Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes

Abstract

Background Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur via disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP. MethodsWe used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score. ResultsWe detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production in vitro. The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.Conclusions Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.

Severe Infection in Anti-Glomerular Basement Membrane Disease: A Retrospective Multicenter French Study

“…Some researchers have observed that, in addition to their inflammatory profile, AAV patients have neutrophils with a high apoptosis rate and reduced activation capacity [37], which may contribute to their diminished ability to contain or eliminate bacterial pathogens. Some researchers recently detected inhibitory anti-peroxidasin autoantibodies present in serum from patients before and at the onset of anti-GBM disease [38]. Peroxydasin shares structural homology with MPO, and anti-peroxidasin autoantibodies cross-react in vitro with MPO, which could account for some "false" MPO positive patients [39].…”

ANCA-associated vasculitis

“…Although the AAVs are typically considered systemic autoimmune diseases, each with dominant autoreactivity to only a single autoantigen, other autoantigens have been associated with AAV. These autoantigens include lysosome-associated membrane protein 2 (LAMP2) 54 , complementary PR3 (cPR3) peptides 55,56 , moesin 57 , plasminogen 58,59 , peroxidasin 60 and pentraxin 3 (reF. 61 ).…”

Biallelic Deletion of Pxdn in Mice Leads to Anophthalmia and Severe Eye Malformation

“…PXDN is expressed in endothelial cells, epithelial cells, and fibroblasts. Relatively high expression of PXDN is observed in several human tissues such as the heart, spleen, kidney, and lung [17,18]. As PXDN stabilizes Col IV, a major component of BM, its deficiency in lower animals leads to lethality because of disorganized tissue structures.…”