title: Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis.
abstract: OBJECTIVE
  In lupus nephritis (LN), severe tubulointerstitial inflammation (TII) predicts progression to renal failure. Severe TII is associated with tertiary lymphoid neogenesis and in situ antigen-driven clonal B cell selection. The autoantigen(s) driving in situ B cell selection in TII are not known. This study was undertaken to identify the dominant driving autoantigen(s).
  
  
  METHODS
  Single CD38+ or Ki-67+ B cells were laser captured from 7 biopsy specimens that were diagnostic for LN. Eighteen clonally expanded immunoglobulin heavy- and light-chain variable region pairs were cloned and expressed as monoclonal antibodies. Seven more antibodies were cloned from flow-sorted CD38+ cells from an eighth biopsy specimen. Antigen characterization was performed using a combination of confocal microscopy, enzyme-linked immunosorbent assay, screening protoarrays, immunoprecipitation, and mass spectrometry. Serum IgG titers to the dominant antigen in 48 LN and 35 non-nephritic lupus samples were determined using purified antigen-coated arrays. Autoantigen expression on normal and LN kidney was localized by immunohistochemistry and immunofluorescence.
  
  
  RESULTS
  Eleven of 25 antibodies reacted with cytoplasmic structures, 4 reacted with nuclei, and none reacted with double-stranded DNA. Vimentin was the only autoantigen identified by both mass spectrometry and protoarray. Ten of the 11 anticytoplasmic TII antibodies directly bound vimentin. Vimentin was highly expressed by tubulointerstitial inflammatory cells, and the TII antibodies tested preferentially bound inflamed tubulointerstitium. Finally, high titers of serum antivimentin antibodies were associated with severe TII (P = 0.0001).
  
  
  CONCLUSIONS
  Vimentin, an antigenic feature of inflammation, is a dominant autoantigen targeted in situ in LN TII. This adaptive autoimmune response likely feeds forward to worsen TII and renal damage.
authors.affiliation: University of Chicago, Chicago, Illinois.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kinloch
authors.forename: Anthony
authors.initials: A
authors.lastname: Chang
authors.forename: Kichul
authors.initials: K
authors.lastname: Ko
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Henry Dunand
authors.forename: Scott
authors.initials: S
authors.lastname: Henderson
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.forename: Natalya
authors.initials: N
authors.lastname: Kaverina
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Marlene
authors.initials: M
authors.lastname: Salgado Ferrer
authors.forename: Don
authors.initials: D
authors.lastname: Wolfgeher
authors.forename: Vladimir
authors.initials: V
authors.lastname: Liarski
authors.forename: D James
authors.initials: DJ
authors.lastname: Haddon
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.forename: Marcus R
authors.initials: MR
authors.lastname: Clark
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001706:Biopsy; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D056724:Immunity, Humoral; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D009395:Nephritis, Interstitial / Q000276:immunology* / Q000473:pathology; D012720:Severity of Illness Index; D014746:Vimentin / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D014746:Vimentin