Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.
Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional single-nucleotide polymorphism (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118 kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation, increasing risk of both SLE and SSc.
Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC.
Keratinocyte-conditioned media of resting, IL-17A-, and/or transforming growth factor-β-primed primary keratinocytes were used to stimulate healthy donors and scleroderma fibroblasts.
Thal treatment: (a) reduced skin, and pulmonary tissue fibrosis, inflammation score, and hydroxyproline content (P < .001) in BLM-induced SSc mice; (b) reduced the percentages of Th17 cells and associated interleukin (IL)-17A expression (both P < .05) but increased the percentages of Treg cells and its transcription factor Foxp3 expression (both P < .05); (c) correlation analysis found positive correlations between Th17/Treg ratio, the inflammatory score of the skin and pulmonary tissues, hydroxyproline content, and type I collagen messenger RNA expression (r = .8546, .8656, .6902, .6807, .8118, and .8424, respectively, P < .01); (d) Thal inhibited TGF-β1 expression and Smad3 phosphorylation (both P < .05); (e) TGF-β1 was positively correlated with the IL-17A and Th17/Treg ratio (r = .5856, P = .005; r = .6684, P = .0107, respectively).
In multiple logistic regression, only the NLR (regression coefficient = 3.49, p = 0.031) and CRP (regression coefficient = 0.17, p = 0.037) remained significantly different between SSc and healthy control groups (Cox and Snell R<sup>2</sup> = 0.243, Nagelkerke R<sup>2</sup> = 0.337, p < 0.001).
Thal treatment: (a) reduced skin, and pulmonary tissue fibrosis, inflammation score, and hydroxyproline content (P < .001) in BLM-induced SSc mice; (b) reduced the percentages of Th17 cells and associated interleukin (IL)-17A expression (both P < .05) but increased the percentages of Treg cells and its transcription factor Foxp3 expression (both P < .05); (c) correlation analysis found positive correlations between Th17/Treg ratio, the inflammatory score of the skin and pulmonary tissues, hydroxyproline content, and type I collagen messenger RNA expression (r = .8546, .8656, .6902, .6807, .8118, and .8424, respectively, P < .01); (d) Thal inhibited TGF-β1 expression and Smad3 phosphorylation (both P < .05); (e) TGF-β1 was positively correlated with the IL-17A and Th17/Treg ratio (r = .5856, P = .005; r = .6684, P = .0107, respectively).
Thal can effectively prevent skin and pulmonary tissue fibrosis in a mouse model of SSc through the TGF-β1/Smad3 signaling pathway and can rectify the distortion of the Th17/Treg balance in SSc by potentially regulating Th17 and Treg cell production, as well as their related factors expression.
Thal treatment: (a) reduced skin, and pulmonary tissue fibrosis, inflammation score, and hydroxyproline content (P < .001) in BLM-induced SSc mice; (b) reduced the percentages of Th17 cells and associated interleukin (IL)-17A expression (both P < .05) but increased the percentages of Treg cells and its transcription factor Foxp3 expression (both P < .05); (c) correlation analysis found positive correlations between Th17/Treg ratio, the inflammatory score of the skin and pulmonary tissues, hydroxyproline content, and type I collagen messenger RNA expression (r = .8546, .8656, .6902, .6807, .8118, and .8424, respectively, P < .01); (d) Thal inhibited TGF-β1 expression and Smad3 phosphorylation (both P < .05); (e) TGF-β1 was positively correlated with the IL-17A and Th17/Treg ratio (r = .5856, P = .005; r = .6684, P = .0107, respectively).
Previously, disturbances in plasma levels of angiotensin II (Ang II) and its antagonistic angiotensin-(1-7) (Ang-(1-7)) were found in patients with SSc.
Our meta-analysis showed that the FAS-670 A/G polymorphism was associated with the risk of autoimmune diseases (GG vs. GA: OR=1.079, 95% CI=1.004-1.160, P=0.038), especially in Caucasians (GG vs. GA: OR=1.12, 95% CI=1.03-1.23, P=0.012), Asians (G vs. A: OR=0.89, 95% CI=0.83-0.96, P=0.002), systemic lupus erythematosus (SLE) (G vs. A: OR=0.85, 95% CI=0.77-0.94, P=0.001), multiple sclerosis (MS) (GG+GA vs. AA: OR=0.83, 95% CI=0.70-0.99, P=0.043), systemic sclerosis (SSc) (GG vs. GA: OR=1.20, 95% CI=1.07-1.36, P=0.003) and Hashimoto's thyroiditis (HT) (G vs. A: OR=1.45, 95% CI=1.10-1.90, P=0.008); the FAS-1377 G/A polymorphism was associated with the risk of autoimmune diseases (A vs. G: OR=1.11, 95% CI=1.03-1.20, P=0.008), especially in Asians (A vs. G: OR=1.15, 95% CI=1.05-1.25, P=0.002) and high quality studies (A vs. G: OR=1.14, 95% CI=1.05-1.24, P=0.002).
Our meta-analysis showed that the FAS -670 A/G polymorphism was associated with the risk of autoimmune diseases (GG vs. GA: OR=1.079, 95% CI=1.004-1.160, P=0.038), especially in Caucasians (GG vs. GA: OR=1.12, 95% CI=1.03-1.23, P=0.012), Asians (G vs. A: OR=0.89, 95% CI=0.83-0.96, P=0.002), systemic lupus erythematosus (SLE) (G vs. A: OR=0.85, 95% CI=0.77-0.94, P=0.001), multiple sclerosis (MS) (GG+GA vs. AA: OR=0.83, 95% CI=0.70-0.99, P=0.043), systemic sclerosis (SSc) (GG vs. GA: OR=1.20, 95% CI=1.07-1.36, P=0.003) and Hashimoto's thyroiditis (HT) (G vs. A: OR=1.45, 95% CI=1.10-1.90, P=0.008); the FAS -1377 G/A polymorphism was associated with the risk of autoimmune diseases (A vs. G: OR=1.11, 95% CI=1.03-1.20, P=0.008), especially in Asians (A vs. G: OR=1.15, 95% CI=1.05-1.25, P=0.002) and high quality studies (A vs. G: OR=1.14, 95% CI=1.05-1.24, P=0.002).
Forty female BALB/c mice were randomly divided into a normal control (NC) group, SSc group (bleomycin [BLM]-induced experimental SSc), BLM + Thal (10 mg/kg/day) group, BLM + Thal (20) group, and BLM + Thal (30) group.Thal was administered a day after BLM.
<b>Objectives:</b> The usage of oral therapies, endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in patients with pulmonary arterial hypertension related to systemic sclerosis (SSc-PAH).
CCR9 + T helper (Th) cells can induce Sjögren-like symptoms in mice and both CCR9 + Th cells and their ligand CCL25 are increased in the salivary glands of primary Sjögren's syndrome (pSS) patients.