy are also the beneficial findings made with GSL lowering agents for systemic lupus erythematosus (SLE). This autoimmune disease manifests with chronic inflammation and leads to damage of tissue (Tsokos, 2011; Kidani and Bensinger, 2014). In SLE there is a prominent T cell dysfunction: CD4+ T cells from patients have lipid rafts with an altered GSL composition.…”

Section: Introduction To Glycosphingolipidsmentioning

confidence: 99%

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

Aerts

Artola

Eijk

et al. 2019

Front. Cell Dev. Biol.

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Glycosphingolipids (GSLs), the main topic of this review, are a subclass of sphingolipids. With their glycans exposed to the extracellular space, glycosphingolipids are ubiquitous components of the plasma membrane of cells. GSLs are implicated in a variety of biological processes including specific infections. Several pathogens use GSLs at the surface of host cells as binding receptors. In addition, lipid-rafts in the plasma membrane of host cells may act as platform for signaling the presence of pathogens. Relatively common in man are inherited deficiencies in lysosomal glycosidases involved in the turnover of GSLs. The associated storage disorders (glycosphingolipidoses) show lysosomal accumulation of substrate(s) of the deficient enzyme. In recent years compounds have been identified that allow modulation of GSLs levels in cells. Some of these agents are well tolerated and already used to treat lysosomal glycosphingolipidoses. This review summarizes present knowledge on the role of GSLs in infection and subsequent immune response. It concludes with the thought to apply glycosphingolipid-lowering agents to prevent and/or combat infections.

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Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

Cited by 19 publications

References 28 publications

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

RNA-seq Analysis Reveals Unique Transcriptome Signatures in Systemic Lupus Erythematosus Patients with Distinct Autoantibody Specificities

The regulatory roles of glycosphingolipid‐enriched lipid rafts in immune systems

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

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