Autoantibodies against Linear Epitopes of Myeloperoxidase in Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: Approximately 20%-30% of patients with anti-glomerular basement membrane disease present coexisting anti-myeloperoxidase (MPO) autoantibodies. We previously showed the recognition of a linear fragment of the MPO heavy chain N-terminus ((1)H, MPO279-409) in plasma from most double-positive patients. Herein, we investigated the frequency of autoantibodies against overlapping (1)H-derived linear peptides in plasma from patients with anti-glomerular basement membrane disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We synthesized 13 overlapping linear peptides ((1)H-1 to (1)H-13) covering MPO279-409. We retrospectively collected plasma samples from 67 patients with anti-glomerular basement membrane disease from 1996 to 2012, and we screened them for IgG autoantibodies by ELISA using intact human MPO and the overlapping peptides as antigens, and we further investigated the clinical significance. Autoantibody binding to the linear MPO structure was confirmed by Western blotting.
RESULTS: We followed up the 67 patients until 2015, with a median follow-up time of 10.0 (2.3-36.0) months, and 56 ESRD events occurred among the 67 patients with follow-up data. Plasma from 23.9% (16) of the patients recognized intact human MPO, whereas 62.7% (42) plasma samples recognized MPO279-409 linear peptides. Of the 13 linear peptides, (1)H-4 (44.8%, 30 patients) and (1)H-12 (40.3%, 27 patients) exhibited the highest recognition frequencies. Patients with autoantibodies against (1)H-11 or (1)H-12 (MPO371-400) were older (46.1±18.8 versus 34.1±16.6 years; P<0.01), had higher serum creatinine upon diagnosis (median 7.8 mg/dl, interquartile range 4.9-12.6 mg/dl versus median 5.4 mg/dl, interquartile range 2.4-7.3 mg/dl; P=0.02), and had a higher probability of progressing to ESRD; however, multivariate Cox regression analysis showed that (1)H-11 or 12 reaction was not an independent risk factor for renal failure (hazard ratio, 1.2; 95% confidence interval, 0.8 to 2.8; P=0.19).
CONCLUSIONS: Autoantibodies against linear peptides of MPO can be detected in the majority of patients with anti-glomerular basement membrane disease, and several are associated with disease severity. The potential common pathogenic mechanism between anti-glomerular basement membrane antibodies and anti-MPO autoantibodies in anti-glomerular basement membrane disease requires further investigation.