title: Autoimmunity as a result of escape from RNA surveillance.
abstract: In previous studies, we detected a frame shift mutation in the gene encoding the autoantigen La of a patient with systemic lupus erythematosus. The mutant La mRNA contains a premature termination codon. mRNAs that prematurely terminate translation should be eliminated by RNA quality control mechanisms. As we find Abs specific for the mutant La form in approximately 30% of sera from anti-La-positive patients, we expected that mutant La mRNAs circumvent RNA control and the expression of mutant La protein could become harmful. Indeed, real-time PCR, immunostaining, and immunoblotting data of mice transgenic for the mutant La form show that mutant La mRNAs are not repressed in these animals and are translated to mutant La protein. In addition to the mutant La protein, we detected a minor portion of native human La in the mutant La-transgenic mice. Therefore, ribosomal frame shifting may allow the mutant La mRNA to escape from RNA control. Interestingly, expression of the mutant La mRNA results in a lupus-like disease in the experimental mice. Consequently, escape of mutant La mRNA from RNA control can have two effects: it 1) results in the expression of an immunogenic (neo)epitope, and 2) predisposes to autoimmunity.
authors.affiliation: Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany. michael.bachmann@mailbox.tu-dresden.de
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bachmann
authors.forename: Holger
authors.initials: H
authors.lastname: Bartsch
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Gross
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Maier
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Gross
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Workman
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: A Darise
authors.initials: AD
authors.lastname: Farris
authors.forename: Bettina
authors.initials: B
authors.lastname: Jung
authors.forename: Claudia
authors.initials: C
authors.lastname: Franke
authors.forename: Karsten
authors.initials: K
authors.lastname: Conrad
authors.forename: Marc
authors.initials: M
authors.lastname: Schmitz
authors.forename: Cordula
authors.initials: C
authors.lastname: Büttner
authors.forename: Jill P
authors.initials: JP
authors.lastname: Buyon
authors.forename: Imre
authors.initials: I
authors.lastname: Semsei
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: E Peter
authors.initials: EP
authors.lastname: Rieber
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D018389:Codon, Nonsense; D000939:Epitopes / Q000097:blood / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D020871:RNA Stability / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology; D000097585:SS-B Antigen
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D018389:Codon, Nonsense; D000939:Epitopes; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000097585:SS-B Antigen