Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis

Ugor, Emese; Simon, Diána; Almanzar, Giovanni; Pap, Ramóna; Najbauer, Joseph; Németh, Pèter; Balogh, Péter; Prelog, Martina; Czirják, László; Berki, Tímea

doi:10.1016/j.clim.2017.05.013

Cited by 40 publications

(24 citation statements)

References 39 publications

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“…[11][12][13] In SSc, decreased regulatory T-cell (Treg) counts and impaired immunosuppressive function have been associated with loss of self-tolerance, correlating with disease severity. [14][15][16][17] Diminished thymopoiesis and abnormalities of T-cell receptor (TCR) repertoire, with fewer polyclonal families, overexpression of skewed families, and reduced overall TCR diversity were described. 18,19 The role of B cells in the pathogenesis of SSc has been investigated, 20 with reports of B-cell hyperactivation, [21][22][23] autoantibody production, 24 decreased regulatory B-cell (Breg) counts, and impaired interleukin-10 (IL-10) production.…”

Section: Introductionmentioning

confidence: 99%

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

et al. 2018

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• Clinical response of SSc patients after AHSCT is associated with thymic and bone marrow rebounds.• Responder patients showed higher Treg and Breg counts and lower pre-/post-AHSCT TCR repertoire overlap than nonresponder patients. compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre-and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.

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Section: Introductionmentioning

confidence: 99%

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

et al. 2018

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“…Subsequently, TGF-β signaling provokes typical pro-fibrotic modifications in SSc ( 13 ). Detection of autoantibodies directed against endothelial antigens and others, as well as T cell alterations in sera of SSc patients, supports the assumption that an impaired regulation of the immune system drives SSc pathogenesis ( 32 – 34 ).…”

Section: Introductionmentioning

confidence: 55%

Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

et al. 2017

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Systemic sclerosis (SSc) is a rare multi-organ autoimmune disease characterized by progressive skin fibrosis. Inflammation, type 2 immunity, and fibrogenic processes are involved in disease development and may be affected by sphingolipids. However, details about early-stage pathophysiological mechanisms and implicated mediators remain elusive. The sphingolipid sphingosine-1-phosphate (S1P) is elevated in the sera of SSc patients, and its receptor S1P5 is expressed in skin tissue. Nevertheless, almost nothing is known about the dermatological contribution of S1P5 to inflammatory and pro-fibrotic processes leading to the pathological changes seen in SSc. In this study, we observed a novel effect of S1P5 on the inflammatory processes during low-dose bleomycin (BLM)-induced fibrogenesis in murine skin. By comparing 2-week-treated skin areas of wild-type (WT) and S1P5-deficient mice, we found that S1P5 is important for the transcriptional upregulation of the Th2 characteristic transcription factor GATA-3 under treatment-induced inflammatory conditions, while T-bet (Th1) and FoxP3 (Treg) mRNA expression was regulated independently of S1P5. Additionally, treatment caused a regulation of S1P receptor 1 and S1P receptor 3 mRNA as well as a regulation of long-chain ceramide profiles, which both differ significantly between the genotypes. Despite S1P5-dependent differences regarding inflammatory processes, similar macroscopic evidence of fibrosis was detected in the skin histology of WT and S1P5-deficient mice after 4 weeks of subcutaneous BLM treatment. However, at the earlier 2-week point in time, the mRNA data of pro-collagen type 1 and SMAD7 indicate a pro-fibrotic S1P5 contribution in the applied SSc mouse model. In conclusion, we propose that S1P5 plays a role as a novel modulator during the early phase of BLM-caused fibrogenesis in murine skin. An immediate relationship between dermal S1P5 expression and fibrotic processes leading to skin alterations, such as formative for SSc pathogenesis, is indicated but should be studied more profound in further investigations. Therefore, this study is an initial step in understanding the role of S1P5-mediated effects during early stages of fibrogenesis, which may encourage the ongoing search for new therapeutic options for SSc patients.

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“…Treg prevent aberrant immune reactions and are associated with the pathogenesis of several autoimmune disorders [18][19][20][21]. Importantly, systemic lupus erythematosus (SLE) and systemic sclerosis, which both can cause ESRD, are associated with functional and quantitative altered Tregs [22][23][24]. Reduced numbers and impaired suppressive function of Tregs has been observed in ESDR patients with different underlying renal diseases [25].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

Propionate supplementation promotes the expansion of peripheral regulatory T-Cells in patients with end-stage renal disease

et al. 2020

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Patients with end-stage renal disease (ESRD) suffer from a progressively increasing low-grade systemic inflammation, which is associated with higher morbidity and mortality. Regulatory T cells (Tregs) play an important role in regulation of the inflammatory process. Previously, it has been demonstrated that short-chain fatty acids reduce inflammation in the central nervous system in a murine model of multiple sclerosis through an increase in tissue infiltrating Tregs. Here, we evaluated the effect of the short-chain fatty acid propionate on the chronic inflammatory state and T-cell composition in ESRD patients. Analyzing ESRD patients and healthy blood donors before, during, and 60 days after the propionate supplementation by multiparametric flow cytometry we observed a gradual and significant expansion in the frequencies of CD25 high CD127 − Tregs in both groups. Phenotypic characterization suggests that polarization of naïve T cells towards Tregs is responsible for the observed expansion. In line with this, we observed a significant reduction of inflammatory marker CRP under propionate supplementation. Of interest, the observed anti-inflammatory surroundings did not affect the protective pathogen-specific immunity as demonstrated by the stable frequencies of effector/memory T cells specific for tetanus/diphtheria recall antigens. Collectively, our data suggest that dietary supplements with propionate have a beneficial effect on the elevated systemic inflammation of ESRD patients. The effect can be achieved through an expansion of circulating Tregs without affecting the protective pathogen-reactive immunity.

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Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis

Cited by 40 publications

References 39 publications

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study

Propionate supplementation promotes the expansion of peripheral regulatory T-Cells in patients with end-stage renal disease

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