Levels In Systemic Sclerosis Patients Research Articles

Disturbed Balance between Serum Levels of Receptor Tyrosine Kinases Tie-1, Tie-2 and Angiopoietins in Systemic Sclerosis

Objective: The aim of this study was to determine the characteristic factors for vascular development and maintenance levels as well as correlation between Tie-1 receptors, Tie-2 receptors and the corresponding ligands - angiopoietins - in systemic sclerosis (SSc) patients. Materials and Methods: Serum levels of Tie-1, Tie-2, Ang-1 and Ang-2 were measured in 25 SSc patients and healthy controls. Results: There was a statistically significant difference in serum Tie-1 (p = 0.009) and Ang-2 (p = 0.001) levels in SSc patients compared with healthy controls. Significant correlations between Tie-1 and Tie-2 (ρ = 0.70, p = 0.0001) and between Tie-1 and Ang-2 (ρ = -0.92, p = 0.002) were found in the SSc group. Serum levels of Tie-2 were positively associated with esophagus changes (U = 2.03, p = 0.041) and Ang-1 was negatively correlated with duration of Raynaud's phenomenon (ρ = -0.75, p = 0.00008). Conclusion: The increase in serum concentration of Tie-1 and Ang-2 in patients with SSc may confirm a molecular imbalance between receptor tyrosine kinases Tie and their ligands.

Brief Report: Lysyl Oxidase Is a Potential Biomarker of Fibrosis in Systemic Sclerosis

Fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). Levels of lysyl oxidase (LOX), an extracellular enzyme that stabilizes collagen fibrils, have been found to be elevated in the skin of SSc patients, but have not been evaluated in the serum or correlated with the clinical parameters. We undertook this study to evaluate serum LOX levels in SSc patients and to correlate these levels with clinical parameters of SSc. SSc patients were evaluated for demographic features, clinical manifestations, routine laboratory tests, serum autoantibodies, serum LOX concentrations, and nailfold capillaroscopy patterns. They underwent pulmonary function testing, echocardiography, and high-resolution computed tomography scans of the lung, assessment of skin fibrosis by the modified Rodnan skin thickness score (MRSS), and assessment of disease severity and activity by the Medsger severity scale and the Valentini activity index. Twenty-six SSc patients were evaluated and compared with 25 healthy controls and with 9 disease control patients with primary myelofibrosis. Almost 62% of the SSc patients (16 of 26) had limited cutaneous SSc (lcSSc), while 38% had diffuse cutaneous SSc (dcSSc) (10 of 26); 31% of the patients (8 of 26) had lung involvement. The LOX concentration in SSc patients was higher than that in healthy controls and similar to that in disease controls (P < 0.0001), and it was significantly higher in patients with dcSSc than in those with lcSSc (P = 0.006). The LOX concentration correlated with the MRSS in patients without lung fibrosis. This study is the first to demonstrate high serum LOX levels in SSc patients that correlate specifically with skin fibrosis. These correlations suggest that LOX levels may serve as a novel biomarker of fibrosis. Future studies are warranted to determine whether LOX is a potential therapeutic target in SSc.

Left heart disease: a frequent cause of early pulmonary hypertension in systemic sclerosis, unrelated to elevated NT-proBNP levels or overt cardiac fibrosis but associated with increased levels of MR-proANP and MR-proADM: retrospective analysis of a French Canadian cohort

Objectives: Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH.Method: A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM).Results: The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH.Conclusions: Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Serum resistin levels: a possible correlation with pulmonary vascular involvement in patients with systemic sclerosis

Our latest studies demonstrated the potential role of adipocytokines, including adiponectin, visfatin, retinol binding protein-4, and apelin, in the pathogenesis of systemic sclerosis (SSc). Given that resistin is another member of adipocytokines with pro-inflammatory and pro-angiogenic properties, we measured serum resistin levels by enzyme-linked immunosorbent assay in 52 SSc and 19 control subjects and evaluated their clinical correlation. Since serum resistin levels greatly and inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction [r = -0.78, p < 0.05 (n = 9)], we evaluated the clinical correlation of serum resistin levels in SSc patients with normal renal function (n = 43). Although serum resistin levels were comparable between diffuse cutaneous SSc (n = 22), limited cutaneous SSc (n = 21), and control subjects (n = 19) [median (25-75 percentiles); 18.7 ng/ml (13.3-48.0), 23.3 ng/ml (12.9-54.1), and 22.9 ng/ml (9.4-36.7), respectively], the prevalence of elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum resistin levels than in those with normal levels [67 % (4/6) vs. 16 % (6/37), p < 0.05], and serum resistin levels were significantly increased in SSc patients with elevated RVSP (n = 10) as compared to those with normal RVSP (n = 33) [52.1 ng/ml (20.8-117.5) vs. 18.5 ng/ml (12.2-46.2), p < 0.05]. Thus, serum resistin levels may serve as a useful marker for pulmonary vascular involvement in SSc, suggesting a possible contribution of resistin to the pathogenesis of pulmonary arterial hypertension associated with SSc.

