CXCR6 within T-helper (Th) and T-cytotoxic (Tc) type 1 lymphocytes in Graves’ disease (GD)

Aust, Gabriela; Kamprad, Manja; Lamesch, P.; Schmücking, E

doi:10.1530/eje.1.01892

Cited by 7 publications

(6 citation statements)

References 40 publications

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“…CXCR6 defines a subset of memory/effector T cells with tissue-homing potential,30 and consistent with this CXCR6 + T cells are enriched in inflamed tissues from a number of inflammatory conditions, including rheumatoid arthritis,30 Graves' disease31 and sarcoidosis,32 and treatment with an anti-CXCL16 monoclonal antibody reduces the severity of collagen-induced arthritis in mice 33. This first association of CXCR6 on CD4 T cells with SLE might thus be associated with tissue inflammation.…”

Section: Discussionmentioning

confidence: 67%

Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis

Lyons

McKinney

Rayner

et al. 2010

Annals of the Rheumatic Diseases

102

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ObjectiveTo optimise a strategy for identifying gene expression signatures differentiating systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis that provide insight into disease pathogenesis and identify biomarkers.Methods44 vasculitis patients, 13 SLE patients and 25 age and sex-matched controls were enrolled. CD4 and CD8 T cells, B cells, monocytes and neutrophils were isolated from each patient and, together with unseparated peripheral blood mononuclear cells (PBMC), were hybridised to spotted oligonucleotide microarrays.ResultsUsing expression data obtained from purified cells a substantial number of differentially expressed genes were identified that were not detectable in the analysis of PBMC. Analysis of purified T cells identified a SLE-associated, CD4 T-cell signature consistent with type 1 interferon signalling driving the generation and survival of tissue homing T cells and thereby contributing to disease pathogenesis. Moreover, hierarchical clustering using expression data from purified monocytes provided significantly improved discrimination between the patient groups than that obtained using PBMC data, presumably because the differentially expressed genes reflect genuine differences in processes underlying disease pathogenesis.ConclusionAnalysis of leucocyte subsets enabled the identification of gene signatures of both pathogenic relevance and with better disease discrimination than those identified in PBMC. This approach thus provides substantial advantages in the search for diagnostic and prognostic biomarkers in autoimmune disease.

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Section: Discussionmentioning

confidence: 67%

Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis

Lyons

McKinney

Rayner

et al. 2010

Annals of the Rheumatic Diseases

102

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“…Our analysis (Figure 2E) suggests that Etv6, Med12 and Zfx drive this self-renewing population ( Discussion ). Next, cells from the LN and CNS adopt similar (overlapping) cell states in the central region of our PCA plot (Figure 2C), reflecting effector Th17-like cells with a pre-Th1-like phenotype, characterized by induction of receptors for IFN ( Ifngr2 ) and IL-18 ( Il18r1 , Figure 2D) (Holzer et al, 2013), and of chemokine receptors Cxcr6 (Figure 2D) (Aust et al, 2005) and Ccr2 (Figure 2D) (Mahad and Ransohoff, 2003), which may all poise the cells for recruitment to the CNS. In turn, IL-17A/GFP + sorted cells acquire a Th17/Th1-like effector phenotype in the CNS (Figure 2C), with up-regulation (p<10 −3 , KS test, Table S4) of: Ifn -γ (Figure 2D), Rankl , ( Tnfsf11 ) (Nakae et al, 2007) (Komatsu et al, 2014), and cell cycle genes ( e.g., Geminin , Figure 2D), a strong correlation with a salt-induced pathogenic Th17 cell signature (Wu et al, 2013) (Figure 2A), and association with both canonical Th17 TFs (Stat3 and Hif1a) and Th1-associated factors, including Rel and Stat4 (Figure 2E), which are associated with EAE (Hilliard et al, 2002; Mo et al, 2008) or with human autoimmune disease (Gilmore and Gerondakis, 2011).…”

Section: Resultsmentioning

confidence: 92%

Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity

Gaublomme

Yosef

Lee

et al. 2015

Cell

538

571

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SUMMARY Extensive cellular heterogeneity exists within specific immune-cell subtypes classified as a single lineage, but its molecular underpinnings are rarely characterized at a genomic scale. Here, we use single-cell RNA-seq to investigate the molecular mechanisms governing heterogeneity and pathogenicity of Th17 cells isolated from the central nervous system (CNS) and lymph nodes (LN) at the peak of autoimmune encephalomyelitis (EAE) or differentiated in vitro under either pathogenic or non-pathogenic polarization conditions. Computational analysis relates a spectrum of cellular states in vivo to in vitro differentiated Th17 cells, and unveils genes governing pathogenicity and disease susceptibility. Using knockout mice, we validate four new genes: Gpr65, Plzp, Toso and Cd5l (in a companion paper). Cellular heterogeneity thus informs Th17 function in autoimmunity, and can identify targets for selective suppression of pathogenic Th17 cells while potentially sparing non-pathogenic tissue-protective ones.

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“…Their activation through IGF-1R enhances survival and promotes proliferation, resulting in a disproportionate increase in CD45RO + IGF-1R + memory T cells (54). Trafficking of these lymphocytes to affected tissues may be dependent on cell surface expression of the IGF-1R (54) and CXCR6 (55) or on the tissue expression of markers such as CD1 (56). …”

Section: Emerging Concepts In Disease Pathogenesismentioning

confidence: 99%

Recent insights into the pathogenesis and management of thyroid-associated ophthalmopathy

Gianoukakis¹,

Smith

2008

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review To identify and critique the most recent experimental findings regarding the pathogenesis and therapy of thyroid-associated ophthalmopathy (TAO). Recent findings Much of the recent work in this field has focused on identifying genetic alterations associated with the phenotypes of Graves' disease (GD) and TAO and investigating their functional consequences. Identified candidate genes include CD40, cytotoxic T-lymphocyte antigen-4 (CTLA-4), protein tyrosine phosphatase-22 (PTPN22), HLA-MHC and those associated with the X-chromosome. Efforts to generate a complete rodent model of GD continue with little progress. These uniformly involve the immunization of animals with the thyrotropin receptor (TSHR). Studies conducted in vitro have focused on the actions of cytokines in orbital fibroblasts, the potential role of the insulin-like growth factor-1 receptor and activating antibodies directed against it as a fibroblast and T cell activation pathway. Reports continue to appear examining the potential relationship between the TSHR and orbital adipogenesis. Regarding therapy for TAO, small molecules and antibodies disrupting cytokine pathways and lymphocyte function are currently under examination and have yielded promising albeit preliminary results. Summary TAO remains a vexing medical problem, the pathogenesis of which remains uncertain. A number of obstacles continue to plague major advances, not the least of which is the absence of a robust animal model. A few new insights seem to represent departure from traditional thinking about this disease and may herald important innovation.

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CXCR6 within T-helper (Th) and T-cytotoxic (Tc) type 1 lymphocytes in Graves’ disease (GD)

Abstract: CXCR6 was overexpressed in Th1 and Tc1 TLs compared with PBLs in GD. CXCR6 could be a marker for lymphocytes that have migrated into the thyroid and assist in the thyroid, independently of the bias of the underlying disease.

Cited by 7 publications

References 40 publications

Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis

Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis

Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity

Recent insights into the pathogenesis and management of thyroid-associated ophthalmopathy

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