title: Novel Autoantigens Associated with Lupus Nephritis.
abstract: Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Onishi
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Endy
authors.initials: E
authors.lastname: Adnan
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishizaki
authors.affiliation: Department of Pathology, Gifu University Hospital, Gifu, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Integrated Center for Sciences, Ehime University, Ehime, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suemori
authors.affiliation: Integrated Center for Sciences, Ehime University, Ehime, Japan.
authors.forename: Masachika
authors.initials: M
authors.lastname: Shudou
authors.affiliation: Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Okura
authors.affiliation: Proteo-Science Center, Ehime University, Ehime, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Proteo-Science Center, Ehime University, Ehime, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sawasaki
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D000936:Antigen-Antibody Complex / Q000378:metabolism; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology*; D004247:DNA / Q000276:immunology; D063326:Exosome Multienzyme Ribonuclease Complex / Q000276:immunology*; D005260:Female; D006801:Humans; D007672:Kidney Cortex / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000175:diagnosis / Q000276:immunology*; D008780:Methyltransferases / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000276:immunology*; D016601:RNA-Binding Proteins
chemical_list: D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C053886:spermatid transition proteins; D004247:DNA; D008780:Methyltransferases; C529371:RRP8 protein, human; D063326:Exosome Multienzyme Ribonuclease Complex