Summary
Background
LL‐37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis ...(SSc).
Objectives
To elucidate the potential role of LL‐37 in SSc.
Methods
The expression of target molecules was evaluated by immunostaining and quantitative reverse‐transcription real‐time polymerase chain reaction in human and murine skin. The mechanisms regulating LL‐37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL‐37 levels were determined by enzyme‐linked immunosorbent assay.
Results
In SSc lesional skin, LL‐37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon‐α expression, possibly reflecting LL‐37‐dependent induction of interferon‐α. In SSc animal models, bleomycin‐treated skin exhibited the expression pattern of CRAMP, a murine homologue of LL‐37, similar to that of LL‐37 in SSc lesional skin. Furthermore, Fli1+/− mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP (LL‐37 gene) promoter and Fli1 deficiency‐dependent induction of LL‐37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SSc had serum LL‐37 levels significantly higher than in healthy controls. Furthermore, serum LL‐37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without.
Conclusions
LL‐37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SSc.
What's already known about this topic?
LL‐37, an antimicrobial peptide, has been shown to be upregulated in systemic sclerosis dermal fibroblasts.
LL‐37 potentially contributes to dermal fibrosis through its antiapoptotic effect on those cells.
What does this study add?
LL‐37 potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in systemic sclerosis.
This further supports the critical role of antimicrobial peptides in the development of autoimmune and inflammatory diseases.
What is the translational message?
LL‐37 induction due to Fli1 deficiency in endothelial cells supports the notion that Fli1 deficiency is a key predisposing factor in the pathogenesis of systemic sclerosis.
This has recently been demonstrated by the establishment of a new systemic sclerosis animal model, with mice double heterozygous for the Klf5 and Fli1 genes.
Background
Early lesions of localized scleroderma are histologically characterized by perivascular lymphocytic infiltrate in the reticular dermis and swollen endothelial cells. However, there have ...been few information regarding histological features other than these findings in localized scleroderma.
Objective
Since en coup de sabre (ECDS) is a certain subset of localized scleroderma with a relatively uniform clinical manifestation, we focused on this disease subset and evaluated its histopathological features.
Methods
A total of 16 patients with ECDS were retrospectively evaluated on the basis of clinical and histological findings.
Results
Regardless of clinical manifestations, vacuolar degeneration was found in all of the ECDS patients. Importantly, keratinocyte necroses were restricted to early and active ECDS lesions. In early ECDS patients (disease duration of <3 years), moderate to severe perivascular and/or periappendageal lymphocytic infiltrate and vacuolar changes in follicular epithelium were more prominent, whereas epidermal atrophy was less frequently observed, than in late ECDS patients (disease duration of ≥6 years).
Conclusion
Vacuolar degeneration at the dermoepidermal junction is a common histological feature in ECDS and perivascular and/or periappendageal lymphocytic infiltrate and vacuolar degeneration of follicular epithelium are characteristic especially in early ECDS, further supporting a canonical idea that the elimination of mutated epidermal cells by immune surveillance contributes to tissue damage and resultant fibrosis in localized scleroderma.
Backgrounds Adiponectin has been demonstrated to be one of anti‐inflammatory and anti‐fibrotic factors, suggesting the potential of this cytokine to be involved in the developmental process of ...systemic sclerosis (SSc).
Objective The aim of this study was to investigate the clinical significance of serum adiponectin levels in patients with SSc.
Methods Serum adiponectin levels were determined using enzyme‐linked immunosorbent assay (ELISA) in 32 patients with diffuse cutaneous SSc (dcSSc), 28 with limited cutaneous SSc (lcSSc) and 27 healthy controls. No significant difference between these groups existed in terms of gender, age and body mass index.
Results Serum adiponectin levels in dcSSc patients (4.93 ± 6.48 μg/mL) were significantly lower than those in lcSSc patients (9.69 ± 7.61 μg/mL, P < 0.01) and healthy controls (9.36 ± 5.57 μg/mL, P < 0.01). dcSSc patients with disease duration of ≤5 years had significantly decreased serum adiponectin levels (2.15 ± 1.69 μg/mL) than those with disease duration of >5 years (13.29 ± 8.36 μg/mL, P < 0.01), lcSSc patients with disease duration of ≤5 years (8.07 ± 7.98μg/mL, P < 0.05), lcSSc patients with disease duration of >5 years (10.9 ± 7.34 μg/mL, P < 0.01) and healthy controls (9.36 ± 5.57 μg/mL, P < 0.01). Longitudinal studies in five patients with early dcSSc treated with oral prednisone demonstrated that serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in dcSSc patients.
Conclusion Serum levels of adiponectin may serve as a useful marker to evaluate the activity of progressive skin sclerosis in dcSSc.
Background Apelin is a bioactive peptide exerting its pro‐angiogenic and pro‐fibrotic effects in a context‐dependent manner through the activation of its receptor APJ, which is ubiquitously ...expressed on the surface of various cell types. The activation of apelin/APJ signalling appears to be involved in the pathological process of fibrotic disorders, including liver cirrhosis.
Objective As an initial step to clarify the role of apelin/APJ signalling in the pathogenesis of systemic sclerosis (SSc), we investigated serum apelin levels and their clinical association in patients with SSc.
Methods Serum apelin levels were determined by a specific enzyme‐linked immunosorbent assay in 56 SSc patients and 18 healthy controls.
Results Serum apelin levels were comparable among three groups, including diffuse cutaneous SSc, limited cutaneous SSc and control subjects (1.77 ± 1.48, 1.63 ± 1.51 and 1.61 ± 0.44 ng/mL, respectively). When we classified SSc patients into three groups according to disease duration, serum apelin levels were elevated in early SSc (<3 years) compared with mid‐stage SSc (3–10 years) (1.74 ± 1.26 vs. 1.02 ± 0.52 ng/mL, P < 0.05). Importantly, in late stage SSc (>10 years), the prevalence of severe vascular involvements, including intractable skin ulcers, scleroderma renal crisis and pulmonary arterial hypertension, was significantly higher in patients with elevated serum apelin levels than in those without (100% vs. 20%, P < 0.05).
Conclusion Apelin may be associated with altered and activated angiogenesis prior to fibrotic responses in early SSc and with the development of proliferative vasculopathy in late stage SSc.
Summary
Background Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two ...high‐quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown.
Objectives To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc.
Methods Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed.
Results The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy.
Conclusions Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.
Background Retinol binding protein‐4 (RBP‐4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance.
Objective ... To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy.
Methods Serum RBP4 levels were determined by enzyme‐linked immunosorbent assay in 62 SSc patients and 19 healthy controls.
Results Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m2. Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects median (25–75 percentile); 25.8 μg/mL (19.6–47.0) vs. 43.1 μg/mL (31.7–53.4), P < 0.05, while there was no significant difference between limited cutaneous SSc (lcSSc) 28.0 μg/mL (25.4–43.3) and control subjects. In both of dcSSc and lcSSc, patients with Raynaud’s phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc.
Conclusion Decreased RBP4 levels are associated with the prevalence of Raynaud’s phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.
