Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals

Abstract

Anti-neutrophil cytoplasmic antibodies (ANCAs) have a pathogenic role in ANCA-associated vasculitis. The origin of ANCAs and anti-glomerular basement membrane (GBM) antibodies, however, is unknown. In this study, we determined whether natural autoantibodies against myeloperoxidase (MPO), proteinase 3 (PR3), and GBM were present in each of 10 healthy Chinese and Swedish individuals, negative for all three antigens by routine ELISA. Antibodies were purified from isolated IgG by antigen-specific affinity columns. Natural anti-GBM autoantibodies gave a linear staining pattern along the GBM of human renal sections. On ethanol-fixed granulocytes, both natural anti-MPO and anti-PR3 autoantibodies gave cytoplasmic staining. The titers of natural anti-MPO/PR3 autoantibodies were significantly lower than those from patients with vasculitis. In competition ELISA, the binding of natural anti-MPO autoantibodies could be inhibited by MPO, but not by PR3 or noncollagenous domains from type IV collagen. The same specificity results were found for natural anti-PR3 and anti-GBM autoantibodies. Overall, individuals of the Chinese origin had more natural autoantibodies than did those of the Swedish origin, but no other differences were found. Hence, our study shows that healthy individuals have masked circulating, noncross-reactive, antigen-specific natural autoantibodies against MPO, PR3, and GBM in their serum and IgG fractions. Further studies are needed to determine their role if any in the etiology of ANCA-associated vasculitis and anti-GBM disease.

Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis

“…The reactivity to p24 PR3/MBN with serum from a healthy donor is consistent with previous reports of naturally occurring antibodies to PR3 in normal individuals. 19 Titers of PR3 antibodies were similar among the patients' sera that reacted to p24 PR3/MBN (145.8637.4) and patients' sera that failed to react (146.4626.0), indicating that a high antibody titer does not explain reactivity to p24 PR3/MBN . Instead, the reactivity to PR3 among patients with PR3-ANCA disease indicates that p24 PR3/MBN may be antigenic.…”

Clinical analysis of patients with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis

“…On the other hand, ANCA (-) patients may suffer from AAV [i.e., the ANCA (-) AAV according to the 2012 CHCC]. There may be unmeasured MPO-ANCA in the serum of these patients (Cui et al, 2010;Jennette et al, 2013). One of the purposes of this study was to analyze the possible role of MPO-ANCA in the pathogenesis of MPO-AAV.…”

Clustering of Anti-GBM Disease: Clues to an Environmental Trigger?

“…It is conceivable that nonspecific inflammation at the time of respiratory or systemic infection may result in the release of sequestered epitopes in the lung or kidney, akin to the mechanisms implicated for smoking in the induction of disease. Alternatively, T or B lymphocytes that are autoreactive to GBM antigens (the presence of which are confirmed in healthy individuals [23][24][25]) may undergo bystander activation at the time of intercurrent infection, thus initiating anti-GBM disease. More specific molecular mechanisms may also be at work, and observations in a more common form of crescentic GN that associated with ANCA may be informative.…”