Involvement of functional autoantibodies against vascular receptors in systemic sclerosis

Riemekasten, Gabriela; Philippe, Aurélie; Näther, Melanie; Slowinski, Torsten; Müller, Dominik N.; Heidecke, Harald; Matucci‐Cerinic, Marco; Czirják, László; Lukitsch, Ivo; Becker, Mike; Kill, Angela; Laar, Jacob M van; Catar, Rusan; Luft, Friedrich C.; Burmester, Gerd R.; Hegner, Björn; Dragun, Duska

doi:10.1136/ard.2010.135772

Cited by 255 publications

(254 citation statements)

References 30 publications

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“…Autoantibodies that bind to and activate the AT 1 receptor exist in patients with hypertensive disorders and contribute to disease pathophysiology in preeclampsia, in kidney transplant recipients who develop refractory vascular rejection, and in patients with malignant hypertension (Roberts, 2000;Lodwick, 2001;Dechend et al, 2004;Herse et al, 2008;LaMarca et al, 2011;Herse and LaMarca, 2013;Xia and Kellems, 2013). More recently, AT 1 receptor-directed autoantibodies have been seen in patients with the autoimmune diseases, including systemic sclerosis, featuring autoimmunity, vasculopathy, and tissue fibrosis (Fu et al, 2000;Liao et al, 2002;Ansari et al, 2005;Dragun et al, 2005;Riemekasten et al, 2011). The AT 1 receptor autoantibodies found in preeclampsia, renal allograft rejection, and malignant hypertension are directed to an epitope, -AFHYESQ-, in the second extracellular loop of the AT 1 receptor (Wallukat et al, 1999).…”

Section: G Pathophysiological Aspects Of Angii Type 1 Receptor Activmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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Section: G Pathophysiological Aspects Of Angii Type 1 Receptor Activmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

et al. 2015

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“…Vasculopathy is profound in SSc and involves neointimal thickening and vascular occlusion, with eventual loss of microvascular function (44) . Abnormal endothelial phenotype is typical, with a loss of vascular endothelial cadherin and upregulation of both type 1 IFNs and regulator of G protein signaling 5 (45), molecules associated with vascular rarefaction.…”

Section: Discussionmentioning

confidence: 99%

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Delaney¹,

Morehouse²,

Brohawn³

et al. 2016

The Journal of Immunology

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Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.

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“…19 In SSc-PAH, autoimmune dysregulation may also be preponderant. 20 For example, a study by Riemekasten et al 21 showed that angiotensin II type-1 receptor antibodies and endothelin-1 receptor type A antibodies were present in most patients with SSc. In vitro, these antibodies upregulated infl ammatory mediators and increased cytotoxicity, suggesting a signifi cant role in vascular remodeling.…”

Section: Autoimmune Dysfunctionmentioning

confidence: 99%

Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Pavec

Humbert

Mouthon

et al. 2010

Am J Respir Crit Care Med

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Systemic sclerosis (SSc) is a complex, multisystem disease characterized by fi brosis and excessive collagen deposition within the skin and internal organs, chronic infl ammation, autoimmune dysregulation, and microvascular endothelial dysfunction. There are two forms of SSc that are characterized by the extent of skin involvement. Limited cutaneous SSc predominantly involves the skin of the hands, arms, and face, and diffuse SSc involves large areas of skin and multiple organs. 1 Both forms are systemic diseases associated with signifi cant morbidity and mortality. Historically, mortality was largely caused by renal disease. With the advent of angiotensin-converting enzyme inhibitors to treat SSc renal crisis, SSc-associated pulmonary arterial hypertension (SSc-PAH) has emerged as a leading cause of morbidity and mortality, accounting for up to 30% of premature deaths. 2 Although SSc-PAH represents a signifi cant proportion of the pulmonary arterial hypertension (PAH) population (15%-30%), 3,4 much of what we know about PAH is derived from studies of idiopathic PAH (IPAH).Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc ) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease. CHEST 2013; 144(4):1346-1356Abbreviations: 6MWD 5 6-min walk distance; CCB 5 calcium channel blocker; CTD 5 connective tissue disease; D lco 5 diffusing capacity of lung for carbon monoxide; EIPAH 5 exercise-induced pulmonary arterial hypertension; ERA 5 endothelin receptor antagonist; FC 5 functional class; ILD 5 interstitial lung disease; IPAH 5 idiopathic pulmonary arterial hypertension; LV 5 left ventricular; mPAP 5 mean pulmonary artery pressure; PAH 5 pulmonary arterial hypertension; PASP 5 pulmonary artery systolic pressure; PDE-5I 5 phosphodiesterase type 5 inhibitor; PFT 5 pulmonary function test; PH 5 pulmonary hypertension; pro-BNP 5 pro-brain natriuretic pe...

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Involvement of functional autoantibodies against vascular receptors in systemic sclerosis

Abstract: Functional autoimmunity directed at AT(1)R and ET(A)R is common in patients with SSc. AT(1)R and ET(A)R autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.

Cited by 255 publications

References 30 publications

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease

Systemic Sclerosis-associated Pulmonary Arterial Hypertension

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