Mapping novel immunogenic epitopes in IgA nephropathy

Abstract

Background and objectives IgA plays a key role in IgA nephropathy (IgAN) by forming immune complexes and depositing in the glomeruli, leading to an inflammatory response. However, the antigenic targets and functional characterization of IgA have been incompletely defined in this disease. Design, setting, participants, & measurements This study was performed in sera frompatients who were studied as part of a prospective, observational study of IgAN. These patients (n=22) all had biopsy-proven IgAN within 3 years of study initiation, complete clinical data, annual urinary inulin clearance for GFRs, and at least 5 years of follow-up. Progression was defined as loss of ˃.5 ml/min per 1.73 m2 per year of inulin clearance measured over at least 5 years. A protein microarray was used for detection of IgAN-specific IgA autoantibodies in blood across approximately 9000 human antigens to specifically identify the most immunogenic protein targets that drive IgA antibodies in IgAN (n=22), healthy controls (n=10), and non-IgAN glomerular diseases (n=17). Results were validated by ELISA assays in sera and by immunohistochemistry in IgAN kidney biopsies. IgA-specific antibodies were correlated with clinical and histologic variables to assess their effect on disease progression and prognosis. Results Fifty-four proteinsmounted highly significant IgA antibody responses in patients with IgAN with a false discovery rate (q value) of ≤ 10%; 325 antibodies (P ≤ 0.05) were increased overall. Antitissue transglutaminase IgA was significantly elevated in IgAN (P ˂ 0.001, q value of 0%). IgA antibodies to DDX4 (r=20.55, P=0.01) and ZADH2 (r=20.48, P=0.02) were significantly correlated with the decline of renal function. Specific IgA autoantibodies are elevated in IgAN compared with normal participants and those with other glomerular diseases. Conclusions In this preliminary study, IgA autoantibodies target novel proteins, highly expressed in the kidney glomerulus and tubules. These IgA autoantibodies may play important roles in the pathogenesis of IgAN.