title: The Transcriptional Coactivator Bob1 Is Associated With Pathologic B Cell Responses in Autoimmune Tissue Inflammation.
abstract: The molecular mechanisms steering abnormal B cell responses in autoimmune diseases remain poorly understood. We undertook this study to identify molecular switches controlling pathologic B cell responses in rheumatoid arthritis (RA).
  
  
  
  Candidate molecules were identified by gene expression profiling of RA synovitis and validated by quantitative polymerase chain reaction and immunohistochemistry. B cell-specific expression was confirmed by immunofluorescence, immunoblotting, and flow cytometry. The role of Bob1 in pathologic B cell responses was assessed in collagen-induced arthritis (CIA).
  
  
  
  Transcriptional profiling of RA synovitis revealed a prominent B cell signature, with the transcriptional coactivator Bob1 and its putative target BCMA being among the most up-regulated genes. Further analysis confirmed the microarray data and demonstrated elevated levels of Bob1 in B cells in RA synovium. A functional study showed that Bob1-deficient mice failed to produce pathogenic anti-type II collagen (anti-CII) antibodies and were resistant to CIA. Adoptive transfer of cells from Bob1-deficient and Bob1-sufficient mice to recombination-activating gene 1-null mice demonstrated that Bob1 deficiency exclusively in B cells abrogated germinal center (GC) B cell formation, anti-CII antibody production, and CIA development. Consistent with data from animal studies, immunophenotyping of human B cell subsets revealed increased expression of Bob1, predominantly in centrocytes and centroblasts. Correspondingly, Bob1 expression in RA synovitis was strongly correlated with CD21L, a molecular marker of GCs. In addition, similar Bob1 overexpression and correlation with CD21L expression was evidenced in parotid salivary gland tissue from patients with primary Sjögren's syndrome.
  
  
  
  These expression and functional data identify the transcriptional coactivator Bob1 as a candidate molecular switch of pathogenic B cell responses in autoimmune diseases in humans.
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Levels
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Van Tok
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.affiliation: Hospital Clinic of Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: Juan D
authors.initials: JD
authors.lastname: Cañete
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Kroese
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kristine
authors.initials: K
authors.lastname: Germar
authors.affiliation: Academic Medical Center, University of Amsterdam and AIMM Therapeutics, Amsterdam, The Netherlands.
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dominique L P
authors.initials: DL
authors.lastname: Baeten
authors.affiliation: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nataliya G
authors.initials: NG
authors.lastname: Yeremenko
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D051379:Mice; D015534:Trans-Activators / Q000502:physiology*
chemical_list: C091546:POU2AF1 protein, human; C490424:Pou2af1 protein, mouse; D015534:Trans-Activators