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Autoimmunity as a Result of Escape from RNA Surveillance¹

Michael P. Bachmann^2,*, Holger Bartsch^*, Joanne K. Gross, Shannon M. Maier^,, Timothy F. Gross, Jennifer L. Workman, Judith A. James^,, A. Darise Farris^,, Bettina Jung^*, Claudia Franke^*, Karsten Conrad^*, Marc Schmitz^*, Cordula Büttner^*, Jill P. Buyon, Imre Semsei^¶, John B. Harley^,,|| and E. Peter Rieber^*

^* Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany; Arthritis and Immunology Program, Oklahoma Medical Research Foundation, and University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104; New York University School of Medicine, Hospital for Joint Diseases, New York, NY 10003; ^¶ Medical and Health Science Center, Third Department of Medicine, University of Debrecen, Debrecen, Hungary; and ^|| U.S. Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104

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 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.

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The JI 2006 177: 1373-1374. [Full Text]