Mean Platelet Volume Seems To Be a Valuable Marker in Patients with Systemic Sclerosis

The predictors for the development of cardiovascular diseases and peripheral arterial diseases in patients with systemic sclerosis (SSc) were not clearly established, and there is no specific study conducted to investigate the mean platelet volume (MPV) levels in SSc patients. Therefore, this study evaluates the MPV levels in SSc and possible relationship between SSc, its clinical features and activity/severity scores, and MPV. In total, 76 SSc patients (67 women and 9 men, mean age 50.44 ± 13.21 years) diagnosed according to the classification criteria of the American College of Rheumatology and 45 healthy volunteers were enrolled into study. Data relating to anamnesis, physical examination, MPV, erythrocyte sedimentation rate, C-reactive protein levels, electrocardiography, echocardiography, high-resolution computerized tomography findings, complaints, and treatment processes were recorded into the database. Of the total cases, 17 had (22.3 %) cardiac involvement, 45 had gastrointestinal involvement (59.2 %), 47 had (61.8 %) lung involvement, 31 (32 %) had finger flexion deformity, and 27 (35.5 %) had digital ulcers at the fingertips. The mean MPV levels of SSc patients were significantly higher than those of the control group (p = 0.008). The mean MPV levels of SSc patients with cardiac involvement, digital ulcers, and gangrene presence were significantly high, and lower in Ilomedin-receiving patients than in the Ilomedin naives (p < 0.05). A negative relationship was discovered between the mean MPV levels, Valentini score, and Disease Severity Index of the patients with systemic sclerosis (p = 0.006, r = -0.310; p = 0.047, r = -0.229). MPV levels were significantly elevated in SSc patients and they were negatively correlated with disease activity scores. Increased MPV levels would be a predictive marker in the diagnosis of macrovascular and microvascular disease involvement in SSc patients.

Decreased interleukin-20 level in patients with systemic sclerosis: are they related with angiogenesis?

In this study, we aimed to evaluate the relation between angiogenesis indicators and T helper 17 cytokine group in patients with systemic sclerosis (SSc) which is a disease characterized by impaired angiogenesis and autoimmune response. In our study, patients with SSc are compared with patients with primary Raynaud's phenomenon (RP) and healthy controls. Forty SSc patients, 18 primary RP cases, and 20 healthy controls were included in our study. The demographic and clinical features of patients with SSc were recorded. The serum levels of vascular endothelial growth factor (VEGF), vascular endothelial (VE)-cadherin, interleukin (IL)-20, IL-22, and IL-23 were assessed. In the SSc group, IL-20 level was significantly lower than in both primary RP group and controls (p values <0.001). VE-cadherin level in SSc was significantly higher than in primary RP (p = 0.016). The IL-22 and IL-23 and VEGF levels of SSc, primary RP, and control groups were similar (p values >0.05). In SSc patients, IL-23 correlated negatively with VEGF (r = -0.36, p = 0.025) and positively with VE-cadherin (r = 0.55, p < 0.001). IL-20 levels in SSc patients correlated with disease duration (r = 0.32, p = 0.044). SSc patients with limited involvement had significantly higher VE-cadherin levels than SSc patients with diffuse involvement (p = 0.044). We observed that IL-20 which is an IL-10 group angiogenesis indicator was observed to be suppressed in SSc, suggesting abnormal angiogenesis.

AB0817 Vitamin D serum levels in a cohort of patients with systemic sclerosis: Prevalence, determinants and associations with clinical and biological aspects

BackgroundBesides the genetic background, it is known that environmental factors play an important role in the pathogenesis and activity of autoimmune diseases and vitamin D deficiency has been associated with...

