Functional autoantibodies in pulmonary arterial hypertension (PAH)
| Frequency | Targets | Effects | |
| Vascular cells | |||
| Anti-endothelial cell [74–81] | iPAH (62%), CTD-PAH (63–82%), HC (5–33%) | Lamin A/C Tubulin-β chain Vimentin | Induction of pro-inflammatory (increased IL-6, IL-8, CCL2 and CCL5 expression) and pro-adhesive (increased E-selectin, ICAM-1 and VCAM-1 production) properties in endothelial cells |
| Anti-smooth muscle cell [82, 83] | More frequent in SSc-PAH, SSc-no PAH and iPAH than in HC | STIP1 α-Enolase | Induction of contraction and proliferation of SMCs |
| Anti-fibroblast [84, 85] | iPAH (40%), SSc-PAH (30%), SSc-no PAH (15%), HC (3%) | Vimentin, calumenin, PI3K Tropomyosin 1 HSP-27, HSP-70, G6PD | Induction of pro-inflammatory (increased IL-1β and IL-6 secretion), pro-adhesive (enhanced ICAM-1 expression) and pro-fibrotic (production of ROS and ECM remodelling) properties in fibroblasts |
| Vascular receptors: GPCRs | |||
| Anti-AT1R/ETAR [62, 86–89] | Anti-AT1R: SSc-PAH (69%), CTD-PAH (63%), iPAH (21%) Anti-ETAR: SSc-PAH (65%), CTD-PAH (55%), iPAH (11%) Positivity predicts occurrence of PAH in SSc and mortality in SSc-PAH | AT1R ETAR | Agonistic properties on AT1R/ETAR: Endothelial cells: vasoconstriction, permeability, expression of VEGF-A and PDGF-B, pro-inflammatory (IL-8 and CXCL8 production, neutrophil recruitment) and pro-adhesive (VCAM-1 expression) properties SMCs: proliferation and expression of PDGF-Rβ |
| Anti-ETBR [90] | Higher titres in SSc-PAH than HC (but not iPAH) | ETBR | Not investigated (hypothesised to be antagonistic, as ETBR-deficient mice develop a PAH phenotype) |
| Anti-α1AR [91, 92] | Pre-capillary PH (95%), with PAH (100%) | α1AR | Activation of α1AR on rat cardiomyocytes, inducing long-lasting stimulatory effects without receptor desensitisation (contrary to its natural agonist) |
| Anti-S1PR [93] | Anti-S1PR1: SSc-PAH (16%), SSc-no PAH (18%), HC (3%) Anti-S1PR2: SSc-PAH (26%), SSc-no PAH (15%), HC (4%) Anti-S1PR3: SSc-PAH (28%), SSc-no PAH (18%), HC (8%) | S1P receptors | Not investigated (anti-S1PR2/3 hypothesised to be agonistic, promoting PA-SMC proliferation and medial thickening) |
| Vascular receptors: TGFβ-Rs | |||
| Anti-BMPR2 [11, 94, 95] | iPAH/hPAH (0–1.4%), CTD (0%), HC (0%) | Extracellular domain of BMPR2 | Diminution of BMP4 signalling in PA-SMCs |
| Anti-BMPR1A [95] | Higher titres in SLE-PAH than in SLE-no PAH and HC | BMPR1A (=ALK3) | Not investigated (hypothesised to interfere with ligand binding) |
| Anti-ALK1 [94, 95] | No detection in MCTD-PAH and iPAH Higher titres in SLE-PAH than in SLE-no PAH and HC | ALK1 | Not investigated (hypothesised to interfere with ligand binding) |
| Other | |||
| Anti-fibrillin 1 [96, 97] | iPAH (93%), anorexigen PAH (67%), HC (2%) | N-terminal fragment of fibrillin 1 | Release of sequestered TGFβ1 from fibrillin-1-containing microfibrils in the ECM, leading to fibroblast activation into a profibrotic phenotype |
| Anti-ACE-2 [98] | More frequent in CTD patients with vasculopathy (including PAH) than those without | ACE 2 | Inhibition of ACE-2 activity (which transforms AngII into Ang(1–7), an Ang isoform with vasodilating and antiproliferative properties) |
GPCR: G-protein coupled receptor; AT1R: angiotensin receptor 1; ETAR: endothelin receptor A; ETBR: endothelin receptor B; α1AR: α1-adrenergic receptor; S1PR: sphingosine-1-phosphate receptor; TGFβ-R: transforming growth factor β receptor; BMPR: bone morphogenetic protein receptor; ALK: activin receptor-like kinase; ACE: angiotensin converting enzyme; iPAH: idiopathic PAH; CTD: connective tissue disease; HC: healthy control; IL: interleukin; CCL: C-C motif chemokine ligand; ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule; SSc: systemic sclerosis; STIP1: stress-induced phosphoprotein 1; PI3K: phosphoinositide 3-kinase; HSP: heat shock protein; G6PD: glucose-6-phosphate dehydrogenase; ROS: reactive oxygen species; ECM: extracellular matrix; VEGF: vascular endothelial growth factor; PDGF-R: platelet-derived growth factor receptor; CXCL: chemokine (C-X-C motif) ligand; SMC: smooth muscle cell; PH: pulmonary hypertension; PA: pulmonary artery; hPAH: heritable PAH; SLE: systemic lupus erythematosus; MCTD: mixed connective tissue disease; Ang: angiotensin.