Clinical and Immunoserological Characteristics of Mixed Connective Tissue Disease Associated with Pulmonary Arterial Hypertension

Végh, Judit; Szodoray, Péter; Kappelmayer, János; Csípő, István; Udvardy, M.; Lakos, Gabriella; Aleksza, Magdolna; Soltész, Pál; Szilagyi, Anna; Zeher, Margit; Szegedi, Gyula; Bodolay, Edit

doi:10.1111/j.1365-3083.2006.01770.x

Cited by 51 publications

(29 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A type of PAH occurs secondarily to collagen vascular disorders, such as systemic sclerosis and mixed connective tissue disease (MCTD). Interestingly, PAH with MCTD presents with a prominent characteristic of endothelial degeneration and proliferation, probably due to the pathogenic contribution of autoantibodies to endothelial cells [28,29]. This characteristic may be a pathological consequence of immune-mediated mechanisms shared with the present model.…”

Section: Discussionmentioning

confidence: 92%

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

et al. 2011

View full text Add to dashboard Cite

BackgroundPulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 ligand in the pathogenesis of PAH.ResultsSpontaneous onset of PAH was stably identified in mice with immune abnormality because of overexpression of the tumor necrosis factor (TNF) family molecule OX40 ligand (OX40L). Histopathological and physical examinations revealed the onset of PAH-like disorders in the C57BL/6 (B6) strain of OX40L transgenic mice (B6.TgL). Comparative analysis performed using different strains of transgenic mice showed that this onset depends on the presence of OX40L in the B6 genetic background. Genetic analyses demonstrated a susceptibility locus of a B6 allele to this onset on chromosome 5. Immunological analyses revealed that the excessive OX40 signals in TgL mice attenuates expansion of regulatory T cells the B6 genetic background, suggesting an impact of the B6 genetic background on the differentiation of regulatory T cells.ConclusionPresent findings suggest a role for the OX40L-derived immune response and epistatic genetic effect in immune-mediated pathogenesis of PAH.

show abstract

Section: Discussionmentioning

confidence: 92%

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Previous studies from Miyata, et al 4,10 and Vegh, et al 11 showed a higher prevalence of aCL antibodies in patients with MCTD and PAH, but they did not investigate anti-β 2 -GPI levels.…”

Section: Discussionmentioning

confidence: 94%

The frequency of anti-β2-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

Hasegawa

Caleiro

Fuller

et al. 2009

Lupus

View full text Add to dashboard Cite

The objective of this study is to evaluate the prevalence of antiphospholipid antibodies, mainly anti-beta(2)-glycoprotein I (anti-beta(2)-GPI), and their possible clinical and laboratory relevance in mixed connective tissue disease (MCTD). This study included 39 consecutive patients with MCTD (Kasukawa's criteria) from January, 2005, to March, 2007, and compared them with 21 age- and sex-matched healthy controls. IgG and IgM anticardiolipin (aCL) and anti-beta(2)-GPI were measured by ELISA. Lupus anticoagulant (LA) was detected by functional coagulation tests. Medium to high titres of aCL and anti-beta(2)-GPI antibodies were found in sera from four (10.2%) MCTD patients. One of these patients was found to be positive for IgM aCL, IgM anti-beta(2)-GPI and LA antibodies simultaneously. Additionally, this patient had a previous history of foetal loss in the second trimester and new-onset pulmonary arterial hypertension (PAH). The other three patients had none of the manifestations of antiphospholipid syndrome (APS) or PAH. The mean value of IgG anti-beta(2)-GPI was higher among those MCTD patients with PAH than in the group without PAH (34.2 +/- 46.8 vs 12.3 +/- 9.1, P = 0.018). None of the controls were positive for antiphospholipid antibodies. High to moderate titres of anti-beta(2)-GPI as well as APS were rare in MCTD, and these antibodies may be correlated with the development of PAH in these patients.

show abstract

“…vWFAg is a circulating glycoprotein, synthesized by endothelial cells - and an increased serum concentration of vWFAg has been shown to be a marker of endothelial dysfunction in scleroderma, SLE and MCTD patients with PAH [10,44]. …”

Section: Discussionmentioning

confidence: 99%

“…The lung is the most frequent predilection place of the vascular damage, however, and may eventually lead to pulmonary arterial hypertension (PAH) [8]. Our group and others found that PAH might be associated with coexistent antiphospholipid and anti-endothelial cell antibodies (AECAs) [9,10]. In our previous study we found that AECA provokes the surface expression of E-selectin and the activation of endothelial cells [11].…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease

et al. 2010

View full text Add to dashboard Cite

IntroductionThe aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease.MethodsFifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed.ResultsThe endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2 ± 8.1 ng/ml vs. 3.2 ± 1.3 ng/ml; P < 0.001) and vWFAg (224.1 ± 115% vs. 89.4 ± 27.1%, P < 0.001) were the highest in MCTD patients with CVD.ConclusionsFMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.

show abstract

Clinical and Immunoserological Characteristics of Mixed Connective Tissue Disease Associated with Pulmonary Arterial Hypertension

Cited by 51 publications

References 28 publications

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

Indispensable roles of OX40L-derived signal and epistatic genetic effect in immune-mediated pathogenesis of spontaneous pulmonary hypertension

The frequency of anti-β2-glycoprotein I antibodies is low and these antibodies are associated with pulmonary hypertension in mixed connective tissue disease

Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease

Contact Info

Product

Resources

About