Autoantibodies to angiotensin-converting enzyme 2 in patients with connective tissue diseases

Serum was examined from 42 patients with systemic lupus erythematosus (SLE), scleroderma, or mixed connective tissue disease. Eighteen vasculopathy patients with PAH (five cases) and/or persistent digital ischemia (16 cases) were compared with 24 patients without these vasculopathies (control patients) for serum reactivity to purified recombinant human ACE2, using an ELISA.The sera from 17 of the 18 (94%) vasculopathy patients had ELISA scores above the baseline level determined using control sera from 28 healthy subjects, and the mean ELISA score in the vasculopathy patients was significantly higher than that in the control patients (P < 0.0005). The relative activity of serum ACE2, which was defined using a reference serum, correlated inversely with the ELISA scores for serum anti-ACE2 antibodies in the 18 vasculopathy patients (R2 = 0.6872). The IgG fraction from vasculopathy patients, but not from healthy subjects, inhibited ACE2 activities in vitro. Consistent with this, immunosuppressive therapy given to one SLE patient with digital necrosis markedly decreased the anti-ACE2 antibody titer and restored serum ACE2 activity.Autoantibodies to ACE2 may be associated with constrictive vasculopathies.Angiotensin-converting enzyme (ACE) 2, a homolog of ACE, is a carboxypeptidase that degrades angiotensin (Ang) II to Ang(1-7) [1]. Ang(1-7) has vasodilating, antiproliferative, and antithrombotic properties that antagonize the action of Ang II and play vasoprotective roles [2-4]. Recent studies have demonstrated the therapeutic effects of ACE2 activation by a synthetic molecule [5] or of ACE2 gene transfer [6] in experimental pulmonary hypertension models.Pulmonary arterial hypertension (PAH), a vasculopathy of unknown etiology, is a serious complication of connective tissue disease (CTD) [7]. One clinical study found reduced metabolism of ACE synthetic substrate in the pulmonary vascular bed of PAH-CTD patients, but not in primary PAH patients [8]. Persistent digital is