Editorial: Interleukin‐7 and Its Receptor: The Axis of Evil to Target in Sjögren's Syndrome?

Roon, Joël A G van; Kruize, Aike A.

doi:10.1002/art.38002

Cited by 10 publications

(8 citation statements)

References 15 publications

(22 reference statements)

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“…In addition, CCR9+ Th cells are IL-7Rhi and robustly respond to IL-7 in vitro (26). Since the IL-7/IL-7R axis plays an important role in pSS immunopathology and in GC formation this supports a role for CCR9+ Th cells in pSS (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 73%

“…Significantly elevated levels of CCL5 were measured in the CCR9+ Th cell cultures as compared to CXCR5+ and CCR9-CXCR5- Th cells (p ≤ 0.05, Figure 5C ). Since antigen triggering and IL-7 stimulation, as previously demonstrated ( 31 , 50 ) may be key drivers of CCR9+ Th activation and thereby CCL5 secretion, cells were cultured with superantigen Staphylococcal Enterotoxin B (SEB) or IL-7. Interestingly, IL-7 strongly upregulated CCL5 production by co-cultured CCR9+ Th cells.…”

Section: Resultsmentioning

confidence: 99%

“…Besides this we have demonstrated rapid release of CCL5 by CCR9+ Th cells and a strongly increased secretion of CCL5 by co-cultured CCR9+ Th cells as compared to CXCR5+ and DN Th cells. Interestingly, IL-7 which is a key early mediator of salivary gland inflammation ( 31 – 34 ) and is a crucial factor in lymphoid structure organization ( 38 , 58 ), significantly increased CCL5 production by CCR9+ Th cells to a higher level than CXCR5+ and CCR9-CXCR5- Th cells. As IL-7 has previously been shown to increase responsiveness of auto-reactive T cells ( 59 , 60 ) this could implicate that IL-7-driven self-reactive T cell responses associated with CCL5 production plays a significant role in early inflammatory responses in pSS, attracting multiple leukocyte subsets to affected sites.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule

et al. 2021

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IntroductionCCR9+ Tfh-like pathogenic T helper (Th) cells are elevated in patients with primary Sjögren’s syndrome (pSS) and indicated to play a role in pSS immunopathology. Here we delineate the CCR9+ Th cell-specific transcriptome to study the molecular dysregulation of these cells in pSS patients.MethodsCCR9+, CXCR5+ and CCR9-CXCR5- Th cells from blood of 7 healthy controls (HC) and 7 pSS patients were FACS sorted and RNA sequencing was performed. Computational analysis was used to identify differentially expressed genes (DEGs), coherent gene expression networks and differentially regulated pathways. Target genes were replicated in additional cohorts.Results5131 genes were differentially expressed between CCR9+ and CXCR5+ Th cells; 6493 and 4783 between CCR9+ and CCR9-CXCR5- and between CXCR5+ and CCR9-CXCR5-, respectively. In the CCR9+ Th cell subset 2777 DEGs were identified between HC and pSS patients, 1416 and 1077 in the CXCR5+ and CCR9-CXCR5- subsets, respectively. One gene network was selected based on eigengene expression differences between the Th cell subsets and pathways enriched for genes involved in migration and adhesion, cytokine and chemokine production. Selected DEGs of interest (HOPX, SOX4, ITGAE, ITGA1, NCR3, ABCB1, C3AR1, NT5E, CCR5 and CCL5) from this module were validated and found upregulated in blood CCR9+ Th cells, but were similarly expressed in HC and pSS patients. Increased frequencies of CCR9+ Th cells were shown to express higher levels of CCL5 than CXCR5+ and CCR9-CXCR5- Th cells, with the highest expression confined to effector CCR9+ Th cells. Antigenic triggering and stimulation with IL-7 of the Th cell subsets co-cultured with monocytes strongly induced CCL5 secretion in CCR9+ Th cell cocultures. Additionally, effector CCR9+ Th cells rapidly released CCL5 and secreted the highest CCL5 levels upon stimulation.ConclusionTranscriptomic analysis of circulating CCR9+ Th cells reveals CCR9-specific pathways involved in effector T cell function equally expressed in pSS patients and HC. Given the increased numbers of CCR9+ Th cells in the blood and inflamed glands of pSS patients and presence of inflammatory stimuli to activate these cells this suggests that CCR9-specific functions, such as cell recruitment upon CCL5 secretion, could significantly contribute to immunopathology in pSS.

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Section: Introductionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule

et al. 2021

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“…High expression levels of IL-7Ra in circulating CCR91 T helper cells compared to CXCR51 T helper cells, and elevated proportions of circulating CCR91 T helper cells coexpressing ICOS and PD-1 in primary SS. Since the IL-7/IL-7Ra pathway plays an important role in the pathogenesis of primary SS (8,(33)(34)(35)(36)(37) and in (ectopic) GC formation, including that occurring in LSGs, expression of IL-7Ra on circulating CCR91 and CXCR51 T helper cells from patients with primary SS and healthy controls was studied (32,38,39). CCR91 T helper cells showed a higher median fluorescence intensity of IL-7Ra expression as compared to CXCR51 T helper cells, both in patients with primary SS and in healthy controls (Figures 3A-C).…”

Section: Resultsmentioning

confidence: 99%

Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis

Blokland

Hillen

Kruize

et al. 2017

Arthritis & Rheumatology

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Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.

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“…Data from humans and mice demonstrate that IL-7 drives a range of processes involved in pSS immunopathology, including epithelial cell apoptosis, lymphocyte infiltration and reduction of salivary output 3. The IL-7/IL-7R axis is involved in the formation of (ectopic) lymphoid structures in salivary glands (SGs),3 4 which is a predictor for lymphoma development in pSS 5 6. IL-7 activity is potentiated by the soluble form of its receptor (sIL-7R), which is produced in inflamed tissues by activated stromal cells 7.…”

mentioning

confidence: 99%

High soluble IL-7 receptor expression in Sjögren's syndrome identifies patients with increased immunopathology and dryness

et al. 2016

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Editorial: Interleukin‐7 and Its Receptor: The Axis of Evil to Target in Sjögren's Syndrome?

Cited by 10 publications

References 15 publications

Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule

Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren’s Syndrome Patients Identifies CCL5 as a Novel Effector Molecule

Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis

High soluble IL-7 receptor expression in Sjögren's syndrome identifies patients with increased immunopathology and dryness

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