title: Mapping novel immunogenic epitopes in IgA nephropathy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  This study was performed in sera from patients 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 m(2) 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 proteins mounted 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=-0.55, P=0.01) and ZADH2 (r=-0.48, 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.
authors.affiliation: Division of Hospital Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania;
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Surgery, University of California, San Francisco, California;
authors.forename: Tara K
authors.initials: TK
authors.lastname: Sigdel
authors.affiliation: Department of Surgery, University of California, San Francisco, California;
authors.forename: Van T
authors.initials: VT
authors.lastname: Dinh
authors.affiliation: Department of Surgery, University of California, San Francisco, California;
authors.forename: Minh-Thien
authors.initials: MT
authors.lastname: Vu
authors.affiliation: Department of Surgery, University of California, San Francisco, California; czar@stanford.edu minnie.sarwal@ucsfmedctr.org.
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
authors.affiliation: Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford University, Stanford, California czar@stanford.edu minnie.sarwal@ucsfmedctr.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lafayette
mesh_terms: D000328:Adult; D000954:Antigens, Surface / Q000276:immunology; D019540:Area Under Curve; D001323:Autoantibodies / Q000097:blood*; D001798:Blood Proteins / Q000276:immunology; D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D018450:Disease Progression; D018604:Epitope Mapping; D000939:Epitopes; D005260:Female; D019204:GTP-Binding Proteins / Q000276:immunology; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D009124:Muscle Proteins / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000276:immunology; D011446:Prospective Studies; D040081:Protein Array Analysis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012319:RNA Polymerase II / Q000276:immunology; D012372:ROC Curve; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000276:immunology; D011503:Transglutaminases / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D001798:Blood Proteins; D004268:DNA-Binding Proteins; D000939:Epitopes; D018398:Homeodomain Proteins; D007070:Immunoglobulin A; C089465:MPP1 protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C433812:POLR2M protein, human; C484762:SIX2 protein, human; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D014157:Transcription Factors; C000604561:ZADH2 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; C506696:ARIH2 protein, human; D044767:Ubiquitin-Protein Ligases; D012319:RNA Polymerase II; C498288:DDX4 protein, human; D019204:GTP-Binding Proteins; D053487:DEAD-box RNA Helicases
keywords: IgA nephropathy; nephritis; primary GN