Endothelin B Receptor Immunodynamics in Pulmonary Arterial Hypertension

Abstract

IntroductionInflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ETA) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ETB) remain obscure.MethodsSerum levels of anti-ETB receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ETB deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ETB-deficient mice (ETB-/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ETB-/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses.ResultsAnti-ETB autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ETB deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ETB-/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ETB-/- mice.ConclusionThis study provides evidence for an anti-inflammatory role of ETB. ETB seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ETB autoantibodies may modulate ETB-mediated immune homeostasis.

Comprehensive autoantibody profiles in systemic sclerosis: Clinical cluster analysis

“…Results were reported using a positive cut-off at ≥20 RU/ml. Anti-AT 1 R and Anti-ET A R antibody serum levels were measured by ELISA (CellTrend GmbH, Luckenwalde, Germany [since 2012, One Lambda, Inc., Canoga Park, CA]) as described ( 24 ), analogously to anti-ET B receptor autoantibody quantification performed earlier in a partially overlapping cohort ( 44 ).…”

Comprehensive Autoantibody Profiles in Systemic Sclerosis: Clinical Cluster Analysis

“…Anti-AT 1 R and Anti-ET A R antibody serum levels were measured by ELISA (CellTrend GmbH, Luckenwalde, Germany [since 2012, One Lambda, Inc., Canoga Park, CA]) as described 24 , analogously to anti-ET B receptor autoantibody quantification performed earlier in a partially overlapping cohort. 44…”

Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

“…In addition to its vasoactive properties, ET-1 plays an important role in modulating several inflammation pathways, both directly, by inducing the migration of neutrophils and monocytes [ 26 , 27 ], and indirectly, by increasing the production of inflammatory cytokines [ 28 ] and adhesion molecules in different cell types [ 29 , 30 ]. A recent study on ETBR immunodynamics highlighted the presence of a regulatory feedback of the effect of ET-1 on immune cells: ETBR deficiency in engineered mice led to PAH, pulmonary vascular hyperresponsiveness and right ventricular hypertrophy with lymphocytic alveolitis and marked lymphocytic perivascular infiltrate, suggesting that ETBR-mediated signalling pathways may have an immunomodulatory effect [ 31 ]. Increased ET-1 levels have been found in the serum and in the lungs of IPAH patients [ 32 , 33 ].…”

“…Guo et al [ 117 ] demonstrated higher titres of anti-ETAR antibodies in SLE patients complicated by PAH vs. those in SLE patients without PAH (41.5% vs. 17.1%, respectively), with a correlation between the anti-ETAR titres and the sPAP value measured by echocardiography and RHC. A recent study evaluated the prevalence of anti-ETBR antibodies in SSc patients, finding more elevated serum levels in SSc-PAH patients vs. those of healthy controls [ 31 ]; given the immunomodulatory role of ETBR , it could be hypothesised that these autoantibodies can block its downstream signalling pathway, thus enhancing inflammation, but more studies are required to ascertain their exact pathogenetic role.…”