Autoimmunity as a result of escape from RNA surveillance.
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.
Bachmann
Michael P
MP
Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany. michael.bachmann@mailbox.tu-dresden.de
Bartsch
Holger
H
Gross
Joanne K
JK
Maier
Shannon M
SM
Gross
Timothy F
TF
Workman
Jennifer L
JL
James
Judith A
JA
Farris
A Darise
AD
Jung
Bettina
B
Franke
Claudia
C
Conrad
Karsten
K
Schmitz
Marc
M
Büttner
Cordula
C
Buyon
Jill P
JP
Semsei
Imre
I
Harley
John B
JB
Rieber
E Peter
EP
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
D001323:Autoantibodies; D001324:Autoantigens; D018389:Codon, Nonsense; D000939:Epitopes; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000097585:SS-B Antigen