title: Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.
abstract: It remains unclear how and why autoimmunity occurs. Here we show evidence for a previously unrecognized and possibly general mechanism of autoimmunity. This new finding was discovered serendipitously using material from patients with inflammatory vascular disease caused by antineutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase-3 (PR-3). Such patients harbor not only antibodies to the autoantigen (PR-3), but also antibodies to a peptide translated from the antisense DNA strand of PR-3 (complementary PR-3, cPR-3) or to a mimic of this peptide. Immunization of mice with the middle region of cPR-3 resulted in production of antibodies not only to cPR-3, but also to the immunogen's sense peptide counterpart, PR-3. Both human and mouse antibodies to PR-3 and cPR-3 bound to each other, indicating idiotypic relationships. These findings indicate that autoimmunity can be initiated through an immune response against a peptide that is antisense or complementary to the autoantigen, which then induces anti-idiotypic antibodies (autoantibodies) that cross-react with the autoantigen.
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7155, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Pendergraft
authors.forename: Gloria A
authors.initials: GA
authors.lastname: Preston
authors.forename: Ruchir R
authors.initials: RR
authors.lastname: Shah
authors.forename: Alexander
authors.initials: A
authors.lastname: Tropsha
authors.forename: Charles W
authors.initials: CW
authors.lastname: Carter
authors.forename: J Charles
authors.initials: JC
authors.lastname: Jennette
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D017931:DNA Primers; D010446:Peptide Fragments; C483322:complementary human autoantigen proteinase-3 (105-201)