FRI0379 Cytokines in bronchoalveolar lavage fluid and serum predict deterioration of lung function and mortality in systemic sclerosis patients

BackgroundCytokine production and release are key events in the pathogenesis of systemic sclerosis (SSc) as they are involved in T and B cell activation leading to inflammation, auto-antibody production, microvascular...

Serum B-cell activating factor assessment in a population of Egyptian patients with systemic sclerosis

Systemic sclerosis (SSc) is a rare systemic connective tissue disease characterized by abnormal fibroblast proliferation and micro-vascular inflammatory changes. To assess serum B-cell activating factor (BAFF) levels in patients with systemic sclerosis and to correlate this with disease features and disease severity. This is a case-control study in which patients with the established diagnosis of SSc were recruited. The diagnosis of SSc was established according to the American Rheumatology Association 1980 criteria for the classification of scleroderma. Patients' assessment included evaluation of skin involvement using the Modified Rodnan score and disease severity using the Medsger score. Twenty-five healthy matching controls were included. The sandwich enzyme-linked immunosorbent assay technique was used for direct assessment of serum BAFF in patients and controls. The study included 60 patients (54 female and 6 male), with a mean age of 38.18 ± 12.06 years, with mean disease duration of 7.85 ± 4.075 years. Serum BAFF in patients ranged 98.2-5015 pg/mL with mean BAFF 1100 ± 835.4 pg/mL. In controls serum BAFF levels ranged 188.5-2314 pg/mL with mean BAFF 546.1 ± 471.1 pg/mL, showing a statistically significant elevation of serum BAFF levels in SSc patients (P = 0.0001) with insignificant correlation to skin disease or total Medsgar Score of the study population (P > 0.05). Serum BAFF levels showed significant correlation with episodes of pseudo-obstruction and methotrexate (MTX) use in the patients studied (P < 0.05). Serum BAFF levels were significantly elevated in patients with SSc irrespective of disease subtype, disease duration or age of patients. This elevation in serum BAFF significantly related to gastrointestinal track involvement and MTX therapy.

Mapping QTL affecting a systemic sclerosis-like disorder in a cross between UCD-200 and red jungle fowl chickens

Systemic sclerosis (SSc) or scleroderma is a rare, autoimmune, multi-factorial disease characterized by early microvascular alterations, inflammation, and fibrosis. Chickens from the UCD-200 line develop a hereditary SSc-like disease, showing all the hallmarks of the human disorder, which makes this line a promising model to study genetic factors underlying the disease. A backcross was generated between UCD-200 chickens and its wild ancestor – the red jungle fowl and a genome-scan was performed to identify loci affecting early (21days of age) and late (175days of age) ischemic lesions of the comb. A significant difference in frequency of disease was observed between sexes in the BC population, where the homogametic males were more affected than females, and there was evidence for a protective W chromosome effect. Three suggestive disease predisposing loci were mapped to chromosomes 2, 12 and 14. Three orthologues of genes implicated in human SSc are located in the QTL region on chromosome 2, TGFRB1, EXOC2-IRF4 and COL1A2, as well as CCR8, which is more generally related to immune function. IGFBP3 is also located within the QTL on chromosome 2 and earlier studies have showed increased IGFBP3 serum levels in SSc patients. To our knowledge, this study is the first to reveal a potential genetic association between IGFBP3 and SSc. Another gene with an immunological function, SOCS1, is located in the QTL region on chromosome 14. These results illustrate the usefulness of the UCD-200 chicken as a model of human SSc and motivate further in-depth functional studies of the implicated candidate genes.

Serum Tie2 levels: clinical association with microangiopathies in patients with systemic sclerosis

