title: Anti-ribosomal-P antibodies accelerate lupus glomerulonephritis and induce lupus nephritis in naïve mice.
abstract: BACKGROUND
  Lupus nephritis is known to be associated with several antibodies including autoantibodies that target the DNA, C1q and histone, α-actinin, and the nucleosome. In addition, circulating anti-phosphoribosomal protein antibodies (anti-Ribos.P) were found to be associated with lupus nephritis.
  
  
  OBJECTIVE
  We have assessed the direct role of anti-Ribos.P in the development of glomerulonephritis in-vitro and in animal models.
  
  
  METHODS
  NZBxW/F1 lupus prone mice were immunized with recombinant Ribos.P0 (rRibos.P). Evaluation of renal disease included mice evaluation for proteinuria and histologic analysis of the kidneys. Anti-Ribos.P monoclonal Ab was prepared from the rRibos.P immunized NZBxW/F1 mice by hybridoma technology. MAPKs expression was analyzed by MAPKs protein array and confirmed by real-time PCR and western blot. To elucidate whether anti-Ribos.P induce glomerulonephritis, naïve C3H mice were immunized with recombinant rRibos.P and the glomerulonephritis was followed up as described above.
  
  
  RESULTS
  The immunized NZBxW/F1 lupus prone mice developed anti-Ribos.P which was cross reactive with Sm and not dsDNA. The mice developed accelerated glomerulonephritis manifested by early proteinuria and immunoglobulin deposites in the mesangium of the kidneys. Anti-Ribos.P deposited in the glomerular mesangium were eluted from the kidney. The Ribos.P immunized naïve C3H/Hen mice developed glomerulonephritis manifested by circulating autoantibodies directed to Ribos.P, dsDNA and Sm. The anti Ribos.P were cross reactive with Sm but not with dsDNA, and were deposited in the glomeruli. Interestingly these mice developed alopecia. In vitro. Primary mesangial cells exposed to mouse anti-Ribos.P mAb originated from the immunized lupus mice and to human anti-Ribos.P Abs, induced activation of mesangial cells via p38α, JNK, AKT and HSP27 MAPKs expression pathway.
  
  
  CONCLUSIONS
  Our data show for the first time that anti-Ribos.P are nephritogenic autoantibodies, as illustrated by in-vitro and in-vivo experiments: a) They accelerate the development of glomerulonephritis in lupus prone mice; b) They induce nephritis in naïve mice. c) Anti-Ribos.P Abs trigger MAPKs expression in primary mesangial cells. These data contribute a direct mechanistic link between anti-Ribos.P and nephritis in lupus mice.
authors.affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Ben-Ami Shor
authors.affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: mblank@post.tau.ac.il.
authors.forename: Miri
authors.initials: M
authors.lastname: Blank
authors.affiliation: AESKU.KIPP Institute, Mikroforum Ring, Wendelsheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Reuter
authors.affiliation: AESKU.KIPP Institute, Mikroforum Ring, Wendelsheim, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Matthias
authors.affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Inbal
authors.initials: I
authors.lastname: Beiglass
authors.affiliation: Institute of Pathology, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Volkov
authors.affiliation: Institute of Pathology, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address: shoenfel@post.tau.ac.il.
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Shoenfeld
mesh_terms: D000505:Alopecia / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007114:Immunization; D008181:Lupus Nephritis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D050527:Mesangial Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010750:Phosphoproteins / Q000276:immunology / Q000633:toxicity; D011507:Proteinuria / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D012269:Ribosomal Proteins / Q000276:immunology / Q000633:toxicity
chemical_list: D001323:Autoantibodies; D010750:Phosphoproteins; D012269:Ribosomal Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Anti-ribosomal-P; Glomerulonephritis; Systemic lupus erythematosus