Tie2 and its ligand, angiopoietins (Ang), regulate the transition between vascular quiescence and angiogenesis. Although defective angiogenesis is one of the major causes of microangiopathies in systemic sclerosis (SSc), the role of Ang/Tie2 signalling in the development of SSc has never been examined. To investigate the clinical significance of the soluble Tie2 domain (sTie2) in serum samples from SSc patients. Serum sTie2 levels were determined by a specific enzyme-linked immunosorbent assay in 48 SSc patients and nine normal controls. There was no significant difference in serum sTie2 levels between SSc patients and healthy controls (14.8 ± 3.4 vs. 14.7 ± 1.1 ng/mL). When we set the cut-off value at 16.97 ng/mL (mean + 2SD) based on the data of normal controls, 27% of SSc patients showed elevated serum sTie2 levels. The frequencies of nailfold bleeding and pulmonary arterial hypertension (PAH) were significantly higher in patients with increased serum sTie2 levels than in those with sTie2 levels not elevated (70% vs. 47% and 60% vs. 21%, respectively, P < 0.05). There was also a trend towards the elevation of serum sTie2 levels in SSc patients with PAH compared to those without; however, it did not reach statistical significance (16.7 ± 3.6 vs. 14.2 ± 3.4 ng/mL, P = 0.059). Soluble Tie2 domain (sTie2) may be related to the development of vascular abnormalities in SSc, possibly by modulating the Ang/Tie2-mediated angiogenic process. Furthermore, the serum sTie2 levels may serve as a useful marker for SSc-related PAH, contributing to early diagnosis and therapeutic intervention.

Increasing levels of serum antioxidant status, total antioxidant power, in systemic sclerosis

Oxidative stress is one of the important factors that contribute to tissue damage in systemic sclerosis (SSc). Since the physiological response to oxidative stress is regulated by multiple antioxidant systems, it is important to measure quantitatively the total antioxidant capacity in the biological specimens. To determine the clinical significance of total antioxidant power (TAP) in SSc, we investigated the prevalence and clinical correlation of serum TAP levels in SSc patients. Serum TAP levels were examined in 49 patients with SSc by colorimetric microplate assay. The assay measures the total abilities for reducing Cu++ into Cu+. Clinical evaluation including medical history, physical examination, and laboratory tests were conducted for all SSc patients. Serum TAP levels were significantly elevated in SSc patients compared to normal controls (p < 0.01). When values higher than the mean + 2SD of the control serum samples were considered to be elevated, TAP levels were elevated in 24% of total SSc patients, with 26% of diffuse cutaneous SSc patients and 23% of limited cutaneous SSc patients. Serum TAP levels were correlated positively with C-reacting protein (r = 0.35, p ≤ 0.05). However, no other significant correlation was observed between serum TAP levels and clinical features in SSc patients. These results suggested that oxidative stress is enhanced in SSc patients, and serum TAP levels increase as an indicator of the global response to oxidative stress.

Evaluation of the Effect of Bosentan Treatment on Proinflammatory Cytokine Serum Levels in Patients Affected by Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular and fibrotic changes in the skin and in internal organs. Endothelin-1 (ET-1) is a peptide that has a role in promoting both vascular injury and the fibrotic process in SSc; indeed, patients with systemic sclerosis have higher levels of ET-1 compared with healthy subjects. Moreover, ET-1 enhances expression of pro-inflammatory cytokines in animal model. Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension and digital ulcers in scleroderma patients. In animal models and in vitro models, after treatment with Bosentan, a significant reduction of cytokine (TNF α, IFN γ,IL-8, IL-4) levels was observed. The aim of the study is to verify whether Bosentan treatment in SSc patients can reduce circulating cytokines levels. We enrolled 10 patients affected by SSc with digital ulcers and/or pulmonary hypertension, treated with Bosentan 125 mg twice daily. Patients were tested for cytokines and ET-1 level before treatment and after 12 months. The cytokines tested were IL-10, IL-2, IL-4, IL-5, IL-6, IL-8, GM-CSF, IFN-γ and TNF. Levels of ET-1, IL-10, IL-4, IL-5, GM-CSF and TNFalpha did not show consistent modification during treatment with Bosentan in respect to baseline, while IL-2, IL-6, IL-8 and IFN-γ were significantly decreased. Bosentan significantly reduced IL-2, IL-6, IL-8 and IFN- γ levels in SSc patients, probably slowing progression to fibrosis and vascular damage. This is the first report showing a decrease of profibrotic and proinflammatory cytokines levels in humans during treatment with Bosentan.

Serum interleukin‐6 level is reflected in elevated high‐sensitivity C‐reactive protein level in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology which presents immunological, vascular and connective tissue abnormalities. Serum interleukin (IL)-6 has been reported to be elevated in patients with SSc. Clinical and laboratory findings affecting the elevated level of high-sensitivity C-reactive protein (hs-CRP) were studied in patients with SSc. Clinical and laboratory findings also included serum IL-6 level. Thirty-nine SSc patients (male : female = 7:32, age 19-84 years, mean 62.6 years) were studied. hs-CRP was measured with a nephelometric assay. Serum IL-6 level was measured by enzyme-linked immunosorbent assay. The distributions of hs-CRP showed that 18 cases (46.2%) were not elevated (<0.07 mg/dL), but 21 cases (53.8%) were (≥0.07 mg/dL). Alkaline phosphatase and IL-6 in SSc patients with elevated hs-CRP (291 ± 95 U/L, 3.23 ± 2.74 pg/mL) were significantly more elevated than those in not elevated patients (221 ± 75 U/L, 1.53 ± 1.12 pg/mL) (P < 0.02, P < 0.01). The correlation between hs-CRP level and IL-6 level in SSc patients was 0.687 (P < 0.001). In conclusion, elevated serum IL-6 levels are reflected in elevated hs-CRP levels in SSc patients.

Elevated serum levels of a proliferation-inducing ligand in patients with systemic sclerosis: Possible association with myositis?

Objective A proliferation-inducing ligand (APRIL) is a new member of the tumour necrosis factor family which is intimately connected to the regulation of cellular pathways. The aim of this study was to assess serum concentrations of APRIL in systemic sclerosis patients, and to correlate them with the main clinical and serological features of the disease. Methods Sera from 35 patients with systemic sclerosis, 25 had limited cutaneous and 10 had diffuse cutaneous subtypes, and 35 normal healthy subjects were assayed for APRIL by Enzyme Linked Immunosorbant Assay. Demographic, clinical, autoantibodies and serological data were prospectively assessed. Results Serum APRIL concentrations were higher in patients with systemic sclerosis and in both its subtypes compared to the healthy controls ( p < 0.0001 in all). Patients with elevated APRIL levels had significantly higher incidences of myositis than those with normal levels ( p = 0.04). We did not find significant differences in other organ involvement prevalence between systemic sclerosis patients with elevated vs. normal APRIL levels. In addition, the frequencies of autoantibodies (i.e., anti-topoisomerase I, anti-centromere) were comparable between both groups. Serum APRIL levels were correlated with serum γ-globulins concentrations ( r = 0.404, p = 0.016) but not with C-reactive protein, skin score, nor pulmonary functions. Serum APRIL was also correlated with creatine kinase levels only in systemic sclerosis patients with myositis ( r = 0.786, p = 0.02). Conclusion Our preliminary results suggest increased serum APRIL levels in systemic sclerosis patients, particularly in those associated with myositis and hypergammaglobinemia. To confirm our results, we propose that larger scale, multicentre studies with longer evaluation periods are needed.

Elevated Serum Concentrations of Triggering Receptor Expressed on Myeloid Cells-1 in Diffuse Cutaneous Systemic Sclerosis: Association with Severity of Pulmonary Fibrosis

To determine serum concentrations and clinical association of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with systemic sclerosis (SSc). Serum sTREM-1 levels from 17 patients with limited cutaneous SSc (lSSc), 24 patients with diffuse cutaneous SSc (dSSc), and 29 healthy control individuals were examined by ELISA. Total SSc patients exhibited significantly elevated serum sTREM-1 levels relative to controls (p < 0.01). Serum sTREM-1 levels were significantly elevated in patients with dSSc compared to controls (p < 0.005) and lSSc patients (p < 0.05). By contrast, sTREM-1 levels in lSSc were similar to those in controls. Serum sTREM-1 levels were significantly elevated in SSc patients with decreased percentage vital capacity (%VC). Consistent with this, serum sTREM-1 levels in SSc patients correlated negatively with %VC (r = -0.24, p < 0.005). Among SSc patients with pulmonary fibrosis, sTREM-1 levels were significantly increased in patients with decreased %VC or decreased percentage of diffusion capacity for carbon monoxide relative to those with normal values (p < 0.05). Serum sTREM-1 levels were elevated in dSSc patients and correlated with severity of pulmonary fibrosis, suggesting that serum sTREM-1 is a novel serological marker for the disease severity of SSc.

Autoantibody against one of the antioxidant repair enzymes, methionine sulfoxide reductase A, in systemic sclerosis: association with pulmonary fibrosis and vascular damage

Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis and vascular changes in the skin and internal organs with autoimmune background. It has been suggested that oxidative stress plays an important role in the development of SSc. To determine the prevalence and clinical correlation of autoantibody to methionine sulfoxide reductase A (MSRA), one of the antioxidant repair enzymes, in SSc, serum anti-MSRA autoantibody levels were examined in patients with SSc by enzyme-linked immunosorbent assay using recombinant MSRA. The presence of anti-MSRA antibody was evaluated by immunoblotting. To determine the functional relevance of anti-MSRA antibody in vivo, we assessed whether anti-MSRA antibody was able to inhibit MSRA enzymatic activity. Serum anti-MSRA antibody levels in SSc patients were significantly higher compared to controls and this autoantibody was detected in 33% of SSc patients. Serum anti-MSRA levels were significantly elevated in SSc patients with pulmonary fibrosis, cardiac involvement, or decreased total antioxidant power compared with those without them. Anti-MSRA antibodies also correlated positively with renal vascular damage determined as pulsatility index by color-flow Doppler ultrasonography of the renal interlobar arteries and negatively with pulmonary function tests. Furthermore, anti-MSRA antibody levels correlated positively with serum levels of 8-isoprostane and heat shock protein 70 that are markers of oxidative and cellular stresses. Remarkably, MSRA activity was inhibited by IgG isolated from SSc sera containing IgG anti-MSRA antibody. These results suggest that elevated anti-MSRA autoantibody is associated with the disease severity of SSc and may enhance the oxidative stress by inhibiting MSRA enzymatic activity.

Autoantibody against caspase-3, an executioner of apoptosis, in patients with systemic sclerosis

The objective of the study was to determine the presence or levels of antibodies (Abs) against caspase-3 and their clinical relevance in systemic sclerosis (SSc). Anti-caspase-3 Ab was examined by enzyme-linked immunosorbent assay and immunoblotting. IgG anti-caspase-3 Ab levels in SSc patients were higher than in normal controls. SSc patients positive for IgG anti-caspase-3 Ab had significantly longer disease duration, more frequent presence of decreased %VC and %DLco, and elevated levels of serum immunoglobulin and erythrocyte sedimentation rates. IgG anti-caspase-3 Ab levels correlated positively with serum IgG levels, renal vascular resistance, and serum levels of 8-isoprostane. Immunoblotting analysis confirmed the presence of anti-caspase-3 Ab in sera from SSc patients. Caspase-3 enzymatic activity was inhibited by IgG isolated from SSc sera containing IgG anti-caspase-3 Ab. These results suggest that autoantibody against caspase-3 is generated in SSc and that this Ab is related to the severity of pulmonary fibrosis, vascular damage, and inflammation.

Bosentan increases serum IL-12 levels in systemic sclerosis patients with pulmonary arterial hypertension

Bosentan increases serum IL-12 levels in systemic sclerosis patients with pulmonary arterial hypertension

Decreased levels of autoantibody against histone deacetylase 3 in patients with systemic sclerosis

Systemic sclerosis (SSc) is characterized by immunological abnormalities, especially the production of autoantibodies against various cellular components. Treatment with histone deacetylase (HDAC) inhibitors prevents collagen accumulation in a mouse SSc model. Additionally, autoantibody against HDAC-3 is produced in colon cancer patients, while HDAC-1 and HDAC-2 do not elicit autoantibody response. To determine the presence and levels of antibodies (Abs) against HDAC-3 in SSc. Anti-HDAC-3 Ab was examined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using human recombinant HDAC-3. The HDAC-3 activity was evaluated by ELISA using the fluorimetric HDAC lysyl substrate that comprises an acetylated lysine side chain. Contrary to our hypothesis that autoimmune background in SSc induced the production of autoantibody against HDACs, IgG and IgM anti-HDAC-3 Ab levels in SSc patients were significantly lower than in normal controls (p < 0.0005 and 0.001, respectively). Furthermore, decreased levels of IgG anti-HDAC-3 Ab were specific to SSc, since IgG anti-HDAC-3 Ab levels in patients with dermatomyositis (DM) and those with systemic lupus erythematosus (SLE) were similar and slightly increased relative to normal controls, respectively. Immunoblotting analysis showed that anti-HDAC-3 Ab was detected in normal controls and patients with DM or SLE, while it was absent in SSc patients. The HDAC-3 activity was significantly inhibited by IgG isolated from sera of normal controls, whereas such inhibitory effect was not observed by IgG isolated from sera of SSc patients. These results indicate the lack of anti-HDAC-3 autoantibody in SSc patients, which is produced in healthy individuals as well as DM and SLE patients, suggesting that this autoantibody might function as protective Ab.